SGMS2 encodes sphingomyelin synthase 2 (SMS2), a membrane-associated enzyme catalyzing the reversible transfer of phosphocholine from phosphatidylcholine to ceramide, producing sphingomyelin and diacylglycerol 12. The enzyme localizes primarily to the plasma membrane and Golgi apparatus, regulating signal transduction by controlling levels of mitogenic diacylglycerol, proapoptotic ceramide, and sphingomyelin—a key structural component of membrane lipid rafts 23. SGMS2 is essential for normal bone matrix mineralization 4. Pathogenic SGMS2 variants cause calvarial doughnut lesions with bone fragility, a rare autosomal dominant monogenic osteoporosis characterized by low bone mineral density, skull sclerosis, and increased fracture risk, with severity ranging from childhood-onset osteoporosis to severe spondylometaphyseal dysplasia with neonatal fractures 56. Zebrafish knockdown studies confirm SGMS2's critical role in skeletal development and osteogenic cell function 7. Beyond skeletal homeostasis, SGMS2 contributes to tumor immunity: in hepatocellular carcinoma, SGMS2+ macrophages adopt an M1-like phenotype and recruit cytotoxic NK cells via CXCL2 secretion, correlating with improved prognosis and superior PD-1 immunotherapy response 8. In pancreatic cancer, elevated SGMS2 facilitates immune evasion through sphingomyelin-mediated PD-L1 localization on lipid rafts 9. SGMS2 dysregulation also promotes keloid fibroblast proliferation and migration through miR-485-3p pathway modulation 10.