Variants of SARS-CoV-2

While there are many thousands of variants of SARS-CoV-2,[67] subtypes of the virus can be put into larger groupings such as lineages or clades.[lower-alpha 3] Three main, generally used nomenclatures[68] have been proposed:

• As of January 2021, GISAID—referring to SARS-CoV-2 as hCoV-19[48]—had identified eight global clades (S, O, L, V, G, GH, GR, and GV).[69]
• In 2017, Hadfield et al. announced Nextstrain, intended "for real-time tracking of pathogen evolution".[70] Nextstrain has later been used for tracking SARS-CoV-2, identifying 13 major clades[lower-alpha 4] (19A–B, 20A–20J and 21A) as of June 2021.[71]
• In 2020, Rambaut et al. of the Phylogenetic Assignment of Named Global Outbreak Lineages (PANGOLIN)[72] software team proposed in an article[47] "a dynamic nomenclature for SARS-CoV-2 lineages that focuses on actively circulating virus lineages and those that spread to new locations";[68] as of August 2021, 1340 lineages had been designated.[73][74]

Each national public health institute may also institute its own nomenclature system for the purposes of tracking specific variants. For example, Public Health England designated each tracked variant by year, month and number in the format [YYYY] [MM]/[NN], prefixing 'VUI' or 'VOC' for a variant under investigation or a variant of concern respectively.[17] This system has now been modified and now uses the format [YY] [MMM]-[NN], where the month is written out using a three-letter code.[17]

Variants that appear to meet one or more specific criteria considered during the COVID-19 pandemic may be labeled "variants of interest" or "variants under investigation" ('VUI') pending verification and validation of these properties. Once validated, variants of interest /VUI may be renamed "variants of concern" by monitoring organizations, such as the CDC in the US.[75][76][77] A related category is "variant of high consequence", used by the CDC if there is clear evidence that the effectiveness of prevention or intervention measures for a particular variant is substantially reduced.[78]

The Omicron variant, known as lineage B.1.1.529, was declared a variant of concern by the World Health Organization on 26 November 2021.[87]

The variant has a large number of mutations, of which some are concerning. Some evidence shows that this variant has an increased risk of reinfection. Studies are underway to evaluate the exact impact on transmissibility, mortality, and other factors.[88]

Named Omicron by the WHO,[87][89] it was identified in November 2021 in Botswana and South Africa;[90] one case had travelled to Hong Kong,[91][4][92] one confirmed case was identified in Israel in a traveler returning from Malawi,[93] along with two who returned from South Africa and one from Madagascar.[94] Belgium confirmed the first detected case in Europe on 26 November 2021 in an individual who had returned from Egypt on 11 November.[95] Indian SARS-CoV-2 Genomics Consortium (INSACOG) in its January 2022 bulletin noted that Omicron is in community transmission in India where new cases have been rising exponentially.[96]

According to the WHO, BA.1, BA.1.1, and BA.2 are the most common sublineages of Omicron globally as of February 2022.[97] BA.2 contains 28 unique genetic changes, including four in its spike protein, compared to BA.1, which had already acquired 60 mutations since the ancestral Wuhan strain, including 32 in the spike protein.[98] BA.2 is more transmissible than BA.1.[99] It was causing most cases in England by mid-March 2022, and by the end of March, BA.2 became dominant in the US.[100][98] As of May 2022, the sublineages BA.1 to BA.5 including all their descendants are classified as variants of concern by the WHO,[4] the CDC,[16] and the ECDC[101] (with the latter excluding BA.3).

The variants listed below had previously been designated as variants of concern, but were displaced by other variants. As of May 2022, the WHO lists the following under "previously circulating variants of concern":[4]

First detected in October 2020 during the COVID-19 pandemic in the United Kingdom from a sample taken the previous month in Kent,[102] lineage B.1.1.7,[103] labelled Alpha variant by the WHO, was previously known as the first Variant Under Investigation in December 2020 (VUI – 202012/01)[104] and later notated as VOC-202012/01.[17] It is also known as 20I (V1),[26] 20I/501Y.V1[105] (formerly 20B/501Y.V1),[40][106][107] or 501Y.V1.[108] From October to December 2020, its prevalence doubled every 6.5 days, the presumed generational interval.[109][110] It is correlated with a significant increase in the rate of COVID-19 infection in United Kingdom, associated partly with the N501Y mutation.[109] There was some evidence that this variant had 40–80% increased transmissibility (with most estimates lying around the middle to higher end of this range),[111][112] and early analyses suggested an increase in lethality,[113][114] though later work found no evidence of increased virulence.[115] As of May 2021, the Alpha variant had been detected in some 120 countries.[116]

