PM1 (moderate): Val51 is located in the second ankyrin repeat domain of p16INK4a, a critical functional domain essential for CDK4/CDK6 binding. Multiple pathogenic missense variants cluster in the ankyrin repeat domains and no benign variation is observed at this residue in population databases.¹ PM2 (moderate): The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, confirming it is not a common population polymorphism.² PS3 (supporting): A functional study (PMID:10468619) demonstrated that p.Val51Phe fails to inhibit CDK4 kinase activity and is unable to induce G1 arrest in a p16-null cell line, consistent with loss of tumor suppressor function. Verification of full text is pending. PP2 (supporting): CDKN2A is a tumor suppressor gene in which missense variants are a well-established mechanism of disease, with a low rate of benign missense variation in critical functional domains. Under generic ACMG/AMP 2015 combination rules (PMID:25741868), two moderate criteria (PM1 + PM2) plus two supporting criteria (PS3 + PP2) meets the threshold for Likely Pathogenic (2 Moderate + 2 Supporting).³ CAUTION: PS3 is derived from a single functional study (PMID:10468619) identified by automated literature search; the full text has not been independently verified. If PS3 is not upheld on human review, the combination would be 2 Moderate + 1 Supporting, which does not meet the Likely Pathogenic threshold and would default to Variant of Uncertain Significance. ClinVar classification is Uncertain significance (2 clinical laboratories, criteria provided, single submitter). This variant has been observed once in somatic cancers (COSMIC COSV105891454).⁴