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The abnormal vascular structures of hereditary hemorrhagic telangiectasia (HHT) often cause severe anemia due to recurrent hemorrhage, but HHT causal genes do not predict the severity of hematological complications. We tested for chance inheritance and clinical associations of rare deleterious variants in which loss-of-function causes bleeding or hemolytic disorders in the general population. In double-blinded analyses, all 104 patients with HHT from a single reference center recruited to the 100 000 Genomes Project were categorized on new MALO (more/as-expected/less/opposite) sub-phenotype severity scales, and whole genome sequencing data were tested for high impact variants in 75 HHT-independent genes encoding coagulation factors, or platelet, hemoglobin, erythrocyte enzyme, and erythrocyte membrane constituents. Rare variants (all gnomAD allele frequencies <0.003) were identified in 56 (75%) of these 75 HHT-unrelated genes. Deleteriousness assignments by Combined Annotation Dependent Depletion (CADD) scores >15 were supported by gene-level mutation significance cutoff scores. CADD >15 variants were identified in 38/104 (36.5%) patients with HHT, found for 1 in 10 patients within platelet genes; 1 in 8 within coagulation genes; and 1 in 4 within erythrocyte hemolytic genes. In blinded analyses, patients with greater hemorrhagic severity that had been attributed solely to HHT vessels had more CADD-deleterious variants in platelet (Spearman ρ = 0.25; P = .008) and coagulation (Spearman ρ = 0.21; P = .024) genes. However, the HHT cohort had 60% fewer deleterious variants in platelet and coagulation genes than expected (Mann-Whitney test P = .021). In conclusion, patients with HHT commonly have rare variants in genes of relevance to their phenotype, offering new therapeutic targets and opportunities for informed, personalized medicine strategies., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)