COL3A1 encodes the alpha-1 chain of type III collagen, a major extracellular matrix protein found predominantly in soft connective tissues including blood vessel walls, uterus, and bowel 1. Three alpha-1 chains form the characteristic triple-helical collagen molecule. Type III collagen functions as a structural component conferring tensile strength to hollow organs and participates in blood clotting and wound healing 1. Beyond structural roles, COL3A1 serves as a major ligand for ADGRG1 in developing brain, where binding inhibits neuronal migration via RhoA pathway activation. Mutations in COL3A1 cause vascular Ehlers-Danlos syndrome (vEDS), a severe autosomal dominant disorder characterized by arterial aneurysm, dissection, rupture, and bowel rupture 2. Glycine substitutions and splice-site mutations produce the most severe phenotypes, with median age at first complication of 23 years and median survival of 48-51 years 34. Mutation type significantly influences disease severity and prognosis; variants causing haploinsufficiency or affecting protein termini show milder courses 3. Most deaths result from arterial rupture 5. Beyond vEDS, COL3A1 upregulation contributes to pathological fibrosis in inflammatory bowel disease and acquired immunotherapy resistance in lung cancer through physical barrier formation 67.