{"gene":{"symbol":"HFE","name":"Homeostatic Iron Regulator","protein":"Hereditary hemochromatosis protein HFE","ncbi_gene_id":"3077","locus":"6p22.2","summary":"HFE encodes a protein that regulates iron absorption by controlling hepcidin production. Two common variants, C282Y and H63D, reduce that control, and carrying two copies of C282Y is the main genetic cause of hereditary hemochromatosis type 1, an iron overload disorder common in Northern European populations. The genotype is common but the disease is not: most C282Y homozygotes never develop iron-related organ disease.","function":"Humans have no active way to excrete excess iron, so the only control point is how much is absorbed in the gut. HFE is part of the sensing system: it works with the transferrin receptor in the liver to gauge circulating iron and signals the liver to produce hepcidin, the master hormone that shuts absorption down when stores are full. When HFE is defective the liver under-produces hepcidin, the gut keeps absorbing iron as though the body were deficient, and the excess is deposited in tissues over decades: liver first, then joints, pancreas, heart and skin. The resulting disease is late-onset and gradual, typically appearing after age 40 in men and later in women, whose iron losses through menstruation and pregnancy delay accumulation. Removing iron by regular blood draws (phlebotomy) prevents the organ damage entirely when started early.","category":"disease_risk","key_variants":[{"rsid":"rs1800562","name":"C282Y (p.Cys282Tyr)","alleles":"Plus strand, GRCh37 (as in 23andMe raw data): G reference, A variant (Cys282Tyr, C282Y).","effect":"Breaks a disulfide bond so the HFE protein never reaches the cell surface. Two copies account for the large majority of hereditary hemochromatosis in people of Northern European ancestry. A single copy is carrier status: relevant to family planning but does not cause iron overload on its own.","frequency_note":"Roughly 1 in 150–400 people of Northern European ancestry are homozygous (about 1 in 230 non-Hispanic white participants in the HEIRS study); carrier frequency is around 1 in 10."},{"rsid":"rs1799945","name":"H63D (p.His63Asp)","alleles":"Plus strand, GRCh37 (as in 23andMe raw data): C reference, G variant (His63Asp, H63D). Strand-ambiguous (C/G): the letters are the same on both strands, so you can't tell which strand a file uses, and a homozygote on the other strand reads as the other allele.","effect":"Far more common worldwide but much milder. H63D/H63D on its own does not cause clinically meaningful iron overload; it matters mainly as a compound heterozygote alongside C282Y.","frequency_note":"Far more common worldwide than C282Y."},{"rsid":null,"name":"C282Y/H63D compound heterozygote","alleles":"One rs1800562 A allele plus one rs1799945 G allele","effect":"May show mildly elevated ferritin or transferrin saturation, but rarely progresses to organ disease without an additional factor such as heavy alcohol use, metabolic liver disease or another condition.","frequency_note":null},{"rsid":"rs1800730","name":"S65C (p.Ser65Cys)","alleles":"Plus strand, GRCh37 (as in 23andMe raw data): A reference, T variant (Ser65Cys, S65C). Strand-ambiguous (A/T): the letters are the same on both strands, so you can't tell which strand a file uses, and a homozygote on the other strand reads as the other allele.","effect":"A third, uncommon variant with a small effect. Occasionally reported in panels; not independently actionable.","frequency_note":"Uncommon."}],"phenotypes":["C282Y/C282Y homozygote: main genetic cause of hereditary hemochromatosis type 1; low clinical penetrance","C282Y heterozygote: carrier status, no iron overload on its own","C282Y/H63D compound heterozygote: mildly raised ferritin or transferrin saturation possible; organ disease rare without a second factor","H63D/H63D: no clinically meaningful iron overload on its own"],"clinical_relevance":"Penetrance is the whole story. Population studies, most notably the HEIRS study and subsequent cohorts, consistently find that while most C282Y homozygotes develop biochemical signs (raised transferrin saturation and ferritin), only a minority go on to clinical organ disease; documented iron-overload disease affects a clear minority of male homozygotes and substantially fewer women. When it does progress: liver fibrosis and cirrhosis, joint pain (classically the second and third knuckles), diabetes, cardiomyopathy and skin bronzing, with fatigue and joint pain usually the earliest complaints. Diagnosis is by blood tests, not genotype: fasting transferrin saturation above roughly 45% together with elevated ferritin prompts investigation, and genotype then explains the cause. Phlebotomy started before organ damage gives a normal life expectancy, making this one of the few genetic findings where early awareness genuinely changes the outcome. Inheritance is autosomal recessive; siblings of a homozygote have a 1-in-4 chance of the same genotype, and cascade testing of first-degree relatives is standard practice.","consumer_array_caveat":"One of the genes consumer data covers well: HFE comes down to two ordinary SNPs, rs1800562 (C282Y) and rs1799945 (H63D), both on essentially every consumer array. Allele reporting conventions differ between services, so the same genotype can appear written differently depending on strand orientation. A consumer array result is not a clinical test: before anything is acted on medically it should be confirmed alongside ferritin and transferrin saturation by a clinician. Two C282Y copies in raw data are a reason for a simple, inexpensive blood test, not for alarm.","drugs":[],"sources":[{"label":"MedlinePlus — HFE gene","url":"https://medlineplus.gov/genetics/gene/hfe/"},{"label":"GeneReviews — HFE Hemochromatosis","url":"https://www.ncbi.nlm.nih.gov/books/NBK1440/"},{"label":"dbSNP rs1800562","url":"https://www.ncbi.nlm.nih.gov/snp/rs1800562"},{"label":"NCBI Gene 3077","url":"https://www.ncbi.nlm.nih.gov/gene/3077"},{"label":"EASL Clinical Practice Guidelines on haemochromatosis, J Hepatol 2022","url":"https://pubmed.ncbi.nlm.nih.gov/35662478/"},{"label":"Allen et al., N Engl J Med 2008 (iron-overload-related disease in C282Y homozygotes)","url":"https://pubmed.ncbi.nlm.nih.gov/18199861/"},{"label":"Adams et al., N Engl J Med 2005 (HEIRS: hemochromatosis and iron-overload screening)","url":"https://pubmed.ncbi.nlm.nih.gov/15858186/"},{"label":"Ensembl GRCh37 rs1800562 (1000 Genomes phase 3 population frequencies)","url":"https://grch37.ensembl.org/Homo_sapiens/Variation/Population?v=rs1800562"}],"related_blog":"/blog/what-to-do-with-23andme-raw-data/","disclaimer":"Educational information only, not medical advice or diagnosis. Consult a clinician before acting on genetic information."},"meta":{"disclaimer":"Educational information only, not medical advice or diagnosis. Consult a clinician before acting on genetic information.","api_version":"2026-09-20","docs":"https://deepdna.ai/docs/","status":"live","data_as_of":"2026-10-25T21:32:19.251Z","freshness":"https://deepdna.ai/api/v1/freshness"}}