NM_001126049.2:c.373C>T (p.Arg125Trp) is a missense variant in KLLN, a gene implicated in Cowden syndrome and Cowden-like syndrome through germline promoter hypermethylation. This variant is absent from ClinVar and has not been reported as pathogenic or benign by any clinical laboratory or expert panel.¹ In gnomAD v4.1, the variant is observed at an extremely low allele frequency (0.00446%, 69/1,545,416 alleles, 0 homozygotes; grpmax FAF=4.68e-05), meeting PM2 at supporting strength. The variant is absent from gnomAD v2.1 and gnomAD-Canada v1.0.² Multiple in silico predictors do not support a deleterious effect: REVEL score is 0.138 (low, below typical pathogenic thresholds), BayesDel score is -0.085 (benign direction), and SpliceAI predicts no splice impact (max delta 0.00). These concordant benign predictions meet BP4 at supporting strength.³ No variant-specific functional studies, case-control data, de novo observations, family segregation data, or clinical phenotype information are available. PVS1 is not applicable to this missense variant; PM1, PS3, PS4, PM5, PM6, PP1, PP2, PP4, PP5, BA1, BS1, BS2, BS3, BS4, BP1, BP2, BP5, and BP6 are not met due to insufficient evidence. Applying the generic ACMG/AMP 2015 combination rules (PMID:25741868): one supporting pathogenic criterion (PM2_Supporting) and one supporting benign criterion (BP4_Supporting) are present. These offset, resulting in a final classification of Variant of Uncertain Significance (VUS).⁴