The first human patient with RAS-related C3 botulinum toxin substrate 2 (RAC2) deficiency was an infant with a neutrophil defect resembling leukocyte adhesion deficiency described in 2000 (Williams DA, Tao W, Yang F et al. Blood 96:1646–1654, 2000; Ambruso DR, Knall C, Abell AN et al. Proc Natl Acad Sci USA 97:4654–4659, 2000). The advent of cost-effective, high throughput sequencing has subsequently led to the identification of more than 50 patients with RAC2 mutations. While each patient is unique, mutations and patient presentations can be grouped by altered RAC2 function including guanine diphosphate (GDP)- guanine triphosphate (GTP) exchange, effector binding, and altered cellular functions. This chapter describes how mutations affect specific RAC2 effectors causing altered cellular functions, disparate patient phenotypes, and lead to a primary immune deficiency which is now recognized as an atypical severe combined immune deficiency (SCID) by the International Union of Immunological Societies (Dvorak CC, Haddad E, Heimall J et al. J Allergy Clin Immunol 151:539–546, 2023).