EIF1AX c.43G>T (p.Gly15Cys) is a missense variant located at a statistically significant mutational hotspot (cancerhotspots.org) within the N-terminal eIF1A functional domain critical for translation initiation (PM1_Moderate).¹ The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada across all populations, meeting PM2 at moderate strength.² Multiple lines of in silico evidence suggest no impact on gene product: SpliceAI predicts no splicing alteration (max delta = 0.00), and BayesDel score is negative (-0.143281), consistent with a tolerated/benign prediction (BP4_Supporting).³ No variant-specific functional data were identified. OncoKB notes no reviewed functional evidence for this variant, and the sole linked publication (PMID:31275557) is a pan-cancer splicing mutation resource that does not mention this variant.⁴ ClinVar variation 4484138 has 0 submissions, no classification, and no review status, providing no clinical classification data for this variant (PS5/PP5/BP6 not met).⁵ Overall, 2 moderate pathogenic criteria (PM1, PM2) and 1 supporting benign criterion (BP4) are met. Under the generic ACMG/AMP 2015 classification rules (PMID:25741868), this combination is insufficient to reach Likely Pathogenic (requires ≥3 moderate or 2 moderate + ≥2 supporting) and is also insufficient for Likely Benign (requires ≥1 strong benign + ≥1 supporting benign or ≥2 supporting benign). The variant is classified as a Variant of Uncertain Significance (VUS).⁶