Introduction: Interleukin-1 receptor-associated kinase 4 (IRAK4) is a key mediator of innate immunity . While loss-of-function mutations cause immunodeficiency , specific hypomorphic variants like the recurrent D320Y are linked to autoinflammatory disease, yet their shared pathogenic mechanism remains unclear. Objective: This study aimed to define the mechanism by which hypomorphic IRAK4 variants,including D320Y and Q29P, drive a paradoxical inflammatory phenotype. Methods: We analyzed immune cells from three new patients carrying the heterozygous IRAK4 D320Y variant. Functional studies reconstituted the D320Y and Q29P variants in IRAK4-deficient cells to assess protein expression, cytokine production, and transcriptomic profiles. Pathway dependency was tested using kinase inhibitors targeting IRAK4, p38 MAPK, and TBK1. Results: Patients with the D320Y variant showed systemic autoinflammation. Their immune cells, along with cells expressing either the D320Y or Q29P variant, exhibited elevated interferon signatures. Both variants reduced IRAK4 protein expression and TLR-induced TNF-? ,confirming hypomorphism. Paradoxically, they enhanced constitutive and ligand-stimulated production of IL-6 and IFN-? . Transcriptomics revealed selective hyperactivation of NF-? B,MAPK, and IRF pathways. This gain-ofsignaling depended on residual IRAK4 kinase activity and was rescued by inhibiting downstream p38 or TBK1. Conclusion: We elucidate a shared pathogenic mechanism for hypomorphic IRAK4 variants:they uncouple TLR responses, enabling constitutive inflammation through selective pathway hyperactivation. This work defines a common disease mechanism and identifies p38 and TBK1 as potential therapeutic targets.