Allele‐Specific GNAQ Q209 Mutations Reveal Context‐Dependent Oncogenic Programs in Uveal Melanoma

ABSTRACT Uveal melanoma (UM) is driven by activating GNAQ/GNA11 mutations, predominantly at the hotspot Q209 residue. However, the functional impact of distinct GNAQ Q209 substitutions on downstream signaling and malignant progression remains unclear. Using immune‐competent, multistep UM mouse models combining eye‐restricted mutant GNAQ with BAP1 loss and MYC activation, we directly compared GNAQ Q209L and GNAQ Q209R in an otherwise matched genetic context. Tumors arising from either allele shared similar histology and cell‐state composition. However, GNAQ Q209L tumors progressed faster and were associated with reduced survival. In contrast, GNAQ Q209R tumor‐derived cell lines exhibited greater ex vivo fitness (proliferation, clonogenicity, and migration), whereas GNAQ Q209L ‐derived lines were relatively fragile in 2D culture. At the molecular level, GNAQ Q209R tumors preferentially engaged the FAK‐YAP axis in primary lesions and derived cell lines. Together, these results support an allele‐dependent, context‐specific trade‐off in which higher output GNAQ Q209L favors rapid in vivo expansion, while GNAQ Q209R promotes adaptability, potentially via FAK‐YAP signaling, nominating allele‐stratified therapeutic opportunities.