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Signaling through the hematopoietic receptors requires activation of receptor‐associated Janus (Jak) kinases. For example, Jak1 and Jak3 bind specifically to the IL‐2 receptor beta (IL‐2Rβ) and common gamma (γ c) chains, respectively, and initiate biochemical signals critical in controlling immune responses. The region of Jak responsible for receptor interactions, however, is not well characterized. Here we describe a naturally occurring Jak3 mutation from a patient with autosomal severe combined immunodeficiency (SCID), where a single amino acid substitution, Y100C, in Janus homology domain 7 (JH7) prevents kinase–receptor interaction. This mutation also results in a loss of IL‐2‐induced signaling in a B‐cell line derived from this patient. Using mutational analysis we have identified a region of Jak3, including portions of JH6 and JH7, that is sufficient for kinase–receptor contact and show that this segment …