What are the possible HFE gene mutations that a patient may have?
After two decades of intensive research, the genetic complexity of hereditary hemochromatosis is still unfolding. The majority of hereditary hemochromatosis cases are due to C282Y homozygosity.


  • The C282Y mutation, caused by a guanine to adenine transition at nucleotide 845 (TGC—TAC), results in the substitution of cysteine (C) by tyrosine (Y) at amino acid position 282 in the HFE protein product.
  • The C282Y mutation alters HFE protein structure, disrupting its transport to and presentation on the cell surface.

C282Y HFE Mutation

Normal HFE Gene compared to C282Y Mutation
The C282Y mutation, caused by a guanine (G) to Adenine (A) transition, results in the substitution of cysteine by tyrosine in the HFE protein.


  • The H63D mutation results in the substitution of histidine (H) by aspartate (D) at amino acid position 63 in the HFE protein.
  • The H63D mutation does not appear to prevent cell-surface expression, indicating that the C282Y mutation causes a greater loss of protein function than does H63D.

Other HFE Gene Mutations

  • In addition to C282Y and H63D, more than 10 other missense mutations that cause amino acid substitutions have been documented. A missense mutation indicates a change in DNA, resulting in an amino acid substitution.
  • In one, a substitution of cysteine (C) by serine (S) at amino acid position 65 (S65C) is implicated in a very mild form of hereditary hemochromatosis in rare instances.
  • Other mutations have been described in HFE but most are very low frequency.
  • There may be HFE gene mutations that have yet to be identified, or mutations in other iron-regulating genes that have not been determined. Because of this, having a negative genetic test does not rule out potential significant iron overload or future risk of iron overload.

(Bomford A, 2002; Mura C, 1999; Pointon JJ, 2000; Wallace DF, 2002; Waheed A, 1997)

Note: Amino acid substitutions are given with the standard single-letter notation for amino acids: (tyrosine-Y, cysteine-C, histidine-H, aspartate-D, senine-S) (Umek RM 2001)