COL4A3 encodes the α3 chain of type IV collagen, a critical structural component of basement membranes, particularly in the glomerular basement membrane (GBM), cochlear, and ocular tissues 1. The protein functions as an integrin-binding molecule that regulates endothelial cell apoptosis and negatively controls angiogenesis and vascular endothelial cell proliferation, partly through an anti-angiogenic cleavage fragment called tumstatin that operates via RGD-independent ITGB3-mediated mechanisms. COL4A3 mutations cause autosomal recessive and dominant forms of Alport syndrome, a genetically heterogeneous disorder characterized by progressive hematuria, kidney failure, sensorineural hearing loss, and ocular abnormalities 1. Approximately 15% of Alport syndrome cases result from COL4A3 mutations, with autosomal dominant forms occurring more frequently (1-5%) than previously recognized 2. Heterozygous COL4A3 variants present a phenotypic spectrum ranging from benign familial hematuria to complete Alport syndrome features 3. Recent evidence demonstrates that COL4A3 variants contribute to thinned GBM lesions in sporadic IgA nephropathy, suggesting broader clinical relevance beyond classical Alport syndrome 4. Early genetic testing of COL4A3 is recommended for persistent hematuria and proteinuria, with cascade testing of family members recommended due to kidney function impairment risks 5.