Cancer-associated mutations in the guanosine triphosphatase (GTPase) RHOA are found at different locations from the mutational hotspots in the structurally and biochemically related RAS. Tyr ⁴² -to-Cys (Y42C) and Leu ⁵⁷ -to-Val (L57V) substitutions are the two most prevalent RHOA mutations in diffuse gastric cancer (DGC). RHOA ^Y42C exhibits a gain-of-function phenotype and is an oncogenic driver in DGC. Here, we determined how RHOA ^L57V promotes DGC growth. In mouse gastric organoids with deletion of Cdh1 , which encodes the cell adhesion protein E-cadherin, the expression of RHOA ^L57V , but not of wild-type RHOA, induced an abnormal morphology similar to that of patient-derived DGC organoids. RHOA ^L57V also exhibited a gain-of-function phenotype and promoted F-actin stress fiber formation and cell migration. RHOA ^L57V retained interaction with effectors but exhibited impaired RHOA-intrinsic and GAP-catalyzed GTP hydrolysis, which favored formation of the active GTP-bound state. Introduction of missense mutations at KRAS residues analogous to Tyr ⁴² and Leu ⁵⁷ in RHOA did not activate KRAS oncogenic potential, indicating distinct functional effects in otherwise highly related GTPases. Both RHOA mutants stimulated the transcriptional co-activator YAP1 through actin dynamics to promote DGC progression; however, RHOA ^L57V additionally did so by activating the kinases IGF1R and PAK1, distinct from the FAK-mediated mechanism induced by RHOA ^Y42C . Our results reveal that RHOA ^L57V and RHOA ^Y42C drive the development of DGC through distinct biochemical and signaling mechanisms.