ABCG8 encodes a subunit of an obligate heterodimer with ABCG5 that mediates ATP-dependent sterol transport across cell membranes. This transporter limits intestinal cholesterol absorption and promotes biliary secretion of cholesterol and plant sterols, playing an essential role in sterol homeostasis. Common mutations in ABCG8 confer most of the genetic risk for gallstone development, accounting for approximately 25% of total gallstone risk 1. Loss-of-function mutations in ABCG5 or ABCG8 cause sitosterolemia, a rare autosomal recessive disorder characterized by accumulation of plant sterols and cholesterol in blood and tissues, leading to xanthomas, hematological abnormalities, and premature atherosclerosis 2. Recent evidence suggests that even heterozygous carriers of ABCG5/G8 variants show altered lipid profiles and increased cardiovascular risk 3. At the population level, gnomAD classifies ABCG8 as loss-of-function tolerant; however, this population-level constraint is distinct from clinical pathogenicity in sitosterolemia and gallstone disease contexts. Treatment of sitosterolemia focuses on dietary phytosterol restriction combined with the sterol absorption inhibitor ezetimibe, which effectively reduces lipid and phytosterol levels 4. Screening for ABCG5/G8 variants in hypercholesterolemic patients, identified through xenosterol measurement, supports tailored therapeutic intervention 3.