MMACHC burden variants are associated with higher circulating vitamin B12 in the All of Us cohort

Heterozygous carriers of autosomal recessive disease variants are often considered clinically unaffected, yet population biobanks can reveal measurable carrier phenotypes. MMACHC (MIM: 609831) encodes an intracellular cobalamin-processing protein. Bi-allelic MMACHC loss causes cobalamin C (cblC) disease, with methylmalonic acid (MMA) and homocysteine (Hcy) accumulation. Because Mmachc heterozygous mice show elevated MMA and Hcy,1 we asked whether MMACHC heterozygosity leaves a detectable biochemical signature in humans.