ARHGEF28 encodes a Rho guanine nucleotide exchange factor (RGNEF) that functions as a RHOA-specific GEF regulating signaling downstream of integrins and growth factor receptors. The protein mediates axonal branching, synapse formation, dendritic morphogenesis, focal adhesion formation, and cell motility. ARHGEF28 acts as an NFL mRNA destabilizing factor, binding and affecting neurofilament mRNA stability 1. In amyotrophic lateral sclerosis (ALS), rare coding variants in ARHGEF28 show marginal enrichment in sporadic ALS cases, with the p.Asn1046Ser variant significantly more frequent in patients 2. Frameshift and truncation mutations have been identified in both familial and sporadic ALS cohorts 13. Beyond ALS, ARHGEF28 variants are associated with familial non-medullary thyroid cancer through predicted protein structure alterations and protein-protein interactions involving TP53 and FOXE1 pathways 4. ARHGEF28 also emerges as a prognostic RNA-binding protein in esophageal cancer prognosis models 5 and shows diagnostic potential in psoriasis, where expression is significantly decreased compared to normal skin 6. Recent evidence links ARHGEF28 to alpha-synucleinopathies through RhoA/actin cytoskeleton regulation mechanisms shared with Alzheimer's disease pathways 7. Common variant associations with age-related hearing loss have also been reported 8.