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Here, we report an infant patient who is compound-heterozygous for p.His134Pro and p.Leu194Pro mutations in ORAI1 and whose T cells have strongly reduced SOCE. Whereas the p.Leu194Pro mutant ORAI1 protein is not expressed at the plasma membrane, the p.His134Pro mutation results in a constitutively open channel that is unresponsive to activation by stromal interaction molecule 1. The patient suffered from a severe form of combined immunodeficiency, hemophagocytic lymphohistiocytosis, and fatal chronic cytomegalovirus infection. His immunodeficiency was characterized by an altered composition of T and NK cell compartments, impaired stimulation-induced cytokine production and signs of CD4+ T cell and NK cell activation, but attenuated CD8+ T effector memory cell function. Our findings demonstrate that small constitutive SOCE through a mutant ORAI1 channel is not sufficient to provide immunity to viral infection.<\/jats:p>","DOI":"10.70962\/jhi.20250097","type":"journal-article","created":{"date-parts":[[2025,9,25]],"date-time":"2025-09-25T06:21:24Z","timestamp":1758781284000},"update-policy":"https:\/\/doi.org\/10.70962\/jhi.crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["<i>ORAI1<\/i>\n                    mutation with mixed loss- and gain-of-function properties causes immunodeficiency and HLH"],"prefix":"10.70962","volume":"1","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1369-684X","authenticated-orcid":true,"given":"Lucile","family":"Noyer","sequence":"first","affiliation":[{"name":"New York University Grossman School of Medicine 1 Department of Pathology, , New York, 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