ARHGEF12 is a guanine nucleotide exchange factor (GEF) that activates small GTPases to regulate cell signaling and cytoskeletal dynamics. As a RhoA-GEF, ARHGEF12 promotes Rho protein signal transduction and actin filament organization 1. However, in tight junction-forming endothelial cells, ARHGEF12 selectively activates Rap1A rather than RhoA to protect against TNF-induced capillary barrier disruption 2. ARHGEF12 also activates RhoA/ROCK signaling to drive PI3K/Akt pathway activation, with relevance to chemoresistance and tumor progression 3. Diseases associated with ARHGEF12 variants include primary open-angle glaucoma (POAG), where ARHGEF12 variants represent significant risk loci identified through genome-wide association studies in African ancestry populations 45. ARHGEF12 loci also associate with exfoliation syndrome, a systemic extracellular matrix disorder causing secondary glaucoma 6. Loss-of-function ARHGEF12 variants occur more frequently in congenital heart disease patients with neurodevelopmental delay and extracardiac anomalies 7. The E620K mutation in ARHGEF12 drives gastric cancer metastasis to ovaries through Rap1/ITGA6 signaling and pre-metastatic niche formation 8. In neuroblastoma, ARHGEF12 overexpression maintains tumor malignancy; targeting ARHGEF12 promotes differentiation and MYCN degradation via RhoA/ROCK/GSK3β signaling, suggesting therapeutic potential 9.