ARHGEF12 (Rho guanine nucleotide exchange factor 12) is a GEF that activates RhoA GTPase and may regulate GNA12 and GNA13 signaling. In tight junction-forming endothelial cells, ARHGEF12 selectively activates Rap1A to maintain vascular barrier integrity in response to inflammatory stress 1. The gene regulates actin stress fiber organization and endothelial mechanotransduction. ARHGEF12 carries significant disease associations across multiple cancer types. In gastric cancer with ovarian metastasis, the E620K mutation activates Rap1 signaling to promote tumor-derived exosome formation and pre-metastatic niche establishment 2. In bladder cancer, elevated ARHGEF12 expression drives cisplatin resistance through RhoA/ROCK-dependent PI3K/Akt pathway activation 3. ARHGEF12 knockdown promotes neuroblastoma differentiation and MYCN degradation via RhoA/ROCK/GSK3β signaling, with the small molecule inhibitor Y16 showing antitumor effects 4. Loss-of-function variants in ARHGEF12 are enriched in patients with congenital heart disease, particularly those with extracardiac manifestations 5. Beyond oncology, ARHGEF12 contributes to airway physiology and ophthalmology. IL17A-induced airway hyperresponsiveness depends on ARHGEF12-mediated RhoA activation, and Arhgef12-knockout mice show decreased airway contractility in allergic sensitization 6. Variants in ARHGEF12 are associated with primary open-angle glaucoma and exfoliation syndrome risk in genome-wide association studies [PMID:38242088; 77]. Arhgef12 mutations modify retinal dysplasia severity in CRB1-associated disease, altering photoreceptor and glial cell organization 8.