RAPGEF5 is a guanine nucleotide exchange factor that activates RAP1A, RAP2A, and MRAS small GTPases, regulating fundamental cellular processes including cell adhesion, migration, and signal transduction 1. The protein functions during mammalian embryogenesis and is critical for proper nervous system development 1. RAPGEF5 mutations are associated with both neurological disorders and congenital heart disease 1. A disruptive insertion in the RAPGEF5 gene is linked to idiopathic epilepsy in canines through disruption of Wnt-β-catenin signaling, which is essential for normal brain function 2. In human disease, RAPGEF5 variants show significant associations with multiple primary melanoma risk 3 and with sporadic amyotrophic lateral sclerosis susceptibility 4. Additionally, the circular RNA form of RAPGEF5 (circ-RAPGEF5) has emerged as an oncogenic factor in intrahepatic cholangiocarcinoma and colorectal cancer, promoting tumor progression through miRNA sponging mechanisms 56. In diabetic cardiac pathology, RAPGEF5 expression changes contribute to exaggerated post-myocardial infarction remodeling through effects on cardiomyocyte apoptosis and proliferation 7.