Blood group antigens are the archetypal example of human genetic variation. Here, we characterised the functional metabolic consequences in individuals homozygous for a 17bp deletion in SMIM1 (rs566629828; minor allele frequency 0.0147) and thus lacking the protein defining the Vel blood group. Our analysis, in separate cohorts of SMIM1-/- individuals (UK Biobank, NHS Blood and Transplant, Danish Blood Donor Study, Copenhagen Hospital Biobank) and a mouse model, identified an increase in body weight accompanied by a range of metabolic differences, including dyslipidemia, changes in the leptin-adiponectin ratio, increased liver enzymes and lower total thyroid hormone levels. These changes in the metabolic state were at least in part due to a reduction in resting energy expenditure, as assessed during an in-depth clinical assessment of SMIM1-/- individuals. Additionally, electronic health records suggest that individuals lacking this 78-amino-acid type II transmembrane protein may be more prone to cerebral bleeds and thrombotic stroke.