C282Y

C282Y is a missense mutation in the HFE gene that substitutes tyrosine for cysteine at amino acid position 282 (p.Cys282Tyr). It is one of the most common genetic causes of hereditary hemochromatosis, particularly in people of Northern European descent.

The HFE gene is located on chromosome 6. The C282Y change is commonly described at the cDNA level as c.845G>A, resulting in the amino acid substitution. The mutation impairs trafficking of the HFE protein to the cell surface and disrupts its interaction with transferrin receptor 1, leading to reduced hepcidin regulation and increased intestinal iron absorption.

Inheritance is autosomal recessive. Homozygosity for C282Y is the strongest genetic risk factor for clinically significant iron overload; compound heterozygotes with H63D show variable risk. Penetrance in the general population is incomplete, and many carriers do not develop severe disease. Prevalence varies by ethnicity, with higher frequencies in Northern European populations.

Clinical consequences include progressive iron deposition in the liver, heart, pancreas, and joints. This can lead to cirrhosis and liver cancer, diabetes mellitus, arthritis, and hypogonadism. Biochemical clues are elevated transferrin saturation in early disease and elevated ferritin in established iron overload. Diagnosis is confirmed by genetic testing for HFE mutations.

Management centers on reducing iron stores, most commonly by serial therapeutic phlebotomy to maintain ferritin in a safe range. Chelation therapy may be used in those unsuitable for phlebotomy. Patients should avoid excess iron intake and alcohol, and relatives may be offered genetic counseling and cascade testing.