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Early B cells develop centrally and then migrate peripherally to mediate the essential immune functions of antigen presentation, immune regulation, and immunoglobulin production. B cell development is tightly regulated, ensuring the generation of distinctive B cell clones, each carrying a fixed B cell receptor and therefore antigen specificity. Defects in B cell development can underlie a variety of clinical phenotypes, including immunodeficiency, autoimmunity, and B cell leukemia. The study of human genetic variation has enabled the discovery of critical pathways for immune cell development, differentiation, and generation of immune repertoire diversity. Here, we focus on the complete allelic spectrum impacting central B cell development, including rare and common genetic variation, to shed light on unique and shared mechanisms underlying predisposition to B cell lymphopenia, autoimmunity, and leukemia.