On 16 March 2022, the WHO has de-escalated the Alpha variant and its subvariants to "previously circulating variants of concern".[117][118]

Variant of Concern 21FEB-02 (previously written as VOC-202102/02), described by Public Health England (PHE) as "B.1.1.7 with E484K"[17] is of the same lineage in the Pango nomenclature system, but has an additional E484K mutation. As of 17 March 2021, there were 39 confirmed cases of VOC-21FEB-02 in the UK.[17] On 4 March 2021, scientists reported B.1.1.7 with E484K mutations in the state of Oregon. In 13 test samples analysed, one had this combination, which appeared to have arisen spontaneously and locally, rather than being imported.[119][120][121] Other names for this variant include B.1.1.7+E484K[122] and B.1.1.7 Lineage with S:E484K.[123]

On 18 December 2020, the 501.V2 variant, also known as 501.V2, 20H (V2),[26] 20H/501Y.V2[105] (formerly 20C/501Y.V2), 501Y.V2,[124] VOC-20DEC-02 (formerly VOC-202012/02), or lineage B.1.351,[40] was first detected in South Africa and reported by the country's health department.[125] It has been labelled as Beta variant by WHO. Researchers and officials reported that the prevalence of the variant was higher among young people with no underlying health conditions, and by comparison with other variants it is more frequently resulting in serious illness in those cases.[126][127] The South African health department also indicated that the variant may be driving the second wave of the COVID-19 epidemic in the country due to the variant spreading at a more rapid pace than other earlier variants of the virus.[125][126]

Scientists noted that the variant contains several mutations that allow it to attach more easily to human cells because of the following three mutations in the receptor-binding domain (RBD) in the spike glycoprotein of the virus: N501Y,[125][128] K417N, and E484K.[129][130] The N501Y mutation has also been detected in the United Kingdom.[125][131]

On 16 March 2022, the WHO has de-escalated the Beta variant and its subvariants to "previously circulating variants of concern".[117][118]

The Gamma variant or lineage P.1, termed Variant of Concern 21JAN-02[17] (formerly VOC-202101/02) by Public Health England,[17] 20J (V3)[26] or 20J/501Y.V3[105] by Nextstrain, or just 501Y.V3,[108] was detected in Tokyo on 6 January 2021 by the National Institute of Infectious Diseases (NIID). It has been labelled as Gamma variant by WHO. The new variant was first identified in four people who arrived in Tokyo having travelled from the Brazilian Amazonas state on 2 January 2021.[132] On 12 January 2021, the Brazil-UK CADDE Centre confirmed 13 local cases of the new Gamma variant in the Amazon rainforest.[133] This variant of SARS-CoV-2 has been named lineage P.1 (although it is a descendant of B.1.1.28, the name B.1.1.28.1[18][134] is not permitted and thus the resultant name is P.1), and has 17 unique amino acid changes, 10 of which in its spike protein, including the three concerning mutations: N501Y, E484K and K417T.[133][134][135][136]^{: Figure 5}

The N501Y and E484K mutations favour the formation of a stable RBD-hACE2 complex, thus, enhancing the binding affinity of RBD to hACE2. However, the K417T mutation disfavours complex formation between RBD and hACE2, which has been demonstrated to reduce the binding affinity.[1]

The new variant was absent in samples collected from March to November 2020 in Manaus, Amazonas state, but it was detected for the same city in 42% of the samples from 15 to 23 December 2020, followed by 52.2% during 15–31 December and 85.4% during 1–9 January 2021.[133] A study found that infections by Gamma can produce nearly ten times more viral load compared to persons infected by one of the other lineages identified in Brazil (B.1.1.28 or B.1.195). Gamma also showed 2.2 times higher transmissibility with the same ability to infect both adults and older persons, suggesting P.1 and P.1-like lineages are more successful at infecting younger humans irrespective of sex.[137]

