GNA11 c.626A>T (p.Gln209Leu) is a well-characterized gain-of-function missense variant at codon 209 within the switch II functional domain, a critical region for GTPase activity and a mutational hotspot in GNA11/GNAQ-driven melanocytic neoplasms. Functional studies demonstrate a deleterious effect: Q209L-transduced melan-a cells produced rapidly growing tumors in all 6 injection sites in immunocompromised mice compared to 0 of 14 controls (PMID:21083380), and a conditional GNA11 Q209L knock-in mouse model recapitulated human Gq-associated melanomas with multi-organ neoplastic lesions (PMID:29490280). The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada across all populations, yet is recurrently observed in affected tissue: COSMIC reports 442 somatic occurrences, and it has been identified as the predominant codon 209 mutation in uveal melanoma, blue nevi, cutaneous melanoma, and phakomatosis pigmentovascularis.¹ Two clinical laboratories in ClinVar classify this variant as Pathogenic or Likely Pathogenic (variation ID 376002). In silico prediction with REVEL (score 0.833) supports a damaging effect. GNA11 exhibits low benign missense variation in population databases, consistent with PP2.² Applying generic ACMG/AMP 2015 combination rules: PS3 (strong), PM1 (moderate), PS4 (moderate), PM2 (supporting), PP2 (supporting), PP3 (supporting), PP5 (supporting) support a classification of Pathogenic.³