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We report the first human disease caused by a genetic alteration in ThPOK, specifically, a damaging heterozygous de novo variant in ThPOK (NM_001256455.2:c.1080A&amp;gt;C, p.K360N). This patient exhibited the unusual constellation of persistent CD4+ T cell deficiency, allergy, interstitial lung disease, corneal vascularization and scarring, developmental delay, and growth failure. The ThPOKK360N variant displayed abnormal multimorphic activity, interfering with ThPOKWT (antimorph), failing to bind wild-type ThPOK consensus sequences (amorph), and showing novel DNA-binding specificity (neomorph). Single-cell RNA sequencing revealed defects in CD4+ and CD8+ T cell maturation and activation (hypomorph). Recapitulated in lentivirally transduced healthy control T cells and fibroblasts, the transcriptomic analysis showed ThPOKK360N-transduced T cells had impaired TCR activation and ThPOKK360N-transduced fibroblasts with increased profibrotic gene expression. This novel human disease confirms ThPOK\u2019s role in CD4+ T cell development but also uncovers novel roles in TCR activation and regulation of fibrotic pathways in fibroblasts.<\/jats:p>","DOI":"10.1084\/jem.20241174","type":"journal-article","created":{"date-parts":[[2025,3,29]],"date-time":"2025-03-29T02:20:57Z","timestamp":1743214857000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["A multimorphic variant in ThPOK causes an inborn error of immunity with T cell defects and fibrosis"],"prefix":"10.1084","volume":"222","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8734-169X","authenticated-orcid":true,"given":"Maryam","family":"Vaseghi-Shanjani","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03rmrcq20","id-type":"ROR","asserted-by":"publisher"}],"name":"Experimental Medicine Program, Faculty of Medicine, The University of British Columbia 1 , 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