NM_004936.3:c.338G>A (p.Gly113Asp) is a missense variant in exon 2 of CDKN2B, a tumor suppressor gene at 9p21.3 encoding the cyclin-dependent kinase inhibitor p15INK4b. This variant is extremely rare in large population databases: absent from gnomAD v2.1 and present at an allele frequency of 6.23×10⁻⁷ (1/1,606,290 alleles) in gnomAD v4.1, satisfying PM2 at moderate strength.¹ Multiple lines of computational evidence suggest no significant impact on the gene product: BayesDel predicts a benign effect (−0.094), REVEL (0.484) falls below the commonly used pathogenic threshold of 0.5, and SpliceAI predicts no splicing alteration (max delta = 0.00), satisfying BP4 at supporting strength.² This variant is absent from ClinVar with no submitter classifications, and has not been reported in the literature in association with disease.³ CDKN2B germline loss-of-function mutations have been associated with renal cell carcinoma (PMID:25873077), and 9p21.3 microdeletions encompassing CDKN2A/CDKN2B are associated with a cancer predisposition syndrome (PMID:35422439). However, the specific variant c.338G>A has not been reported in these or other published studies.⁴ No functional studies, case-control data, segregation data, or de novo reports are available for this variant. Per generic ACMG/AMP 2015 combination rules (PMID:25741868), a single moderate pathogenic criterion (PM2) and a single supporting benign criterion (BP4) do not meet the threshold for Likely Pathogenic or Likely Benign; the variant is classified as a Variant of Uncertain Significance (VUS).⁵