NM_001174067.1:c.521C>G (p.Thr174Arg) is a missense variant in exon 5 of FGFR1, encoding a substitution of threonine to arginine at codon 174 in the extracellular Ig-like domain. This variant is present at very low frequency in population databases: gnomAD v2.1 (27/278,536 alleles, AF=0.0097%) and gnomAD v4.1 (483/1,614,016 alleles, AF=0.03%), meeting PM2 at the supporting level. It is absent from gnomAD-Canada v1.0.¹ Computational predictors unanimously suggest a benign or neutral effect: REVEL score is 0.263 (below the pathogenic threshold), BayesDel is −0.147 (benign-leaning), and SpliceAI predicts no splicing impact (max delta 0.01), meeting BP4 at the supporting level.² OncoKB annotates this variant as Likely Neutral. COSMIC records this variant in two somatic cancer samples (COSV58328267), but no germline functional or case-level evidence of pathogenicity is available.³ ClinVar classifies this variant as Uncertain significance (Variation ID: 1024176) based on three submissions, all with criteria provided at the single-submitter level. No expert panel has reviewed this variant.⁴ A comprehensive functional screen of 160 FGFR variants (PMID:34272467) did not include Thr174Arg. No variant-specific functional studies have been performed.⁵ FGFR1 variant classification literature (PMID:37805574) establishes domain-based enrichment for IHH-associated missense variants but does not specifically address the Thr174 residue.⁶ With PM2_supporting and BP4_supporting both met, the evidence is balanced and insufficient to classify this variant as pathogenic or benign. The variant remains a Variant of Uncertain Significance (VUS) per ACMG/AMP 2015 guidelines.⁷