PHLDB1 (pleckstrin homology-like domain family B member 1) encodes a cytoplasmic protein containing a pleckstrin homology domain that binds phosphatidylinositol lipids (PI(3,4)P₂, PI(3,5)P₂, and PI(3,4,5)P₃) 1. Primary function involves enhancing insulin-stimulated Akt phosphorylation and glucose transporter 4 (GLUT4) translocation in adipocytes; PHLDB1 depletion by siRNA inhibits insulin-stimulated Akt activation and glucose uptake 1. The protein translocates from the cytoplasm to the plasma membrane upon insulin stimulation and functions as a modulator of Akt kinase activation 1. Biallelic frameshift variants in PHLDB1 cause autosomal recessive osteogenesis imperfecta (OI-23), a mild-type skeletal disorder characterized by recurrent fractures, osteopaenia, and platyspondyly 2. Pathogenic variants result in decreased PHLDB1 expression levels in blood and fibroblasts 2. Additionally, PHLDB1 polymorphisms associate with increased glioblastoma and glioma risk; the rs498872 variant increases glioma susceptibility across multiple genetic models 3. PHLDB1 also shows altered serum levels in systemic lupus erythematosus patients, serving as a potential systemic SLE biomarker 4. Finally, PHLDB1 variants are associated with nonfunctional pituitary adenoma risk in the Korean population 5.