NM_000075.3:c.322C>T (p.Pro108Ser) is a missense variant in CDK4, a gene in which activating missense variants are associated with autosomal dominant familial melanoma. This variant is absent from all large population databases including gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada, supporting moderate evidence for pathogenicity (PM2).¹ Multiple lines of computational evidence suggest a benign effect: REVEL score is 0.251 (below the pathogenic threshold), BayesDel score is -0.25851 (negative, predicting benign), and SpliceAI predicts no splicing impact (max delta = 0.01). This supports BP4 (supporting benign).² No functional studies, case-control data, segregation data, or clinical phenotype information are available for this variant. The variant is absent from ClinVar and has not been reported in the somatic or germline literature.³ The variant is a missense substitution at a residue (Pro108) that is not a recognized mutational hotspot and has no comparator pathogenic variants at the same position. Overall, the only applicable criterion is PM2 (moderate) for absence from population databases, and BP4 (supporting benign) for concordant benign computational predictions. With one moderate pathogenic criterion and one supporting benign criterion, the evidence is insufficient to classify this variant as pathogenic or likely pathogenic, and insufficient evidence exists to classify it as benign. This variant is classified as a Variant of Uncertain Significance (VUS).⁴