CLPTM1L (CLPTM1 like) functions as a phospholipid scramblase mediating translocation of glucosaminylphosphatidylinositol (GlcN-PI) and other phospholipids across the endoplasmic reticulum membrane, participating in glycosylphosphatidylinositol (GPI) biosynthesis 1. Beyond its canonical GPI-anchoring pathway role 2, CLPTM1L operates in cellular lipid metabolism through interaction with ERLIN2 to stabilize the transcription factor SREBP1, thereby regulating fatty acid synthesis 3. Clinically, CLPTM1L is a well-established cancer susceptibility gene. Genetic variants (rs402710, rs401681, rs2736098) show strong associations with multiple malignancies including lung, bladder, esophageal, gastric, pancreatic, and skin cancers, as well as glioma 45. In nasopharyngeal carcinoma, CLPTM1L overexpression enhances cell proliferation, migration, and invasion through the KLF1/CLPTM1L/ERLIN2/SREBP1 cascade 3. High CLPTM1L expression correlates with poor prognosis in lung cancer patients 6. Additionally, CLPTM1L variants are associated with cervical cancer risk, modulated by HPV infection and DNA methylation 7, and hepatocellular carcinoma susceptibility 8. Enhancer-driven activation of CLPTM1L represents an overlooked disease mechanism, particularly at the CLPTM1L-TERT locus 9.