A study of samples collected in Manaus between November 2020 and January 2021, indicated that the Gamma variant is 1.4–2.2 times more transmissible and was shown to be capable of evading 25–61% of inherited immunity from previous coronavirus diseases, leading to the possibility of reinfection after recovery from an earlier COVID-19 infection. As for the fatality ratio, infections by Gamma were also found to be 10–80% more lethal.[138][139][140]

A study found that people fully vaccinated with Pfizer or Moderna have significantly decreased neutralisation effect against Gamma, although the actual impact on the course of the disease is uncertain. A pre-print study by the Oswaldo Cruz Foundation published in early April found that the real-world performance of people with the initial dose of the Sinovac's Coronavac Vaccine had approximately 50% efficacy rate. They expected the efficacy to be higher after the 2nd dose. As of July 2021, the study is ongoing.[141]

Preliminary data from two studies indicate that the Oxford–AstraZeneca vaccine is effective against the Gamma variant, although the exact level of efficacy has not yet been released.[142][143] Preliminary data from a study conducted by Instituto Butantan suggest that CoronaVac is effective against the Gamma variant as well, and as of July 2021 has yet to be expanded to obtain definitive data.[144]

On 16 March 2022, the WHO has de-escalated the Gamma variant and its subvariants to "previously circulating variants of concern".[117][118]

The Delta variant, also known as B.1.617.2, G/452R.V3, 21A[26] or 21A/S:478K,[105] is a globally dominant variant that spread to at least 185 countries.[145] It was first discovered in India. Descendant of lineage B.1.617, which also includes the Kappa variant under investigation, it was first discovered in October 2020 and has since spread internationally.[146][147][148][149][150] On 6 May 2021, British scientists declared B.1.617.2 (which notably lacks mutation at E484Q) as a "variant of concern", labelling it VOC-21APR-02, after they flagged evidence that it spreads more quickly than the original version of the virus and could spread quicker or as quickly as Alpha.[151][19][152][153] It carries L452R and P681R mutations in Spike;[28] unlike Kappa it carries T478K but not E484Q.

On 3 June 2021, Public Health England reported that twelve of the 42 deaths from the Delta variant in England were among the fully vaccinated, and that it was spreading almost twice as fast as the Alpha variant.[154] Also on 11 June, Foothills Medical Centre in Calgary, Canada reported that half of their 22 cases of the Delta variant occurred among the fully vaccinated.[155]

In June 2021, reports began to appear of a variant of Delta with the K417N mutation.[156] The mutation, also present in the Beta and Gamma variants, raised concerns about the possibility of reduced effectiveness of vaccines and antibody treatments and increased risk of reinfection.[157] The variant, called "Delta with K417N" by Public Health England, includes two clades corresponding to the Pango lineages AY.1 and AY.2.[158] It has been nicknamed "Delta plus"[159] from "Delta plus K417N".[160] The name of the mutation, K417N, refers to an exchange whereby lysine (K) is replaced by asparagine (N) at position 417.[161] On 22 June, India's Ministry of Health and Family Welfare declared the "Delta plus" variant of COVID-19 a Variant of Concern after 22 cases of the variant were reported in India.[162] After the announcement, leading virologists said there was insufficient data to support labelling the variant as a distinct variant of concern, pointing to the small number of patients studied.[163] In the UK in July 2021, AY.4.2 was identified. Alongside those previously mentioned it also gained the nickname 'Delta Plus', on the strength of its extra mutations, Y145H and A222V. These are not unique to it, but distinguish it from the original Delta variant.[164]

On 7 June 2022, the WHO has de-escalated the Delta variant and its subvariants to "previously circulating variants of concern".[118][165]

The Epsilon variant or lineage B.1.429, also known as CAL.20C[166] or CA VUI1,[167] 21C[26] or 20C/S:452R,[105] is defined by five distinct mutations (I4205V and D1183Y in the ORF1ab gene, and S13I, W152C, L452R in the spike protein's S-gene), of which the L452R (previously also detected in other unrelated lineages) was of particular concern.[53][168] From 17 March to 29 June 2021, the CDC listed B.1.429 and the related B.1.427 as "variants of concern".[28][169][170][171] As of July 2021, Epsilon is no longer considered a variant of interest by the WHO,[15] as it was overtaken by Alpha.[172]

