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HFE C282Y

A DNA test for the most common gene change behind hereditary hemochromatosis, a condition where the body absorbs too much iron. Having two copies does not always lead to iron overload.

AI-verified against cited sources. Awaiting expert reviewAlso called C282YLOINC 21695-2

What it is

The HFE gene helps your body control how much iron it absorbs from food. C282Y is a change in HFE that swaps one building block (cysteine for tyrosine) in the HFE protein. You inherit one copy of HFE from each parent. If both copies carry C282Y (called homozygous), your body can absorb too much iron over many years. Among people of European descent, two copies of C282Y account for most cases of hereditary hemochromatosis. The test is a DNA test on a blood sample, and the result is usually not detected, heterozygous (one copy, a carrier) or homozygous (two copies). Labs often report C282Y together with H63D, another common HFE change.

Why it matters

Extra iron mainly builds up in the liver and, over time, can contribute to diabetes and joint problems. Finding it early and treating it can prevent complications such as liver scarring (cirrhosis), liver cancer, diabetes and joint damage. This gene result does not tell you how much iron you have. That is what the blood tests ferritin and transferrin saturation show, and clinicians read them together with this result. Many people with two copies of C282Y never become ill. In one large Australian study that followed people for about 12 years, iron-overload-related disease developed in about 28 of every 100 men but only about 1 of every 100 women with two copies. Because most people with the gene change stay healthy, experts do not recommend testing the general population for it.

If it’s high

One copy (heterozygous) makes you a carrier. Carriers are not expected to develop progressive iron overload from C282Y alone, although they can pass the change to their children. Two copies (homozygous) raise the chance of iron overload, but how much iron builds up differs a lot from person to person, and some people with two copies never have raised iron tests. Your clinician reads the result together with your ferritin and transferrin saturation. One C282Y copy plus one H63D copy (compound heterozygous) is linked to somewhat higher iron levels in some people, but iron-overload-related disease was rare in the one large study that looked.

Common causes

  • Inherited, one gene copy from each parent. Two copies means both parents passed on C282Y
  • About 4 in 1,000 non-Hispanic white adults in a US screening study had two copies. It was much less common in other groups

What can help

  • Ask your clinician whether ferritin and transferrin saturation should be checked, and how often
  • Ask whether close relatives, such as brothers, sisters, parents or children, should be tested. Liver-disease guidelines recommend checking first-degree relatives of someone with HFE-related hemochromatosis
  • Ask whether iron-containing supplements are right for you
  • Ask how alcohol and other liver conditions could affect your liver together with extra iron

If this applies to you

HFE C282Y means a little more for some people. Open the one that fits you.

Hemochromatosis or iron overload

About 80% of people of European origin with hemochromatosis have two copies of C282Y, EASL notes. ACG also counts one C282Y plus one H63D, while EASL asks for more proof for that pairing, such as liver iron on MRI. ACG recommends screening family members, especially first-degree relatives.

Blood tests for hemochromatosis

What can affect your result

  • Sex and age: men usually develop symptoms between ages 40 and 60, and women usually after menopause
  • Ancestry: much more common in people of northern European descent than in other groups
  • Other liver conditions, such as fatty liver disease, hepatitis C or alcohol-related liver disease, can add to liver damage
  • Iron blood tests that go with this result can shift for other reasons, such as menopause, fatty liver disease or alcohol-related liver disease
  • A past bone marrow transplant from a donor can interfere with the DNA test
  • A previous bone marrow transplant from a donor will interfere with the test, because the DNA may come from the donor's cells (Mayo Clinic Laboratories).
  • The gene result does not change with food, supplements or illness. The iron blood tests that go with it can shift for other reasons, such as menopause, fatty liver disease or alcohol-related liver disease.

Your result is fixed at birth and does not change.

When to talk to a clinician

A gene result alone is not an emergency. If you carry two copies of C282Y, talk with your clinician about iron tests soon. Guidelines use a ferritin level of 1,000 ng/mL (1,000 µg/L) as a dividing line: below it, advanced liver scarring is unlikely, and above it clinicians look more closely at the liver. Contact your clinician if you have ongoing tiredness, joint pain, belly pain, or yellowing of the skin or eyes.

Questions you could ask

  • How often should my iron levels be rechecked?
  • Could my alcohol use, supplements or other conditions change how I should think about this result?
  • What do my ferritin and transferrin saturation say about the iron in my body?
  • Do I need any other tests, such as liver checks or imaging?
  • Should my brothers, sisters, parents or children be tested?

Questions people ask

I have two copies of C282Y. Will I get iron overload disease?

