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ASXL1 is an epigenetic modifier not previously linked to an IEI. Clonal hematopoiesis and hematologic neoplasms often feature somatic ASXL1 variants, and Bohring\u2013Opitz syndrome, a neurodevelopmental disorder, is caused by heterozygous truncating ASXL1 variants. We present an IEI caused by biallelic germline missense variants in ASXL1. The patient had a history of hematologic abnormalities and viral-associated complications, including chronic macrocytosis, persistent vaccine-strain rubella granulomas, and EBV-associated Hodgkin lymphoma. Immunophenotyping revealed loss of B cells, hypogammaglobulinemia, and impairments in cytotoxic T and NK cell populations. T cells exhibited skewing toward an exhausted memory phenotype, global DNA methylation loss, and increased epigenetic aging. These aberrations were ameliorated by wild-type ASXL1 transduction, confirming the patient variants\u2019 pathogenicity. 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