NM_002072.5:c.626A>T (p.Gln209Leu) is a well-characterized gain-of-function missense variant in GNAQ. Multiple independent functional studies demonstrate GTPase deficiency, constitutive activation of downstream MAPK/ERK signaling, and malignant transformation (PS3_strong).¹ The variant is located at codon 209, a statistically significant mutational hotspot in the GTPase domain of GNAQ where multiple pathogenic missense substitutions (Q209L, Q209P, Q209H, Q209R) cluster (PM1).² The variant is absent from all large population databases including gnomAD v2.1, v4.1, and gnomAD-Canada (PM2).³ Other pathogenic missense changes at the same residue (Gln209Pro, Gln209Arg, Gln209His) have been established as pathogenic (PM5).⁴ GNAQ has a low rate of benign missense variation and missense variants at residues 183 and 209 are the established gain-of-function disease mechanism (PP2).⁵ Multiple in silico tools predict a deleterious effect: REVEL score 0.936, BayesDel consistent with damaging prediction (PP3).⁶ ClinVar classifies this variant as Pathogenic (variation ID 375955, one clinical laboratory with criteria provided) (PP5).⁷ Applying the ACMG/AMP 2015 generic combination rules: 1 Strong (PS3) + 3 Moderate (PM1, PM2, PM5) + 3 Supporting (PP2, PP3, PP5) satisfies the threshold for Pathogenic.⁸