Interleukin-1 receptor-associated kinase 4 (IRAK4) is a key signaling mediator downstream of Toll-like/IL-1 receptors (TLR/ IL-1R). While loss-of-function (LOF) IRAK4 mutations cause immunodeficiency with impaired TLR agonist responses, the mechanisms linking IRAK4 variants to autoinflammatory/autoimmune phenotypes remain unclear. Here, we identified novel heterozygous IRAK4 variants in three unrelated families with systemic autoinflammatory symptoms. Patient peripheral immune cells showed elevated type I interferon signatures and inflammatory pathway enrichment, alongside hypomorphic TLR responsiveness mimicking LOF phenotypes. However, reconstitution studies in HEK293T cells and IRAK4-deficient THP-1 cells demonstrated that variants (D320Y , Q29P) triggered constitutive and ligand-enhanced proinflammatory cytokine dysregulation (predominantly IL-6, IFN-