Clinical Insights Into the COL4A3 p.Gly407Arg Variant in Alport Syndrome

Alport syndrome is a hereditary nephropathy caused by pathogenic variants in the COL4A3, COL4A4, or COL4A5 genes, encoding type IV collagen chains that are essential for glomerular basement membrane integrity. The missense pathogenic variant p.Gly407Arg in COL4A3 has been reported in Portuguese families, but detailed phenotypic characterization remains limited. This study aimed to describe the renal and extra-renal manifestations and identify predictors of renal outcomes in a cohort of patients carrying the COL4A3 p.Gly407Arg variant.

We conducted a retrospective observational study including 62 patients from 25 families followed at a tertiary nephrology center in northern Portugal between 2007 and 2025 with genetically confirmed Autosomal Dominant Alport syndrome due to monoallelic COL4A3 p.Gly407Arg pathogenic variant. Demographic, clinical, laboratory, audiologic, and ophthalmologic data were analyzed. Renal events were defined as incident kidney failure, estimated Glomerular Filtration Rate (eGFR) <15 mL/min/1.73 m2, or eGFR ≥30% decline from baseline sustained over time. Changes in eGFR over time were analyzed using a univariate linear mixed effects model.

At diagnosis, 98% of patients presented with microscopic hematuria, and 53% had proteinuria (urinary protein-creatinine ratio (UPCR) 240mg/g, IQR 9-840). The mean eGFR was 94 ± 32 mL/min/1.73m2. Mean follow-up time in the study (from the initiation of clinical observation until the occurrence of the event or the end of follow-up) was 4.72 years (IQR 2.43-8.43). During a median follow-up of 4.72 years, 16 patients (26%) developed renal events, with 5 (8%) initiating KRT at a mean age of 58 (range 45-66) years. The mean renal survival was 67 years (63-72). Proteinuria ≥500mg/g was significantly associated with faster eGFR decline (p < 0.001) and a higher risk of renal events (imputed as a time-varying variable, HR 1.03, 95% CI 1.001-1.059, p= 0.04). Hearing loss occurred in 34% of patients and ocular changes in 18% of the patients evaluated.

Patients carrying monoallelic COL4A3 p.Gly407Arg pathogenic variant exhibit variable phenotypic expression, with proteinuria representing the strongest predictor of renal function decline.