INPP5E is a phosphatidylinositol phosphatase that hydrolyzes the 5-phosphate of PtdIns(3,4,5)P3, PtdIns(4,5)P2, and PtdIns(3,5)P2, acting specifically on lipid substrates rather than soluble inositol phosphates. The gene plays an essential role in primary cilium assembly and function by controlling ciliary growth, PI3K signaling, and ciliary stability 1. INPP5E also regulates intracellular processes including endocytosis, exocytosis, and vesicular trafficking, with demonstrated roles in embryonic development, neurological function, and immune regulation 2. Mutations in INPP5E cause Joubert and Meckel-Gruber syndromes, characterized by brain malformations, skeletal abnormalities, and polydactyly 2. The gene also contributes to photoreceptor outer segment maintenance; loss of Inpp5e in mice causes outer segment shortening and photoreceptor cell loss 3. Non-syndromic retinal degeneration and macular dystrophy have been associated with INPP5E mutations 4. Additionally, recent multi-omics evidence suggests INPP5E expression changes converge with epigenetic alterations in cocaine use disorder, implicating the gene in prefrontal cortex function 5. At the population level, gnomAD v4.1 classifies INPP5E as LoF-tolerant (LOEUF=1.18); this is distinct from the clinical pathogenicity demonstrated by 79 ClinVar pathogenic/likely pathogenic variants identified in disease contexts.