In summary, our study confirms that bi-allelic SERPINH1 variants result in severe OI and illustrates that the p.(R222S) variant compromises the interaction between HSP47 and type I procollagen, which disturbs the HSP47-mediated quality control of collagen biosynthesis and triggers a cascade of molecular events resulting in altered type I collagen modification and stability. This evidence concerns the gene COL1A2 and osteogenesis imperfecta.