NM_000075.4:c.823A>T (p.Met275Leu) is a missense variant in CDK4, a gene in which missense variants are a known mechanism of autosomal dominant hereditary melanoma.¹ This variant is present at extremely low frequency in population databases: gnomAD v2.1 AF=3.98e-6 (1/251,446 alleles) and gnomAD v4.1 AF=1.86e-6 (3/1,612,194 alleles; grpmax FAF=6.8e-7), satisfying PM2 at supporting level.² The variant meets PP2 at supporting level: CDK4 has a low rate of benign missense variation and missense variants are a well-established disease mechanism (e.g., R24C/H in hereditary melanoma).³ Multiple lines of in silico evidence support a benign interpretation: REVEL score 0.197 (<0.5), BayesDel score -0.0628 (negative), and SpliceAI max delta 0.00 (no splicing impact), satisfying BP4 at supporting benign level.⁴ This variant has been reported in ClinVar as Uncertain Significance by three clinical laboratories (Variation ID 141405). No functional studies, segregation data, case-control comparisons, or de novo observations are available for this variant.⁵ Two supporting pathogenic criteria (PM2, PP2) and one supporting benign criterion (BP4) net to one supporting pathogenic criterion, resulting in a final classification of Variant of Uncertain Significance (VUS) under the generic ACMG/AMP 2015 framework.⁶