Abstract

COL12A1 SNPs are linked to ACL injury risk, but functional effects are unknown. We examined COL12A1 rs970547 genotype distribution in Chinese male ACL injury patients versus controls, and its impact on collagen homeostasis and fibroblast function. ACL‐derived fibroblasts with rs970547(A/A) or (A/G) were obtained from patients and controls. Collagen synthesis, COL12A1 protein stability, and ER stress were assessed. The (A/A) genotype was over‐represented in ACL patients. It reduced COL12A1 protein levels via destabilization, while increasing total collagen synthesis. This was associated with ER stress induction. Inhibiting ER stress rescued the functional phenotype of (A/A) fibroblasts. COL12A1 rs970547(A/A) disrupts collagen regulation and triggers ER stress, functionally impairing ACL fibroblasts and potentially elevating ACL injury risk. The COL12A1 rs970547(A/A) polymorphism is over‐represented in Chinese male anterior cruciate ligament (ACL) injury patients. This variant destabilizes COL12A1 protein without altering transcript levels, driving compensatory upregulation of other collagen genes and inducing endoplasmic reticulum stress in ACL‐derived fibroblasts. The resulting impairment of fibroblast proliferation, migration, and survival uncovers a novel mechanism linking collagen gene polymorphism to ACL injury susceptibility.