From September 2020 to January 2021, it was 19% to 24% more transmissible than earlier variants in California. Neutralisation against it by antibodies from natural infections and vaccinations was moderately reduced,[173] but it remained detectable in most diagnostic tests.[174]

Epsilon (CAL.20C) was first observed in July 2020 by researchers at the Cedars-Sinai Medical Center, California, in one of 1,230 virus samples collected in Los Angeles County since the start of the COVID-19 epidemic.[175] It was not detected again until September when it reappeared among samples in California, but numbers remained very low until November.[176][177] In November 2020, the Epsilon variant accounted for 36 per cent of samples collected at Cedars-Sinai Medical Center, and by January 2021, the Epsilon variant accounted for 50 per cent of samples.[168] In a joint press release by University of California, San Francisco, California Department of Public Health, and Santa Clara County Public Health Department,[178] the variant was also detected in multiple counties in Northern California. From November to December 2020, the frequency of the variant in sequenced cases from Northern California rose from 3% to 25%.[179] In a preprint, CAL.20C is described as belonging to clade 20C and contributing approximately 36% of samples, while an emerging variant from the 20G clade accounts for some 24% of the samples in a study focused on Southern California. Note, however, that in the US as a whole, the 20G clade predominates, as of January 2021.[53] Following the increasing numbers of Epsilon in California, the variant has been detected at varying frequencies in most US states. Small numbers have been detected in other countries in North America, and in Europe, Asia and Australia.[176][177] After an initial increase, its frequency rapidly dropped from February 2021 as it was being outcompeted by the more transmissible Alpha. In April, Epsilon remained relatively frequent in parts of northern California, but it had virtually disappeared from the south of the state and had never been able to establish a foothold elsewhere; only 3.2% of all cases in the United States were Epsilon, whereas more than two-thirds were Alpha.[172]

Zeta variant or lineage P.2, a sub-lineage of B.1.1.28 like Gamma (P.1), was first detected in circulation in the state of Rio de Janeiro; it harbours the E484K mutation, but not the N501Y and K417T mutations.[136] It evolved independently in Rio de Janeiro without being directly related to the Gamma variant from Manaus.[133] Though previously Zeta was labeled a variant of interest, as of July 2021, it is no longer considered as such by the WHO.[15]

The Eta variant or lineage B.1.525, also called VUI-21FEB-03[17] (previously VUI-202102/03) by Public Health England (PHE) and formerly known as UK1188,[17] 21D[26] or 20A/S:484K,[105] does not carry the same N501Y mutation found in Alpha, Beta and Gamma, but carries the same E484K-mutation as found in the Gamma, Zeta, and Beta variants, and also carries the same ΔH69/ΔV70 deletion (a deletion of the amino acids histidine and valine in positions 69 and 70) as found in Alpha, N439K variant (B.1.141 and B.1.258) and Y453F variant (Cluster 5).[180] Eta differs from all other variants by having both the E484K-mutation and a new F888L mutation (a substitution of phenylalanine (F) with leucine (L) in the S2 domain of the spike protein). As of 5 March 2021, it had been detected in 23 countries.[181][182][183] It has also been reported in Mayotte, the overseas department/region of France.[181] The first cases were detected in December 2020 in the UK and Nigeria, and as of 15 February 2021, it had occurred in the highest frequency among samples in the latter country.[183] As of 24 February 56 cases were found in the UK.[17] Denmark, which sequences all its COVID-19 cases, found 113 cases of this variant from 14 January to 21 February 2021, of which seven were directly related to foreign travel to Nigeria.[182]

As of July 2021, UK experts are studying it to ascertain how much of a risk it could be. It is currently regarded as a "variant under investigation", but pending further study, it may become a "variant of concern". Ravi Gupta, from the University of Cambridge said in a BBC interview that lineage B.1.525 appeared to have "significant mutations" already seen in some of the other newer variants, which means their likely effect is to some extent more predictable.[184]

