GJA3 encodes connexin46 (Cx46), a structural component of lens fiber gap junctions that forms dodecameric intercellular channels 1. These gap junctions enable diffusion of small molecules and ions between adjacent lens cells, maintaining lens homeostasis and transparency 1. Cx46 is highly expressed in lens fiber cells alongside connexin50 2. GJA3 mutations cause autosomal dominant and recessive congenital cataracts with diverse phenotypes including posterior lenticonus, nuclear pulverulent, and central pulverulent types 3. Down-regulation of GJA3 is associated with hydrogen peroxide-induced lens epithelial cell apoptosis and age-related cataract development 4. Specific GJA3 variants carry elevated risks for secondary glaucoma and retinal detachment following cataract surgery 5. Computational screening identified 88 high-risk pathogenic GJA3 non-synonymous variants, with mutations affecting conserved sites, extracellular loops, and amino acid properties critical for protein stability 6. Frameshift and missense mutations disrupt connexin expression and function, causing progressive anterior nuclear cataracts in mouse models 7. Beyond lens biology, Cx46 localizes to cancer cell nuclei where it functions as a transcriptional regulator promoting oncogenic pathways 8, suggesting pleiotropic roles for GJA3-encoded protein beyond gap junction formation.