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CD33 is thought to be associated with immune cell function, susceptibility to Alzheimer\u2019s disease, and rare leukemias. Antagonism or genetic ablation of <jats:italic>CD33<\/jats:italic> has been proposed to treat Alzheimer\u2019s disease, hematological cancers, and as a selection mechanism for enriching genetically altered blood cells. To understand the impact of chronic CD33 loss or ablation, we describe individuals who we confirmed to be missing <jats:italic>CD33<\/jats:italic> due to germline loss of function variants. Through PheWAS-based approaches using existing whole exome biobanks and bespoke phenotyping using recall-by-genotype (RBG) studies, we show that <jats:italic>CD33<\/jats:italic> loss of function alters circulating white blood cell counts and distributions, albeit mildly and with no overt clinical pathology. These findings indicate that chronic CD33 antagonism\/ablation is likely to be safe in humans.<\/jats:p>","DOI":"10.1371\/journal.pgen.1011600","type":"journal-article","created":{"date-parts":[[2025,3,5]],"date-time":"2025-03-05T18:25:29Z","timestamp":1741199129000},"page":"e1011600","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":3,"title":["Human CD33 deficiency is associated with mild alteration of circulating white blood cell 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