NM_002529.3:c.316G>A (p.Val106Met) in NTRK1 was identified as a rare missense variant in exon 3 of the extracellular domain. This variant is present at extremely low frequency in population databases: gnomAD v2.1 AF=0.00080% (2/251,148 alleles) and gnomAD v4.1 AF=0.00099% (16/1,613,972 alleles), with no homozygotes observed, meeting PM2 at moderate strength for an autosomal recessive disorder.¹ Multiple lines of computational evidence predict no deleterious effect: REVEL score is 0.175 (below the pathogenic threshold of 0.5), BayesDel is -0.235671 (negative, predicting benign), and SpliceAI predicts no splicing impact (max delta 0.05), meeting BP4 at supporting benign level.² This variant has been reported in ClinVar as Uncertain significance (ClinVar ID 655441) by three clinical laboratories (2-star review status). No expert panel has reviewed this variant, and no submitter has asserted a pathogenic or benign classification.³ No variant-specific functional studies, segregation data, de novo reports, case-control data, or family studies were identified for NM_002529.3:c.316G>A. OncoKB reports 'Unknown Oncogenic Effect' with no reviewed variant-specific evidence. COSMIC reports one somatic occurrence (COSV100693989) without functional assay data.⁴ Applying the generic ACMG/AMP 2015 final classification combination rules (PMID:25741868), the met criteria are PM2 (moderate pathogenic) and BP4 (supporting benign). These criteria are contradictory and do not satisfy any pathogenic or likely pathogenic combination, nor any benign or likely benign combination. The variant is classified as Uncertain significance (VUS).⁵