Hereditary hemochromatosis (HFE gene)

The HFE gene sets how much iron your body absorbs. Two variants, a stronger iron-overload one and a milder iron one, combine to set iron-overload risk, so the pair is read together.

What these two variants do

HFE regulates hepcidin, the hormone that tells your gut how much iron to absorb. When HFE is impaired, hepcidin runs low, the intestine keeps absorbing iron as though you were short of it, and the excess is deposited in the liver, pancreas, heart, joints and skin over decades.

C282Y is the strong variant: two copies leave the protein essentially non-functional and account for the large majority of hereditary hemochromatosis in people of Northern European descent. H63D is the mild one, and on its own it rarely causes iron overload. The combination of one C282Y and one H63D is the intermediate case.

Why the genotype is not the disease

This is the most important thing on the page. Carrying two C282Y copies raises iron absorption, but most people with that genotype never develop iron-overload disease. Studies of C282Y homozygotes that specifically assessed liver disease found penetrance in roughly 24% to 43% of men and 1% to 14% of women, and one long-term follow-up recorded documented iron overload in 34% of homozygotes, iron-overload-related disease in 18% and cirrhosis in 6%.

The gap between sexes is largely explained by iron loss through menstruation and pregnancy, which is also why symptoms in women, when they appear, tend to appear later.

The two tests that settle it

Iron status is measured, not inferred. Transferrin saturation and serum ferritin are inexpensive blood tests that show whether iron is actually accumulating, and they are what clinicians act on. A genotype tells you about a tendency; those two numbers tell you where you currently stand.

When iron overload is confirmed, treatment is old, cheap and effective: regular phlebotomy, the removal of blood, drains the excess. Started before organ damage, it gives normal life expectancy, which is why this is one of the few results here where knowing early genuinely changes the outcome.

How common these variants are

In 1000 Genomes reference data, about 13% of European-ancestry individuals carry one C282Y copy and roughly 1 in 190 carry two, while H63D is carried by about 26% and doubled in around 2%. Both are markedly rarer elsewhere: C282Y is close to absent in East Asian samples and uncommon in African and South Asian ones.

That distribution is why hereditary hemochromatosis is sometimes called a Northern European condition, and why a negative result carries different weight depending on your ancestry.

What this pair does not cover

Rarer forms of hereditary hemochromatosis caused by variants in HJV, HAMP, TFR2 and SLC40A1 are not read here, and they can produce iron overload, sometimes earlier and more severely, with an ordinary HFE result.

Acquired causes are also outside a DNA file entirely: repeated transfusions, chronic liver disease, alcohol and some anaemias all raise iron. A high ferritin has many explanations besides genetics, including simple inflammation, which is why interpretation belongs with a doctor.

What each HFE result means

No hemochromatosis variant. You don't carry either of the two iron variants, so as far as this gene goes your iron regulation is typical.

Carrier of the milder iron variant (H63D ×1). You carry one copy of the milder iron variant. On its own it usually does nothing, and it mainly matters alongside the stronger iron variant.

Carrier of the stronger iron variant (C282Y ×1). You carry one copy of the stronger iron-overload variant. Carriers are usually healthy with only a slightly higher chance of raised iron, and you can pass it on.

Two copies of the milder iron variant (H63D ×2). You carry two copies of the milder iron variant. On its own this rarely causes problems, though a few people show slightly higher iron measures.

Compound carrier, moderate risk (C282Y ×1, H63D ≥1). You carry one copy of the stronger iron variant and one copy of the milder iron variant together. This carries a moderate, usually mild iron-overload risk, and an iron or ferritin blood test can clarify whether it matters for you.

Higher hemochromatosis risk (C282Y ×2). You carry two copies of the stronger iron-overload variant, the classic genotype for hereditary hemochromatosis (slow iron overload). Many people stay healthy because this doesn't always cause disease, but a simple ferritin and iron blood test is a worthwhile check.

Evidence & sources

This panel reads C282Y (rs1800562) and H63D (rs1799945).

Covers the two iron variants (the stronger and the milder) behind nearly all HFE-related hereditary hemochromatosis, so this pair is close to complete for this gene.

Common questions

I have two C282Y copies. Will I get hemochromatosis? Not necessarily, and most likely not in the severe form. Penetrance for liver disease has been measured at roughly 24% to 43% in men and 1% to 14% in women. The genotype is a reason to have transferrin saturation and ferritin checked, and to repeat them periodically, not a diagnosis.

Is being a C282Y carrier a problem? One copy alone very rarely causes iron overload. Carriers can pass it on, and a carrier result is worth knowing if a partner is also of Northern European ancestry and you are planning a family, but for the carrier's own health it usually means little.

Does H63D cause hemochromatosis? On its own, rarely. Two H63D copies occasionally associate with slightly raised iron measures. The combination that carries real, usually mild, risk is one C282Y with one H63D, which is why the two are read together rather than separately.

Should I avoid iron supplements? Iron supplements and high-dose vitamin C, which increases iron absorption, are worth raising with a doctor if you carry the higher-risk genotypes, but the first step is measuring iron status rather than changing supplements on the basis of a genotype.

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