Hereditary hemochromatosis (HH) is an autosomal recessive disorder caused by excess Fe absorption in the gut leading to cirrhosis, cardiac failure, diabetes, hypermelanotic pigmentation of the skin, arthritis, and hepatocellular carcinoma.  HH is the most common genetic disease among people of European ancestry with a prevalence of 0.2%-0.5%.

Two common HFE missense mutations associated with clinical symptoms have been reported.  The clinically most significant mutation, the 845 G ^__> C mutation in exon 4, causes a cysteine to tyrosine substitution at position 282 (C282Y) and is found in the homozygous state in approximately 85% of all clinically affected HH individuals.  Carrier frequencies for the C282Y mutation range from approximately 10% in Northern European populations to near 0% in African and Asian populations.  A clinically milder form of HH is caused by the H63D mutation in exon 2.  The H63D substitution results from a 187 C ^__> G mutation, and is found in approximately 7% of HH probands as the C282Y/H63D compound heterozygous genotype.  This mutation has high carrier frequencies in Northern European and Basque populations, (14% and 30% respectively).  The H63D genotype is associated with even less elevated transferrin saturation in males (33% vs 26%) and as a consequence is rarely found in probands (~1%).

The compound heterozygous genotype involving the H63D substitution exhibits a variably penetrant and mild phenotype and a 7:1 ratio of male to female probands.  In contrast, the C282Y genotype exhibits a highly penetrant and severe phenotype and a 3:1 ratio of male to female probands.  Consequently, the H63D substitution is considered a variant that increases the risk of C282Y carrier males to a clinically mild form of HH.