NM_213647.2:c.317C>T (p.Ser106Phe) is absent from all queried population databases (gnomAD v2.1, v4.1, and gnomAD-Canada), meeting PM2 at moderate strength.¹ Multiple in silico predictors suggest no significant impact on the gene product: BayesDel score is -0.025 (benign range), SpliceAI max delta is 0.00, and REVEL score of 0.43 falls below standard pathogenicity thresholds, meeting BP4 at supporting benign strength.² The variant is absent from ClinVar and the literature; no functional, segregation, de novo, case-control, or clinical classification data are available to assess PS1–PS5, PM6, PP1–PP5, BS2–BS4, BP2, BP5, or BP6.³ PVS1 is not applicable: c.317C>T is a missense variant encoding p.Ser106Phe and does not fall into any null-variant bucket under the ClinGen SVI PVS1 decision tree (PMC6185798).⁴ PM1 is not met: residue 106 is not a statistically significant mutational hotspot and FGFR4 lacks a germline disease-associated hotspot map. PM5 is not applicable: no same-residue pathogenic comparator variant at codon 106 with a different amino acid change was identified in ClinVar.⁵ BP1 is not met: while FGFR4 loss-of-function is supported as a disease mechanism by gene-level literature, the gene-disease validity has not been established at a ClinGen level and missense variants are not excluded as a disease mechanism.⁶ The evidence profile consists of one moderate pathogenic criterion (PM2) and one supporting benign criterion (BP4), resulting in conflicting evidence. Under generic ACMG/AMP 2015 combination rules (PMID:25741868), this is classified as a Variant of Uncertain Significance (VUS).⁷