CLDN16 (claudin 16) is a tight junction protein that forms paracellular cation-selective channels by coassembling with CLDN19, enabling epithelial ion permeability 1. In the thick ascending limb of Henle's loop, CLDN16 facilitates sodium paracellular permeability and the lumen-positive transepithelial potential necessary for magnesium and calcium reabsorption 2. Biallelic loss-of-function mutations in CLDN16 cause familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC), characterized by severe renal magnesium wasting, hypercalciuria, nephrocalcinosis, and progressive renal failure 3. CLDN16 mutations account for approximately 1% of genetic kidney stone disease in adult populations 4. Beyond renal physiology, CLDN16 is significantly upregulated in several cancers including breast, papillary thyroid, and ovarian cancers, where it correlates with aggressive features and metastatic potential 5 6 7. In papillary thyroid cancer, CLDN16 demonstrates superior diagnostic accuracy (ROC=0.922) compared to the standard BRAF-V600E mutation (ROC=0.742) 6. CLDN16 expression in ovarian cancer is modulated by PI3K and PKC signaling pathways 7, suggesting potential therapeutic targeting opportunities.