NM_000077.4:c.151G>T (p.Val51Phe) is a missense variant in exon 2 of CDKN2A, located in the first ankyrin repeat domain critical for CDK4/6 binding and cyclin-dependent kinase inhibition. PM1 (supporting): The variant lies at codon 51 within ankyrin repeat 1, a well-established mutational hotspot and critical functional domain where many pathogenic missense variants cluster in familial melanoma.¹ PM2 (supporting): The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases (allele count 0), consistent with a rare variant.² PVS1 is not applicable as this is a missense variant that does not fall into any null-variant bucket per the ClinGen SVI PVS1 decision tree (PMC6185798).³ In silico predictions are conflicting: REVEL score 0.561 suggests a damaging effect, while BayesDel 0.137 (benign range) and SpliceAI max delta 0.02 (no splice impact) do not support pathogenicity. Neither PP3 nor BP4 can be applied due to discordant computational evidence.⁴ No functional studies directly testing p.V51F, no cosegregation data, no de novo reports, and no case-control data were identified in the reviewed literature. ClinVar submissions from two clinical laboratories classify this variant as Uncertain significance.⁵ Based on generic ACMG/AMP 2015 combination rules (PMID:25741868), two supporting pathogenic criteria (PM1_Supporting + PM2_Supporting) in the absence of any benign criteria is insufficient to reach Likely Pathogenic. The variant is classified as a Variant of Uncertain Significance (VUS).⁶