NM_001845.5:c.343G>A (p.Gly115Ser) is a missense variant in COL4A1 affecting a glycine residue in the collagen triple-helical Gly-X-Y repeat domain. The variant is extremely rare in population databases: gnomAD v2.1 allele frequency is 0.00177% (5/282,856 alleles) and gnomAD v4.1 allele frequency is 0.00192% (31/1,613,960 alleles), both well below the 0.1% PM2 threshold. It is absent from gnomAD-Canada.¹ Gly115 lies within the collagen triple-helical domain, a critical functional domain where glycine substitutions are a well-established pathogenic mechanism across collagen genes and specifically in COL4A1-related disorders (PMID:25719457). This supports application of PM1 at moderate strength. In silico predictors support a deleterious effect: REVEL score 0.963 (highly pathogenic-leaning) and BayesDel score 0.571 (damaging), meeting PP3 at supporting strength.² In ClinVar (ID 2158622), this variant has been reported as Uncertain significance by 5 clinical laboratories and as Likely pathogenic by 1 clinical laboratory (Labcorp Genetics). No expert panel review is available.³ Exploratory evidence recovery suggests potential functional evidence of impaired collagen IV secretion (PMID:15905400) and a possible de novo observation, but these could not be independently verified from available abstracts and require human review of full-text publications. Applying generic ACMG/AMP 2015 criteria: PM1 (moderate) + PM2 (supporting) + PP3 (supporting) = 1 moderate + 2 supporting, which does not reach the Likely Pathogenic threshold (requires ≥2 moderate OR ≥4 supporting OR 1 strong + ≥2 supporting). The classification is Variant of Uncertain Significance. Additional evidence (PS3 functional confirmation, PM6 de novo verification) could upgrade this to Likely Pathogenic.⁴