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Background: Hypomorphic mutations in the phosphoacetylglucosamine mutase 3 (PGM3) gene cause a glycosylation disorder that leads to immunodeficiency. It is often associated with recurrent infections and atopy. The exact etiology of this condition remains unclear. Objective: This study aimed to characterize the phenotypes and immunological features associated with PGM3 insufficiency and investigate potential disease mechanisms. Methods: A systematic review of 44 published cases of PGM3 variants was performed, followed by T-cell phenotyping of two patients with PGM3 variants. A genotype-phenotypic severity study was conducted by comparing the residual PGM3 expression of the 12 reconstituted variants in human B cells. A PGM3 inhibitor was used to assess its effect on CD4+ T cell proliferation and differentiation. Results: Patients with PGM3 variants frequently presented with recurrent infections and atopy, accompanied by reduced naïve CD4+ T cell counts. A genotype–phenotype study showed that low levels of residual PGM3 expression are correlated with disease severity. Notably, inhibition of PGM3 activity impaired TCR-mediated CD4+ T cell proliferation and the synthesis of UDP-GlcNAc, complex N-glycans, O-GlcNAc, glycolytic stress, and mitochondrial respiration during proliferation in a dose-dependent manner. Partial loss of PGM3 activity was observed to preferentially enhance Th1 and Th2 differentiation, while attenuating Th17 and Treg differentiation, consistent with clinical observations. Conclusion: PGM3 is a critical regulator of CD4+ T-cell proliferation and differentiation. These findings provide new insights into the diverse clinical manifestations and therapeutic development of PGM3 deficiency. [ABSTRACT FROM AUTHOR]