PM2 (moderate): The variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada, with an allele frequency of 0% in all queried population databases, supporting moderate evidence for pathogenicity.¹ BP1 (supporting benign): RB1 is a gene in which >80% of pathogenic germline variants are truncating, and missense variants account for only 9.2% of pathogenic variants (PMID:42461076). This missense variant occurs in a gene where the primary disease mechanism is loss of function through null alleles. BP4 (supporting benign): Multiple lines of computational evidence — REVEL score 0.272, BayesDel score -0.129, and SpliceAI max delta 0.01 — converge on a non-deleterious prediction, providing supporting evidence against pathogenicity.² Classification: Uncertain Significance (VUS). There is conflicting evidence: PM2 (moderate pathogenicity) from complete absence in population databases is offset by BP1 (supporting benign) and BP4 (supporting benign). The two supporting benign criteria do not reach the 'likely benign' threshold in the presence of a moderate pathogenic criterion. Additional evidence — particularly functional studies, segregation data, or clinical case reports — is needed to resolve this variant's clinical significance.