On 18 February 2021, the Department of Health of the Philippines confirmed the detection of two mutations of COVID-19 in Central Visayas after samples from patients were sent to undergo genome sequencing. The mutations were later named as E484K and N501Y, which were detected in 37 out of 50 samples, with both mutations co-occurrent in 29 out of these.[185]

On 13 March, the Department of Health confirmed the mutations constitutes a variant which was designated as lineage P.3.[186] On the same day, it also confirmed the first COVID-19 case caused by the Gamma variant in the country. The Philippines had 98 cases of the Theta variant on 13 March.[187] On 12 March it was announced that Theta had also been detected in Japan.[188][189] On 17 March, the United Kingdom confirmed its first two cases,[190] where PHE termed it VUI-21MAR-02.[17] On 30 April 2021, Malaysia detected 8 cases of the Theta variant in Sarawak.[191]

As of July 2021, Theta is no longer considered a variant of interest by the WHO.[15]

In November 2020, a mutant variant was discovered in New York City, which was named lineage B.1.526.[192] As of 11 April 2021, the variant has been detected in at least 48 U.S. states and 18 countries. In a pattern mirroring Epsilon, Iota was initially able to reach relatively high levels in some states, but by May 2021 it was outcompeted by the more transmissible Delta and Alpha.[172]

The Kappa variant[15] is one of the three sublineages of lineage B.1.617. It is also known as lineage B.1.617.1, 21B[26] or 21A/S:154K,[105] and was first detected in India in December 2020.[193] By the end of March 2021, Kappa accounted for more than half of the sequences being submitted from India.[194] On 1 April 2021, it was designated a variant under investigation (VUI-21APR-01) by Public Health England.[27] It has the notable mutations L452R, E484Q, P681R.[195]

The Lambda variant, also known as lineage C.37, was first detected in Peru in August 2020 and was designated by the WHO as a variant of interest on 14 June 2021.[15] It spread to at least 30 countries[196] around the world and, as of July 2021, it is unknown whether it is more infectious and resistant to vaccines than other strains.[197][198] On 16 March 2022, the WHO has de-escalated the Lambda variant to "previously circulating variants of concern".[117][118]

The Mu variant, also known as lineage B.1.621, was first detected in Colombia in January 2021 and was designated by the WHO as a variant of interest on 30 August 2021.[15] There have been outbreaks in South America and Europe.[199][200] On 16 March 2022, the WHO has de-escalated the Mu variant and its subvariants to "previously circulating variants of concern".[117][118]

The variants listed below were once listed under variants under monitoring, but were reclassified due to either no longer circulating at a significant level, not having had a significant impact on the situation, or scientific evidence of the variant not having concerning properties.[4]

As of 26 May 2022[4]

Pango lineage	GISAID clade	Nextstrain clade	Earliest samples	Date of VUM	Date of designation	Country of sampling
AV.1	GR		2021-03	2021-05-26	2021-07-21	UK
AT.1	GR		2021-01	2021-06-09	2021-07-21	Russia
R.1	GR		2021-01	2021-04-07	2021-11-09	Japan
B.1.466.2	GH		2020-11	2021-04-28	2021-11-09	Indonesia
B.1.1.519	GR	20B/S.732A	2020-11	2021-06-02	2021-11-09	Multiple countries
C.36.3	GR		2021-01	2021-06-16	2021-11-09	Multiple countries
B.1.214.2	G		2020-11	2021-06-30	2021-11-09	Multiple countries
B.1.1.523	GR		2020-05	2021-07-14	2021-11-09	Multiple countries
B.1.619	G		2020-05	2021-07-14	2021-11-09	Multiple countries
B.1.620	G	20A/S.126A	2020-11	2021-07-14	2021-11-09	Lithuania
B.1.1.318 AZ.5	GR		2021-01		2021-06-02	England
C.1.2	GR		2021-05		2021-09-01	South Africa
B.1.630	GH		2021-03		2021-10-12	Dominican Republic
B.1.640	GH/490R		2021-09		2021-11-22	Republic of Congo
XD			2022-01		2022-03-09	France

The name of the mutation, del 69-70, or 69-70 del, or other similar notations, refers to the deletion of amino acid at position 69 to 70. The mutation is found in the Alpha variant, and could lead to "spike gene target failure" and result in false negative result in PCR virus test.[224]

