TMEM258 is a transmembrane subunit of the oligosaccharyl transferase (OST) complex that catalyzes N-linked protein glycosylation in the endoplasmic reticulum (ER) 1. As a component of OST-A, TMEM258 interacts with catalytic subunit STT3A and facilitates ribosome binding through a four-helix bundle structure, enabling cotranslational glycan transfer onto nascent secretory proteins 1. All OST subunits, including TMEM258, are required for maximal enzyme activity 2. Mechanistically, TMEM258 is essential for ER quality control and intestinal homeostasis. Tmem258 haploinsufficiency in mice causes severe intestinal inflammation during colitis, while homozygous deficiency in colonic organoids triggers unresolved ER stress and apoptosis 2. Beyond its enzymatic role, TMEM258 modulates immune infiltration networks, positively correlating with M1 macrophages and plasma cells while negatively correlating with neutrophils and naïve CD8+ T cells 3. Clinically, TMEM258 represents a shared susceptibility gene for Crohn disease and acute pancreatitis co-morbidity, increasing AP risk in CD patients by reducing T cell infiltration 3. Genetic variants in TMEM258 also associate with colorectal cancer risk through CD4+ T cell gene expression changes 4 and modulate serum lipid levels through adipose tissue transcriptional regulation 5. Additionally, TMEM258 genetic variants link to polyunsaturated fatty acid metabolism perturbations associated with cancer risk 6.