ABCG5 forms an obligate heterodimer with ABCG8 that mediates ATP-dependent sterol transport across cell membranes, playing an essential role in selective excretion of dietary plant sterols and cholesterol from enterocytes into the intestinal lumen and from hepatocytes into bile. This heterodimer is required for normal sterol homeostasis and prevents accumulation of xenosterols in the body. Loss-of-function mutations in ABCG5 cause sitosterolemia, an autosomal recessive disorder characterized by intestinal hyperabsorption and reduced hepatic secretion of cholesterol and plant sterols 1. Affected individuals present with extreme phenotypic heterogeneity ranging from asymptomatic to severe early-onset disease featuring tendon xanthomas, elevated LDL cholesterol, hemolytic anemia with stomatocytosis, macrothrombocytopenia, and premature atherosclerosis 1. At the population level, gnomAD v4.1 classifies ABCG5 as loss-of-function–tolerant (LOEUF=1.22) because heterozygous carriers are viable; this is distinct from clinical pathogenicity in homozygous or compound heterozygous disease contexts where 65 pathogenic variants have been documented. Clinically, sitosterolemia mimics homozygous familial hypercholesterolemia but responds differently to treatment 2. A low-phytosterol diet forms the cornerstone of management 3, with ezetimibe (a sterol absorption inhibitor) providing additional benefit and potentially synergizing with established therapies like atorvastatin 4. Recent evidence identifies ABCG5/G8 upregulation as a mechanism by which ASGR1 inhibition promotes cholesterol excretion, suggesting therapeutic potential for cholesterol-lowering interventions 4.