GNAS encodes the alpha subunit of stimulatory G proteins (Gsα), which functions as a critical transducer in G protein-coupled receptor (GPCR) signaling pathways 12. The protein alternates between an active GTP-bound state and inactive GDP-bound state, with GPCR activation promoting GDP release and GTP binding, while intrinsic GTPase activity terminates signaling 12. GNAS signaling activates adenylyl cyclases to increase cAMP levels 23 and functions downstream of beta-adrenergic and melanocortin receptors 45. Activating GNAS mutations, particularly R201C and Q227, represent the most frequent mutations among heterotrimeric G proteins in cancer 6. These oncogenic mutations drive intraductal papillary mucinous neoplasms (IPMNs), pituitary adenomas, thyroid tumors, and colorectal cancers 67. In IPMNs, mutant GNAS induces metabolic reprogramming toward enhanced glycolysis and gastric metaplasia 7. Loss-of-function GNAS mutations cause Albright hereditary osteodystrophy, pseudohypoparathyroidism, and severe obesity through impaired GPCR signaling, with variable phenotypes depending on which pathways are affected 58. GNAS imprinting status determines clinical manifestations, as maternal mutations cause greater metabolic complications including obesity and hormone resistance 5.