COL5A1 encodes the alpha-1 chain of type V collagen, a fibrillar collagen that plays crucial roles in connective tissue structure and function. The protein is essential for proper collagen fibril organization and extracellular matrix integrity 1. COL5A1 mutations cause classic Ehlers-Danlos syndrome, with approximately 50% of patients harboring mutations in COL5A1 or COL5A2 genes, typically resulting in haploinsufficiency of type V collagen 1. The gene's polymorphisms significantly influence musculoskeletal injury susceptibility, with variants like rs12722 and rs71746744 affecting tendon-ligament injury risk among Caucasians 23. Functionally, COL5A1 variants affect mechanical properties of collagenous tissues, with certain genotypes showing increased quadriceps muscle-tendon stiffness during moderate contractions 4. Beyond structural roles, COL5A1 is implicated in disease processes, serving as a potential biomarker for aortic dissection when elevated in plasma 5 and being regulated in cancer progression pathways 6. The gene's clinical significance extends to genetic testing specifications for hereditary connective tissue disorders, where null alleles and glycine substitutions are key pathogenic mechanisms 7.