Not necessarily. Many people with two copies have raised iron tests, but only some develop illness from iron. In an Australian study, about 28 of every 100 men and about 1 of every 100 women with two copies had iron-overload-related disease after about 12 years. Your clinician can check your ferritin and transferrin saturation to see where you stand.

I have one copy. Do I need to do anything?

Carriers are not expected to develop progressive iron overload from C282Y alone, according to US liver-disease guidelines. You can pass the change to your children. If your iron tests are raised, another cause, such as a liver condition, may matter more than the gene change, so mention the result to your clinician.

What does C282Y/H63D mean?

It means you have one C282Y copy and one H63D copy, called compound heterozygous. Some people with this result have somewhat higher iron levels, especially women after menopause. In a large study that followed people for about 12 years, iron-related illness was rare: 1 of 82 men and none of 95 women. Your clinician reads the result with your iron tests.

Show the science and sources

For clinicians and researchers

The variant is HFE c.845G>A, p.Cys282Tyr (rs1800562, NM_000410). C282Y homozygotes account for 80 to 85% of typical hereditary hemochromatosis patients, and about 85 to 90% of patients with inherited iron overload are homozygous, with a small minority being C282Y/H63D or C282Y/S65C compound heterozygotes (AASLD 2011). AASLD notes that about 30% of C282Y homozygotes show no phenotypic expression in cross-sectional studies and about 70% have raised ferritin, so general population screening is not indicated; it recommends HFE testing when transferrin saturation is 45% or higher or ferritin is above the upper limit, and recommends iron studies plus HFE analysis for first-degree relatives of an affected person. Ferritin below 1,000 µg/L at diagnosis predicts the absence of cirrhosis (AASLD 2011) and identifies people at low risk of advanced fibrosis (ACG 2019). The 2022 EASL guideline allows a diagnosis of haemochromatosis in C282Y homozygotes with provisional iron overload (transferrin saturation above 45% and ferritin above 200 µg/L in females, above 50% and 300 µg/L in males and postmenopausal women); other HFE genotypes need hepatic iron overload shown by MRI or liver biopsy. In the HEIRS study of 99,711 adults, 299 were C282Y homozygous; prevalence was 0.44% in non-Hispanic white participants versus 0.11% in Native Americans, 0.027% in Hispanics, 0.014% in black participants, 0.012% in Pacific Islanders and 0.000039% in Asians, and among homozygotes without a prior diagnosis, ferritin exceeded 300 µg/L in 88% of men and 200 µg/L in 57% of women (Adams 2005). In 31,192 northern Europeans followed about 12 years, iron-overload-related disease was documented in 28.4% (95% CI 18.8-40.2) of male and 1.2% (0.03-6.5) of female homozygotes (Allen 2008). Compound heterozygotes are about 2% of northern Europeans (range 1.7 to 4.1%), roughly four times as common as homozygotes (about 1 in 200); in the same cohort 1 of 82 male and 0 of 95 female compound heterozygotes had documented iron-overload-related disease, though ferritin rose in women as they went through menopause (Gurrin 2009). Mayo Clinic Laboratories offers HFET by droplet digital PCR with an interpretive report and no numeric reference range, states it is useful to confirm hereditary hemochromatosis in adults, to test people with raised transferrin saturation and ferritin and for predictive testing with a family history, and that it is not recommended for population screening. Mayo reports the test under LOINC 34519-9.

LOINC 21695-2 (primary), 34519-9, 21694-5. Specimen: whole-blood.

Sources

  1. HFE gene, MedlinePlus Genetics, National Library of Medicine
  2. Hereditary hemochromatosis, MedlinePlus Genetics, National Library of Medicine
  3. Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases, Hepatology (2011)
  4. EASL Clinical Practice Guidelines on haemochromatosis, Journal of Hepatology (2022)
  5. ACG Clinical Guideline: Hereditary Hemochromatosis, American Journal of Gastroenterology (2019)
  6. Hemochromatosis and iron-overload screening in a racially diverse population (HEIRS Study), New England Journal of Medicine (2005)
  7. Iron-overload-related disease in HFE hereditary hemochromatosis, New England Journal of Medicine (2008)
  8. HFE C282Y/H63D compound heterozygotes are at low risk of hemochromatosis-related morbidity, Hepatology (2009)
  9. Hereditary Hemochromatosis, HFE Variant Analysis, Varies (test HFET), Mayo Clinic Laboratories (Extended Catalog, testcatalog.org)
  10. dbSNP record for rs1800562 (HFE c.845G>A, p.Cys282Tyr) (NCBI Variation Services API), NCBI dbSNP
  11. LOINC 21695-2 (NLM Clinical Tables API), National Library of Medicine / Regenstrief Institute

AI-verified against cited sources. Awaiting expert review. Last reviewed 2026-10-03. How we build and check these pages.

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