Taken together, our findings provide mechanistic insight into assembly of the IGF/IGFBP3/ALS ternary complex and its disassembly for IGF bioavailability and allow us to interpret the structural effects of IGF1 and ALS mutations in ACLSD and IGF1 deficiency (OMIM #608747). Here, IGF1 is linked to short stature due to primary acid-labile subunit deficiency.