ARHGAP15 encodes a Rho GTPase-activating protein that inactivates Rac1 by catalyzing GTP hydrolysis to the GDP-bound state. 1 The protein functions as a negative regulator of small GTPase signaling in the cytoplasm and plasma membrane, influencing cell shape and cytoskeletal dynamics through actin stress fiber regulation. ARHGAP15 demonstrates significant disease relevance across multiple conditions. In breast carcinoma, ARHGAP15 acts as a tumor suppressor, with higher expression correlating with decreased recurrence risk and improved prognosis; expression is induced by androgens. 1 In diverticular disease, the ARHGAP15 rs4662344 variant associates strongly with both diverticulosis and diverticulitis susceptibility (OR=1.23, P=1.9×10⁻¹⁸), 2 with heterozygous genotypes reducing colonic ARHGAP15 expression. 3 The gene variant also associates with chondromalacia risk (OR=3.70, P=1.4×10⁻⁸). 4 Additionally, ARHGAP15 emerged as a loneliness-related switch gene overlapping with genetic risk factors for schizophrenia and major depressive disorder. 5 Clinically, ARHGAP15 represents a prognostic biomarker in breast cancer and a genetic risk factor in gastrointestinal disease, though the specific mechanisms linking ARHGAP15 variants to diverticular disease pathogenesis remain incompletely understood. 6 Further investigation of ARHGAP15's role in colonic neuromuscular function and psychiatric phenotypes is warranted.