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Homozygous or compound heterozygous variants in the GJC2gene can cause Pelizaeus-Merzbacher-like disease type 1 (PMLD1), a slowly progressive leukodystrophy that typically begins in neonatal or early infancy. This autosomal recessive rare genetic multisystem disorder is characterized by hypomyelination, nystagmus, impaired psychomotor development, ataxia and progressive spasticity. The prevalence is unknown.

At least one pathogenic variant in GJC2can cause hereditary spastic paraplegia 44 (SPG44), with a phenotype less severe than PMLD and autosomal recessive inheritance. SPG44 is characterized by hypomyelination, a late-onset, slowly progressive spastic paraplegia associated with mild ataxia and dysarthria, upper extremity involvement, normal or near-normal psychomotor development, preserved walking capability through adulthood, and mild cognitive impairment, without the presence of nystagmus.

Hereditary lymphedema type 1C (LMPH1C) is also caused by variants in GJC2, with autosomal dominant inheritance, leading to misfunction of the lymphatic system, resulting in chronic swelling of body parts.