NM_002227.3:c.1909G>A (p.Glu637Lys) is extremely rare in population databases, present in gnomAD v4.1 at an allele frequency of 1.24e-06 (2/1,613,736 alleles, 0 homozygotes) and absent from gnomAD v2.1 and gnomAD-Canada v1.0. This meets PM2 at the supporting level.¹ Computational evidence supports a deleterious effect: REVEL predicts a damaging score of 0.762, meeting PP3 at the supporting level under generic ACMG/AMP guidelines. SpliceAI predicts no splicing impact (max delta=0.00).² This variant is a missense substitution (p.Glu637Lys) and does not meet PVS1 null-variant criteria. No functional studies, segregation data, de novo observations, case-control data, or prior clinical classifications are available. The variant has been reported in COSMIC (COSV61089427, n=2) in a somatic context but lacks germline disease association evidence.³ Only two supporting-level pathogenic criteria are met (PM2_supporting, PP3_supporting). No moderate, strong, or very strong pathogenic criteria are met. No benign criteria are met. Under generic ACMG/AMP 2015 combination rules (PMID:25741868), two supporting criteria are insufficient to reach Likely Pathogenic (minimum: 1 strong + 2 supporting, or 2 moderate + 2 supporting, or 3 moderate, etc.). The variant is classified as a Variant of Uncertain Significance (VUS).⁴