SCNN1G encodes the gamma subunit of the epithelial sodium channel (ENaC), one of three pore-forming subunits that form a heterotrimeric channel complex 1. ENaC mediates electrodiffusion of sodium ions across apical epithelial membranes with osmotic water follow, playing a critical role in sodium homeostasis and fluid balance 2. In kidneys, ENaC performs essential electrogenic sodium reabsorption 3, while in airways, it maintains surface liquid homeostasis necessary for proper mucus clearance 4. SCNN1G mutations cause distinct disease phenotypes: gain-of-function variants in the C-terminal PPPxY motif cause Liddle syndrome, an autosomal dominant monogenic hypertension presenting with early-onset hypertension, hypokalemia, and metabolic alkalosis that responds to ENaC inhibitors 56. Loss-of-function variants cause autosomal recessive pseudohypoaldosteronism, with opposite electrolyte abnormalities 5. Notably, SCNN1G expression is dysregulated in cancer contexts—aberrant downregulation in head and neck squamous cell carcinoma correlates with lymphatic metastasis and poor prognosis 7. Cleaved ENaCγ in urinary extracellular vesicles serves as a biomarker for aldosterone-mediated MR signaling, relevant for primary aldosteronism diagnosis 8.