PXK (PX domain containing serine/threonine kinase like) is a multidomain protein primarily involved in receptor trafficking and immune regulation. The gene encodes multiple splice isoforms with tissue-specific expression patterns 1, with isoforms PXK_v1, PXK_v2, and PXK_v4 widely expressed in adult tissues except heart. PXK localizes to endosomal membranes through its PX domain's binding to phosphatidylinositol 3-phosphate and regulates epidermal growth factor receptor internalization and degradation via modulation of receptor ubiquitination 2. The protein may also modulate Na,K-ATPase function, potentially affecting neuronal excitability. PXK has significant disease relevance in autoimmunity. Genetic variants, particularly rs6445975, show association with systemic lupus erythematosus (SLE) susceptibility in Europeans 3, though this association is not consistent across Asian populations 4. The rs6445975 polymorphism associates with SLE subphenotypes including photosensitivity and anti-Sm antibody production in some populations 4. Fine mapping studies suggest ABHD6, not PXK itself, is the primary susceptibility gene at this locus 5. Additionally, PXK variants show associations with reduced sperm count 6 and possible roles in unexplained recurrent pregnancy loss in women 7, suggesting broader reproductive implications. Notably, PXK likely lacks intrinsic kinase activity despite its catalytic domain structure 1.