NM_002072.5:c.289C>T (p.Leu97Phe) is a missense variant in GNAQ, a G protein alpha subunit gene recurrently mutated in uveal melanoma. This variant is extremely rare in population databases, observed in only 2 of 1,613,556 alleles in gnomAD v4.1 (allele frequency 1.24e-06), and is absent from gnomAD v2.1 and gnomAD-Canada v1.0.¹ In silico prediction tools provide supporting evidence for a deleterious effect; REVEL scores the variant at 0.748, above the damaging threshold. BayesDel score is 0.306, which is below commonly used thresholds. SpliceAI predicts no splicing impact.² The variant is absent from ClinVar and has not been reported in the literature as a germline variant. It has been observed in 2 somatic cancer samples in COSMIC (COSV105143328).³ No functional studies, de novo reports, cosegregation data, or case-control data are available for this variant. Residue Leu97 is not within a known GNAQ mutational hotspot (canonical driver residues are Gln209 and Arg183).⁴ The only applicable criteria are PM2 (moderate, based on extreme rarity in population databases) and PP3 (supporting, based on in silico prediction). No other pathogenic or benign criteria are met. With only one moderate criterion (PM2) and one supporting criterion (PP3) met, the overall evidence is insufficient to classify this variant as pathogenic or likely pathogenic under ACMG/AMP 2015 rules. The classification is Variant of Uncertain Significance (VUS).⁵