Otherwise referred to as del 246-252, or other various similar expression, refer to the deletion of amino acid from the position of 246 to 252, in the N-terminal domain of spike protein, accompanied with a replacement of the aspartic acid (D) at the position 253 for asparagine (N).[225][226]

The 7 amino acid deletion mutation is currently described as unique in the Lambda variant, and have been attributed to as one of the cause of the strain's increased capability to escape from neutralizing antibodies according to preprint paper.[227]

The name of the mutation, N440K, refers to an exchange whereby the asparagine (N) is replaced by lysine (K) at position 440.[228]

This mutation has been observed in cell cultures to be 10 times more infective compared to the previously widespread A2a strain (A97V substitution in RdRP sequence) and 1000 times more in the lesser widespread A3i strain (D614G substitution in Spike and a and P323L substitution in RdRP).[229] It was involved in rapid surges of COVID-19 cases in India in May 2021.[230] India has the largest proportion of N440K mutated variants followed by the US and Germany.[231]

The name of the mutation, G446V, refers to an exchange whereby the glycine (G) is replaced by valine (V) at position 446.[228]

The mutation, identified in Japan among inbound travelers starting from May, and among 33 samples from individuals related to 2020 Tokyo Olympic Games and 2020 Tokyo Paralympic Games, are said to be possible to impact affinity of multiple monoclonal antibody, although its clinical impact against the use of antibody medicine is still yet to be known.[232]

The name of the mutation, L452R, refers to an exchange whereby the leucine (L) is replaced by arginine (R) at position 452.[228]

L452R is found in both the Delta and Kappa variants which first circulated in India, but have since spread around the world. L452R is a relevant mutation in this strain that enhances ACE2 receptor binding ability and can reduce vaccine-stimulated antibodies from attaching to this altered spike protein.

L452R, some studies show, could even make the coronavirus resistant to T cells, that are necessary to target and destroy virus-infected cells. They are different from antibodies that are useful in blocking coronavirus particles and preventing it from proliferating.[147]

The name of the mutation, Y453F, refers to an exchange whereby the tyrosine (Y) is replaced by phenylalanine (F) at position 453. The mutation have been found potentially linked to the spread of SARS-CoV-2 among minks in the Netherlands in 2020.[233]

A highly flexible region in the receptor binding domain (RBD) of SARS-CoV-2, starting from residue 475 and continuing up to residue 485, was identified using bioinformatics and statistical methods in several studies. The University of Graz[234] and the Biotech Company Innophore[235] have shown in a recent publication that structurally, the position S477 shows the highest flexibility among them.[236]

At the same time, S477 is hitherto the most frequently exchanged amino acid residue in the RBDs of SARS-CoV-2 mutants. By using molecular dynamics simulations of RBD during the binding process to hACE2, it has been shown that both S477G and S477N strengthen the binding of the SARS-COV-2 spike with the hACE2 receptor. The vaccine developer BioNTech[237] referenced this amino acid exchange as relevant regarding future vaccine design in a preprint published in February 2021.[238]

The name of the mutation, E484Q, refers to an exchange whereby the glutamic acid (E) is replaced by glutamine (Q) at position 484.[228]

The Kappa variant circulating in India has E484Q. These variants were initially (but misleadingly) referred to as a "double mutant".[239] E484Q may enhance ACE2 receptor binding ability, and may reduce vaccine-stimulated antibodies' ability to attach to this altered spike protein.[147]

The name of the mutation, E484K, refers to an exchange whereby the glutamic acid (E) is replaced by lysine (K) at position 484.[228] It is nicknamed "Eeek".[240]

E484K has been reported to be an escape mutation (i.e., a mutation that improves a virus's ability to evade the host's immune system[241][242]) from at least one form of monoclonal antibody against SARS-CoV-2, indicating there may be a "possible change in antigenicity".[243] The Gamma variant (lineage P.1),[133] the Zeta variant (lineage P.2, also known as lineage B.1.1.28.2)[136] and the Beta variant (501.V2) exhibit this mutation.[243] A limited number of lineage B.1.1.7 genomes with E484K mutation have also been detected.[244] Monoclonal and serum-derived antibodies are reported to be from 10 to 60 times less effective in neutralising virus bearing the E484K mutation.[245][246] On 2 February 2021, medical scientists in the United Kingdom reported the detection of E484K in 11 samples (out of 214,000 samples), a mutation that may compromise current vaccine effectiveness.[247][248]

