CD320 is a transmembrane receptor that mediates cellular uptake of transcobalamin-bound vitamin B12, playing a critical role in cobalamin metabolism. The protein is expressed on follicular dendritic cells and functions as a B cell costimulator, promoting B cell proliferation and differentiation during germinal center responses. CD320 is also expressed on the apical membrane of intestinal and renal epithelial cells, suggesting roles in B12 absorption and reabsorption. At the population level, CD320 variants show low constraint (LoF-tolerant); however, clinical pathogenicity emerges in specific contexts. Biallelic loss-of-function variants cause reduced cobalamin uptake in fibroblasts and modest elevation of newborn screening markers in affected individuals 1. Notably, autoantibodies targeting CD320 cause tissue-specific vitamin B12 central deficiency affecting the brain despite normal serum B12 levels, leading to progressive neurologic deficits including tremor, ataxia, and cognitive decline; immunosuppressive therapy and high-dose B12 supplementation restore CNS B12 and improve symptoms 2. Anti-CD320 autoantibodies have been detected in patients with neuropsychiatric lupus and systemic sclerosis, suggesting broader autoimmune relevance 3. CD320 is also overexpressed in multiple cancers and represents a potential therapeutic target using B12-conjugated drugs or CD320-directed antibodies 4.