CD3G encodes the gamma subunit of the T-cell receptor (TCR)-CD3 complex, a critical component of adaptive immunity. As part of the TCR-CD3 signaling complex on T-lymphocyte surfaces, CD3G contains immunoreceptor tyrosine-based activation motifs (ITAMs) that become phosphorylated by Src family kinases upon TCR engagement, initiating downstream signaling cascades essential for T-cell activation 1. Beyond signal transduction, CD3G regulates TCR surface expression through a di-leucine-based sorting motif that controls constitutive receptor cycling. CD3G mutations cause a distinct clinical phenotype compared to other CD3 subunit deficiencies. While homozygous mutations in CD3D and CD3E genes result in severe combined immunodeficiency with complete developmental arrest, CD3G deficiency produces a milder partial T-cell immunodeficiency primarily characterized by autoimmunity 1. This autoimmune manifestation reflects impaired immune tolerance: CD3G-deficient patients exhibit reduced regulatory T-cell diversity and suppressive function, alongside enriched self-reactive T-cell populations 2. Beyond primary immunodeficiency, CD3G expression associates with immune-mediated pathologies including sepsis severity and renal transplant fibrosis 3, 4, suggesting broader roles in immune homeostasis. Genetic variants in CD3G also influence susceptibility to malaria 5, indicating CD3G's importance in infectious disease resistance.