CLDN16 encodes claudin-16, a tight junction protein that coassembles with CLDN19 to form cation-selective paracellular channels in the kidney. In the thick ascending limb of Henle's loop, CLDN16 facilitates sodium reabsorption from the lumen to the interstitium, establishing a lumen-positive potential that drives paracellular magnesium and calcium reabsorption. Biallelic loss-of-function mutations in CLDN16 cause familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC), characterized by renal magnesium wasting, hypercalciuria, nephrocalcinosis, and progressive chr3 kidney disease 1. Monoallelic variants in CLDN16 predispose to nephrolithiasis; among unselected adult kidney stone formers, 8 of 64 carriers of loss-of-function variants had CLDN16 mutations 2. Beyond renal disease, CLDN16 is upregulated in several cancers, including breast cancer, papillary thyroid cancer, and ovarian cancer, where it associates with aggressive features and may serve as a diagnostic biomarker 3, 4, 5. Currently, no disease-specific therapy targets CLDN16; management of FHHNC relies on supportive care including fluid intake, dietary restriction, magnesium supplementation, thiazides, and citrate, with kidney transplantation as the only curative option for end-stage renal disease 1.