Physiologic variants of the corpus callosum include agenesis or hypoplasia. Agenesis of the corpus callosum is an uncommon brain malformation that either leads to a partial or total absence of the corpus callosum. Though rare, it is one of the more frequently occurring congenital malformations, affecting three to seven people per 1000 births.[7] A diagnosis can be made using prenatal ultrasound and can be concurrent with malformations in midline structures like cavum septum pellicidum, as well as cortical and posterior fossa abnormalities.[7][8][7] In part, it is the result of multiple developmental abnormalities, affecting steps as early as midline telencephalic patterning to later neuronal differentiation and axonal guidance.[5] The cause is unknown but appears to be sporadic and possibly non-genetic. Despite the corpus callosum's crucial role in normal cognition, patients with isolated agenesis of the corpus callosum typically have good prognoses. Common deficits observed in this population include difficulty with problem-solving and socializing, often placing patients on the autism spectrum.[9] These deficits, known as "disconnection syndrome," are different from those observed in commissurotomy patients, who most notably have impaired bimanual coordinated motor activity.[5] Currently, 55% to 70% of agenesis of the corpus callosum cases are not identified based on clinical features. Hypoplasia is most benign when the rostrum is absent and often is not clinically significant. Therefore, it is commonly an incidental finding in a magnetic resonance imaging (MRI) scan obtained for other clinical reasons.[5][10]

A corpus callosotomy is a surgical procedure for patients with refractory disorders despite maximum medical management. Also, it is the preferred surgical procedure for patients with refractory seizure disorder with drop attacks. Though controversial, some advocate for the surgical resection of the corpus callosum to treat low-grade gliomas as the migration patterns of these tumors typically involve the invasion of white matter tracts.

The most common pathology associated with the corpus callosum is multiple sclerosis, resulting in demyelinating lesions in the corpus callosum and pericallosal region. Corpus callosum congenital anomalies are often associated with other brain defects, so evidence of an abnormality in corpus callosum development should prompt a workup for other potentially serious defects. In addition to the physiologic variants, corpus callosum lipomas are considered to be congenital malformations of the primitive meninges. Corpus callosum lipomas classify as either curvilinear, which are usually located posteriorly and are asymptomatic, and tubulonodular, which are found anteriorly and associated with severe frontal abnormalities. Ischemia of the corpus callosum is uncommon due to vascular inputs from three main arteries: the anterior communicating, anterior pericallosal, and posterior cerebral arteries. However, ischemia can result from emboli, and stenosis the result of atherosclerotic plaques, or vasospasm of the supplying arteries. Ruptured aneurysms in the anterior cerebral or pericallosal arteries typically cause hemorrhages of the corpus callosum. Consequently, hematomas located in the anterior corpus callosum should be investigated using computed tomogram (CT) angiography or three-dimensional time of flight MR angiography. The corpus callosum has been implicated in many other pathologies as well. Marchiava-Bignami disease involves acute demyelination and necrosis of the corpus callosum, most commonly observed in the body region of the corpus callosum in patients with chronic alcoholism. Other toxins like carbon monoxide and drugs like cocaine and heroin have also correlated with demyelination and lesions in the corpus callosum. Other pathologies that can cause corpus callosum lesions and demyelination include exposure to certain viruses, metabolic dysfunction, and traumatic brain injury. The most common tumors found in the corpus callosum are glioblastomas, as well as lymphomas and metastases.[7] The corpus callosum can undergo infarction, but the presenting symptoms of a corpus callosum stroke are vague and non-specific. One study found the most common signs and symptoms of a corpus callosum stroke in decreasing order are: different degrees of limb dyskinesia (84%), language disorder including some degree of mixed aphasia, complete motor aphasia, incomplete motor aphasia, or unclear words or clumsy speech (48%), cognitive or mental abnormality (40%), grope for action and forced laughter and crying (20%), alien hand syndrome (4%), partial body hypoalgesia(8%) in the patients who can cooperate physical examination, visual field loss (4%), and incontinence (8%).[11]