ARHGAP22 is a Rho GTPase-activating protein that functions as a Rac1-specific GAP, converting active GTP-bound Rac to its inactive GDP-bound state 1. Unlike related family members, ARHGAP22 localizes predominantly at endosomes rather than lamellae, where it is transported to the plasma membrane via Rab11-dependent endosomal recycling to inactivate Rac and suppress lamellipodia formation and cell spreading 12. The protein contains an N-terminal pleckstrin homology (PH) domain required for both Rac-GAP activity and plasma membrane localization, and a C-terminal region critical for endosomal targeting 32. ARHGAP22 regulates actin cytoskeleton dynamics by inhibiting Rac-dependent cell morphology changes 1. Disease relevance includes associations with invasive melanoma, where hypermethylation of ARHGAP22 characterizes invasive cells and metastatic samples 4. Genetic variants in ARHGAP22 are associated with type 2 diabetes risk and progression, with the rs3844492 G allele linked to diabetic kidney disease, decreased glomerular filtration rate, and elevated creatinine 56. Additionally, rs76208937 shows suggestive association with anti-MDA5-positive dermatomyositis susceptibility 7. These findings indicate ARHGAP22's roles in cell motility control and metabolic disease pathogenesis.