A study published in *Nature* (2009) reports frequent somatic mutations in the GNAQ gene in blue nevi and uveal melanoma. These mutations occur exclusively in codon 209 of the GNAQ gene and result in constitutive activation, turning GNAQ into a dominant oncogene. The findings suggest an alternative pathway for MAP-kinase activation in melanocytic neoplasia, offering new therapeutic opportunities. Melanocytic neoplasms, including benign nevi and melanomas, originate from melanocytes in epithelial structures. Most show mutations in the MAP-kinase pathway, particularly in BRAF and NRAS. However, some melanocytic neoplasms, such as uveal melanoma and intradermal melanocytic proliferations, do not show these mutations. Uveal melanoma arises from melanocytes in the choroidal plexus and is distinct from cutaneous melanoma due to its high metastatic potential. Intradermal melanocytic proliferations, such as blue nevi and nevus of Ota, can be congenital or acquired and present in various forms. Using a forward genetic screen in mice, researchers identified GNAQ and GNA11 mutations causing skin hyperpigmentation. Sequencing of GNAQ and GNA11 in human melanocytic neoplasms revealed mutations in GNAQ in 83% of blue nevi, 50% of "malignant blue nevi," and 46% of uveal melanomas. These mutations are somatically acquired and occur exclusively at codon 209, which is essential for GTP hydrolysis. GNAQ mutations in humans lead to constitutive activation, similar to mutations in RAS family members. GNAQ $ ^{Q209L} $ was shown to transform human melanocytes and uveal melanoma cells, inducing anchorage-independent growth and abnormal nuclear morphology. Tumorigenicity studies in nude mice confirmed the oncogenic potential of GNAQ $ ^{Q209L} $. GNAQ $ ^{Q209L} $ also activates the MAP-kinase pathway, consistent with findings in uveal melanomas. Knockdown of GNAQ in uveal melanoma cells reduced MAP-kinase activation, growth, and cell survival. The study identifies GNAQ as a novel oncogene in human neoplasia, operating downstream of GPCRs involved in melanocyte homeostasis. GNAQ mutations are linked to nevus of Ota and uveal melanoma, explaining why nevus of Ota is a risk factor for uveal melanoma. However, the risk is low, with only about 1 in 400 nevi of Ota progressing to uveal melanoma. GNAQ mutations are insufficient forA study published in *Nature* (2009) reports frequent somatic mutations in the GNAQ gene in blue nevi and uveal melanoma. These mutations occur exclusively in codon 209 of the GNAQ gene and result in constitutive activation, turning GNAQ into a dominant oncogene. The findings suggest an alternative pathway for MAP-kinase activation in melanocytic neoplasia, offering new therapeutic opportunities. Melanocytic neoplasms, including benign nevi and melanomas, originate from melanocytes in epithelial structures. Most show mutations in the MAP-kinase pathway, particularly in BRAF and NRAS. However, some melanocytic neoplasms, such as uveal melanoma and intradermal melanocytic proliferations, do not show these mutations. Uveal melanoma arises from melanocytes in the choroidal plexus and is distinct from cutaneous melanoma due to its high metastatic potential. Intradermal melanocytic proliferations, such as blue nevi and nevus of Ota, can be congenital or acquired and present in various forms. Using a forward genetic screen in mice, researchers identified GNAQ and GNA11 mutations causing skin hyperpigmentation. Sequencing of GNAQ and GNA11 in human melanocytic neoplasms revealed mutations in GNAQ in 83% of blue nevi, 50% of "malignant blue nevi," and 46% of uveal melanomas. These mutations are somatically acquired and occur exclusively at codon 209, which is essential for GTP hydrolysis. GNAQ mutations in humans lead to constitutive activation, similar to mutations in RAS family members. GNAQ $ ^{Q209L} $ was shown to transform human melanocytes and uveal melanoma cells, inducing anchorage-independent growth and abnormal nuclear morphology. Tumorigenicity studies in nude mice confirmed the oncogenic potential of GNAQ $ ^{Q209L} $. GNAQ $ ^{Q209L} $ also activates the MAP-kinase pathway, consistent with findings in uveal melanomas. Knockdown of GNAQ in uveal melanoma cells reduced MAP-kinase activation, growth, and cell survival. The study identifies GNAQ as a novel oncogene in human neoplasia, operating downstream of GPCRs involved in melanocyte homeostasis. GNAQ mutations are linked to nevus of Ota and uveal melanoma, explaining why nevus of Ota is a risk factor for uveal melanoma. However, the risk is low, with only about 1 in 400 nevi of Ota progressing to uveal melanoma. GNAQ mutations are insufficient for