NM_006180.4:c.2033C>T (p.Ala678Val) in NTRK2 is a missense variant for which no CSPEC or VCEP gene-specific framework is available; classification proceeds under generic ACMG/AMP 2015 guidelines.¹ This variant is absent from gnomAD v2.1 and gnomAD-Canada, and is present at an extremely low frequency in gnomAD v4.1 (4/1,613,948 alleles, AF = 2.48e-06, 0.00025%), meeting PM2 at supporting strength.² No pathogenic or benign criteria beyond PM2_supporting were met. PVS1/BP7 are not applicable to this missense variant. In silico predictors are discordant (REVEL 0.654 damaging, BayesDel 0.073 benign, SpliceAI delta 0.00), so PP3 and BP4 are not met. No functional studies, segregation data, de novo reports, or hotspot evidence were available.³ The variant is reported in ClinVar (Variation ID 1393489) as Uncertain significance by a single clinical laboratory (Labcorp Genetics, SCV002166224), consistent with the limited evidence available for classification.⁴ With only one supporting pathogenic criterion (PM2) met and no benign criteria met, this variant is classified as a Variant of Uncertain Significance (VUS) under the generic ACMG/AMP 2015 framework.⁵