F490S denotes a change from phenylalanine (F) to serine (S) in amino-acid position 490.[249]

It is one of the mutation found in Lambda, and have been associated with reduced susceptibility to antibody generated by those who were infected with other strains, meaning antibody treatment against people infected with strains carrying such mutation would be less effective.[250]

N501Y denotes a change from asparagine (N) to tyrosine (Y) in amino-acid position 501.[251] N501Y has been nicknamed "Nelly".[240]

This change is believed by PHE to increase binding affinity because of its position inside the spike glycoprotein's receptor-binding domain, which binds ACE2 in human cells; data also support the hypothesis of increased binding affinity from this change.[41] Molecular interaction modelling and the free energy of binding calculations has demonstrated that the mutation N501Y has the highest binding affinity in variants of concern RBD to hACE2.[1] Variants with N501Y include Gamma,[243][133] Alpha (VOC 20DEC-01), Beta, and COH.20G/501Y (identified in Columbus, Ohio).[1] This last became the dominant form of the virus in Columbus in late December 2020 and January and appears to have evolved independently of other variants.[252][253]

N501S denotes a change from asparagine (N) to serine (S) in amino-acid position 501.[254]

As of September 2021, there are 8 cases of patients around the world infected with Delta variant which feature this N501S mutation. As it is considered a mutation similar to N501Y, it is suspected to have similar characteristics as N501Y mutation, which is believed to increase the infectivity of the virus, however the exact effect is unknown yet.[255]

Prevalence of mutation D614G across all reported GISAID strains during the course of 2020. Convergence with unity closely matches the upper limb of the logistics curve.[256]

D614G is a missense mutation that affects the spike protein of SARS-CoV-2. From early appearances in Eastern China early in 2020, the frequency of this mutation in the global viral population increased early on during the pandemic.[257] G (glycine) quickly replaced D (aspartic acid) at position 614 in Europe, though more slowly in China and the rest of East Asia, supporting the hypothesis that G increased the transmission rate, which is consistent with higher viral titres and infectivity in vitro.[51] Researchers with the PANGOLIN tool nicknamed this mutation "Doug".[240]

In July 2020, it was reported that the more infectious D614G SARS-CoV-2 variant had become the dominant form in the pandemic.[258][259][260][261] PHE confirmed that the D614G mutation had a "moderate effect on transmissibility" and was being tracked internationally.[251][262]

The global prevalence of D614G correlates with the prevalence of loss of smell (anosmia) as a symptom of COVID-19, possibly mediated by higher binding of the RBD to the ACE2 receptor or higher protein stability and hence higher infectivity of the olfactory epithelium.[263]

Variants containing the D614G mutation are found in the G clade by GISAID[51] and the B.1 clade by the PANGOLIN tool.[51]

The name of the mutation, Q677P/H, refers to an exchange whereby the glutamine (Q) is replaced by proline (P) or histidine (H) at position 677.[228] There are several sub-lineages containing the Q677P mutation; six of these, which also contain various different combinations of other mutations, are referred to by names of birds. One of the earlier ones noticed for example is known as "Pelican," while the most common of these as of early 2021 was provisionally named "Robin 1."[264]

The mutation has been reported in multiple lineages circulating inside the United States as of late 2020 and also some lineages outside the country. 'Pelican' was first detected in Oregon, and as of early 2021 'Robin 1' was found often in the Midwestern United States, while another Q667H sub-lineage, 'Robin 2', was found mostly in the southeastern United States.[264] The frequency of such mutation being recorded has increased from late 2020 to early 2021.[265]

Logarithmic Prevalence of P681H in 2020 according to sequences in the GISAID database[256]

The name of the mutation, P681H, refers to an exchange whereby the proline (P) is replaced by histidine (H) at position 681.[256]

