Calcium signaling is essential for lymphocyte activation, with genetic disruptions of store-operated calcium (Ca²⁺) entry resulting in severe immunodeficiency. The inositol 1,4,5-trisphosphate receptor (IP₃R), a homo- or heterotetramer of the IP₃R1-3 isoforms, amplifies lymphocyte signaling by releasing Ca²⁺ from endoplasmic reticulum stores following antigen stimulation. Although knockout of all IP₃R isoforms in mice causes immunodeficiency, the seeming redundancy of the isoforms is thought to explain the absence of variants in human immunodeficiency. In this study, we identified compound heterozygous variants of ITPR3 (a gene encoding IP₃R subtype 3) in two unrelated Caucasian patients presenting with immunodeficiency. To determine whether ITPR3 variants act in a nonredundant manner and disrupt human immune responses, we characterized the Ca²⁺ signaling capacity, the lymphocyte response, and the clinical phenotype of these patients. We observed disrupted Ca²⁺ signaling in patient-derived fibroblasts and immune cells, with abnormal proliferation and activation responses following T-cell receptor stimulation. Reconstitution of IP₃R3 in IP₃R knockout cell lines led to the identification of variants as functional hypomorphs that showed reduced ability to discriminate between homeostatic and induced states, validating a genotype-phenotype link. These results demonstrate a functional link between defective endoplasmic reticulum Ca²⁺ channels and immunodeficiency and identify IP₃Rs as diagnostic targets for patients with specific inborn errors of immunity. These results also extend the known cause of Ca²⁺-associated immunodeficiency from store-operated entry to impaired Ca²⁺ mobilization from the endoplasmic reticulum, revealing a broad sensitivity of lymphocytes to genetic defects in Ca²⁺ signaling.

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