COL4A4 encodes the alpha-4 chain of type IV collagen, a major structural component of the glomerular basement membrane (GBM) that forms a 'chicken-wire' meshwork with laminins, proteoglycans, and nidogen 1. This organization is essential for kidney filtration and provides mechanical strength to the GBM 1. Pathogenic COL4A4 variants cause Alport syndrome and benign familial hematuria through disruption of type IV collagen heterotrimer assembly 2. COL4A4 mutations are associated with autosomal recessive Alport syndrome and, less frequently, autosomal dominant forms 2. In autosomal recessive disease, homozygous or compound heterozygous variants lead to severe GBM abnormalities and progressive kidney failure 3. Heterozygous COL4A4 variants can present with variable phenotypes ranging from asymptomatic hematuria to progressive nephropathy 3. Digenic disease involving both COL4A3 and COL4A4 variants results in 75% of collagen IV heterotrimers being affected, associated with increased proteinuria and intermediate kidney failure onset 4. Clinically, COL4A4 ranks among the seven most common genes in early-onset chr2 kidney disease, accounting for significant diagnostic yield 5. Genetic testing for COL4A4 variants is recommended for persistent hematuria, proteinuria, and steroid-resistant nephrotic syndrome; affected individuals should not serve as kidney donors 6. Early diagnosis enables effective intervention to slow kidney disease progression 7.