CLPTM1L encodes a scramblase that mediates the translocation of glucosaminylphosphatidylinositol (GlcN-PI) and phosphatidylinositol (PI) across the endoplasmic reticulum membrane, supporting biosynthesis of glycosylphosphatidylinositol (GPI), a lipid modification essential for post-translational protein modification. The protein localizes to the ER membrane via multiple transmembrane domains and can translocate various phospholipids in vitro. CLPTM1L promotes tumorigenesis through multiple mechanisms. In pancreatic cancer cells, CLPTM1L overexpression enhanced growth 1.3–1.5-fold in vitro and 3.46-fold in vivo, and interacts with non-muscle myosin II to promote aneuploidy 1. In nasopharyngeal carcinoma, CLPTM1L is upregulated and cooperates with ERLIN2 to stabilize the metabolic regulator SREBP1, driving proliferation and migration 2. High CLPTM1L expression associates with poor prognosis in lung cancer, and knockdown suppresses cell migration and invasion by reducing matrix metalloproteinase-2 3. Genetic variants in the TERT-CLPTM1L region confer susceptibility across multiple cancer types. Common variants show strong evidence of association with bladder, esophageal, gastric, lung, pancreatic, and skin cancers, as well as glioma and myeloproliferative neoplasms 4. The T alleles of rs401681 and rs402710 are negatively associated with lung cancer risk in Caucasian and Asian populations 5. In cervical cancer, risk variants rs27070 and rs459961 modulate TERT and CLPTM1L expression through altered DNA methylation 6. Enhancer release and retargeting of a cancer-risk enhancer to CLPTM1L represents an overlooked mechanism activating this disease-susceptibility gene 7.