SGMS2 encodes sphingomyelin synthase 2, an enzyme that catalyzes the reversible transfer of the phosphocholine head group between phosphatidylcholine and ceramide to synthesize sphingomyelin at the plasma membrane. This reaction is reversible and directionally regulated by ceramide and diacylglycerol levels. SGMS2 also transfers phosphoethanolamine to ceramide, forming ceramide phosphoethanolamine. Beyond biosynthesis, SGMS2 regulates signal transduction by controlling the balance of mitogenic diacylglycerol, proapoptotic ceramide, and sphingomyelin—a critical component of membrane rafts that organize signaling complexes—and plays a supporting role in Golgi-mediated secretory transport. SGMS2 is required for normal bone matrix mineralization. Pathogenic heterozygous variants in SGMS2 cause calvarial doughnut lesions with bone fragility, a rare monogenic osteoporosis with onset in childhood or severe congenital presentation depending on variant type; the p.Arg50* nonsense variant yields catalytically inactive enzyme, while p.Ile62Ser and p.Met64Arg enhance de novo sphingomyelin synthesis but impair protein export, each producing distinct severity 1. Bone biopsy demonstrates defective mineralization despite normal osteoclast function 1. Neurological manifestations occur in some patients 2. Beyond skeletal disease, SGMS2 modulates tumor immunity. In pancreatic cancer, elevated SGMS2 promotes sphingomyelin synthesis that enhances PD-L1 localization on membrane lipid rafts, facilitating immune evasion 3. Conversely, in hepatocellular carcinoma, SGMS2-expressing macrophages promote M1-like polarization and recruit NK cells via CXCL2 secretion, correlating with superior PD-1 immunotherapy response 4.