In January 2021, scientists reported in a preprint that the mutation P681H, a characteristic feature of the Alpha variant and lineage B.1.1.207 (identified in Nigeria), is showing a significant exponential increase in worldwide frequency, thus following a trend to be expected in the lower limb of the logistics curve. This may be compared with the trend of the now globally prevalent D614G.[256][266]

The name of the mutation, P681R, refers to an exchange whereby the proline (P) is replaced by arginine (R) at position 681.[228]

Indian SARS-CoV-2 Genomics Consortium (INSACOG) found that other than the two mutations E484Q and L452R, there is also a third significant mutation, P681R in lineage B.1.617. All three concerning mutations are on the spike protein, the operative part of the coronavirus that binds to receptor cells of the body.[147]

According to initial media reports, the Malaysian Ministry of Health announced on 23 December 2020 that it had discovered a mutation in the SARS-CoV-2 genome which they designated as A701B(sic), among 60 samples collected from the Benteng Lahad Datu cluster in Sabah. The mutation was characterised as being similar to the one found recently at that time in South Africa, Australia, and the Netherlands, although it was uncertain if this mutation was more infectious or aggressive than before.[267] The provincial government of Sulu in neighbouring Philippines temporarily suspended travel to Sabah in response to the discovery of 'A701B' due to uncertainty over the nature of the mutation.[268]

On 25 December 2020, the Malaysian Ministry of Health described a mutation A701V as circulating and present in 85% of cases (D614G was present in 100% of cases) in Malaysia.[269][270] These reports also referred to samples collected from the Benteng Lahad Datu cluster.[269][270] The text of the announcement was mirrored verbatim on the Facebook page of Noor Hisham Abdullah, Malay Director-General of Health, who was quoted in some of the news articles.[270]

The A701V mutation has the amino acid alanine (A) substituted by valine (V) at position 701 in the spike protein. Globally, South Africa, Australia, Netherlands and England also reported A701V at about the same time as Malaysia.[269] In GISAID, the prevalence of this mutation is found to be about 0.18%. of cases.[269]

On 14 April 2021, the Malaysian Ministry of Health reported that the third wave, which had started in Sabah, has involved the introduction of variants with D614G and A701V mutations.[271]

On 26 January 2021, the British government said it would share its genomic sequencing capabilities with other countries in order to increase the genomic sequencing rate and trace new variants, and announced a "New Variant Assessment Platform".[288] As of January 2021, more than half of all genomic sequencing of COVID-19 was carried out in the UK.[289]

Wastewater surveillance was demonstrated to be one technique to detect SARS-CoV-2 variants[208] and to track their rise for studying related ongoing infection dynamics.[290][291][292]

Whether one or more mutations visible in RT-PCR tests can be used reliably to identify a variant depends on the prevalence of other variants currently circulating in the same population.[293][294]

Mutations used to identify variants of concern in commercial test assays[295]

Mutation	Alpha	Beta	Gamma	Delta	Omicron
Δ69–70[lower-alpha 5]
ins214EPE[lower-alpha 6]
S371L/S373P[lower-alpha 6]
N501Y
E484K
E484A[lower-alpha 6]
L452R
nsp6:Δ106–108

In early November 2020, Cluster 5, also referred to as ΔFVI-spike by the Danish State Serum Institute (SSI),[301] was discovered in Northern Jutland, Denmark. It is believed to have been spread from minks to humans via mink farms. On 4 November 2020, it was announced that the mink population in Denmark would be culled to prevent the possible spread of this mutation and reduce the risk of new mutations happening. A lockdown and travel restrictions were introduced in seven municipalities of Northern Jutland to prevent the mutation from spreading, which could compromise national or international responses to the COVID-19 pandemic. By 5 November 2020, some 214 mink-related human cases had been detected.[302]

The WHO stated that cluster 5 had a "moderately decreased sensitivity to neutralising antibodies".[303] SSI warned that the mutation could reduce the effect of COVID-19 vaccines under development, although it was unlikely to render them useless. Following the lockdown and mass-testing, SSI announced on 19 November 2020 that cluster 5 in all probability had become extinct.[304] As of 1 February 2021, authors to a peer-reviewed paper, all of whom were from the SSI, assessed that cluster 5 was not in circulation in the human population.[305]