HFE
protein-codinghomeostatic iron regulator, the group of C1-set domain containing
Gene summary
The protein encoded by this gene is a membrane protein that is similar to MHC class I-type proteins and associates with beta2-microglobulin (beta2M). It is thought that this protein functions to regulate iron absorption by regulating the interaction of the transferrin receptor with transferrin. The iron storage disorder, hereditary haemochromatosis, is a recessive genetic disorder that results from defects in this gene. [provided by RefSeq, May 2022]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~11.1 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0021001
Submitter: ClinGen
*HFE*, also known as *HLA-H*, was first reported in relation to autosomal recessive hemochromatosis type 1 in 1996 (Feder et al., PMID:8696333). Hemochromatosis type 1 is characterized by defective regulation of dietary iron absorption resulting in excessive iron accumulation in the body. The disease presents biochemically as elevated serum transferrin-iron saturation and serum ferritin. Patients can be diagnosed and treated for the disease based on the biochemical profile before the onset of clinical manifestations. Clinical manifestations include cirrhosis, liver fibrosis, diabetes mellitus and restrictive cardiomyopathy. At least nine variants, all missense except for one nonsense, have been reported in humans. Two common variants of low penetrance are specifically associated with this disease: C282Y and H63D. It is estimated that 80% or more hemochromatosis type 1 cases carry the C282Y variant. Evidence supporting this gene-disease relationship includes case-level data, case-control data, segregation data, and experimental data. This gene-disease relationship is supported by animal models, expression studies, and in vivo functional assays (PMIDs:1467310, 9482913, 25970244, 9122230, 10756356). RNA sequencing and patient tissue staining both show expression of *HFE* in the liver, small intestine and spleen which are all relevant tissues to the disease (PMIDs:25970244, 9122230). Immunocytochemistry of C282Y/C282Y patient cells also shows that the expression of *HFE *on the cell surface of leukocytes is decreased as compared to wildtype (PMID:10756356). A knockout mouse recapitulates the human phenotype: abnormally high transferrin saturation and excessive iron accumulation in the liver (PMID:9482913). A knockin of the C282Y/H63D and H63D/H63D genotypes also demonstrated results consistent with the biochemical and histopathological results seen in humans with the same genotype (PMID:14673107). More evidence is available in the literature, but the maximum score for experimental evidence (6 pts.) has been reached. Variants in this gene have been reported in hundreds of probands in more than 20 publications (PMIDs:16979952, 18762941, 39568488, 10575540, 38560130, 40034140, 11565552, 11336458, 18809761, 15366698, 37069863, 32153640, 30339210, 9687253, 8696333). Variants in this gene segregated with disease in over 100 additional family members. This gene-disease relationship has been studied in at least one case-control study (PMID:8696333) at the aggregate variant level. All of Us also reports on the association of *HFE* genotypes with hemochromatosis phenotypes (PMID:40034140). More evidence is available in the literature, but the maximum score for genetic evidence and/or experimental evidence (12 pts.) has been reached. In summary, there is definitive evidence to support the relationship between HFE and autosomal recessive hemochromatosis type 1. This evidence has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen General Inborn Errors of Metabolism Gene Curation Expert Panel on the meeting date June 27, 2025 (SOP Version 11).
Inheritance Pattern: AR
Disease ID:MONDO:0009061
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0021001
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0021001
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0021001
Submitter: Laboratory for Molecular Medicine
This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.
Inheritance Pattern: AR
Disease ID:MONDO:0021001
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0021001
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0021001
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Biochemical; Cardiovascular; Endocrine; Gastrointestinal; Hematologic
Intervention: Biochemical; Gastrointestinal; Hematologic
Rationale: Interventions such as phlebotomy (including when presymptomatic) and dietary measures may be effective, though there is some controversy regarding specifics
Comments: Heterozygotes may display mild manifestations in some circumstances; Digenic inheritance (with HAMP) has been described
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to HFE variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000410.4. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 1 | 100 | 101 | |||
| missense | 1 | 4 | 92 | 6 | 103 | |
| nonsense | 12 | 7 | 2 | 21 | ||
| start loss | 0 | |||||
| frameshift | 8 | 3 | 2 | 13 | ||
| splice donor/acceptor (+/-2bp) | 2 | 11 | 1 | 14 | ||
| Total | 23 | 25 | 98 | 106 | 0 | 252 |
Highest pathogenic variant AF is 0.000043778822
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000401.1 | 6 | MANE Select | |
| Ensembl | ENSP00000417404.1 | 6 | MANE Select | |
| RefSeq | NP_001287678.1 | 6 | Standard | |
| RefSeq | NP_001371093.1 | 7 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Hfe effect on hepcidin production
- Transferrin endocytosis and recycling
- Transport of small molecules
- Iron uptake and transport
Biological Process
- antigen processing and presentation of peptide antigen via MHC class I
- negative regulation of T cell antigen processing and presentation
- negative regulation of T cell cytokine production
- cellular iron ion homeostasis
- acute-phase response
Molecular Function
- signaling receptor binding
- protein binding
- beta-2-microglobulin binding
- co-receptor binding
- peptide antigen binding
Cellular Component
- extracellular space
- early endosome
- plasma membrane
- integral component of plasma membrane
- external side of plasma membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000357618
- Coding exons
- 6
- Length
- 11063
- Individuals with no LoFs
- 125698
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 49
- Defined
- 125747
- p
- 0.000195
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.633 | 165 | 190 | 0.871 | 0.0000105 | 2263 |
| Missense (PolyPhen) | 61 | 68.531 | 0.8901 | 882 | ||
| Synonymous | 0.757 | 67 | 75.4 | 0.889 | 0.00000420 | 680 |
| Loss of Function | 0.961 | 14 | 18.5 | 0.759 | 9.01e-7 | 190 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.00026 | 0.00026 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.0013 | 0.0013 | notable |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00011 | 0.00011 | rare |
| South Asian | 0.00013 | 0.00013 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Binds to transferrin receptor (TFR) and reduces its affinity for iron-loaded transferrin. {ECO:0000269|PubMed:9465039}.;
- Disease
- DISEASE: Hemochromatosis 1 (HFE1) [MIM:235200]: A disorder of iron metabolism characterized by iron overload. Excess iron is deposited in a variety of organs leading to their failure, and resulting in serious illnesses including cirrhosis, hepatomas, diabetes, cardiomyopathy, arthritis, and hypogonadotropic hypogonadism. Severe effects of the disease usually do not appear until after decades of progressive iron loading. {ECO:0000269|PubMed:10094552, ECO:0000269|PubMed:10194428, ECO:0000269|PubMed:10401000, ECO:0000269|PubMed:10575540, ECO:0000269|PubMed:11423500, ECO:0000269|PubMed:11446670, ECO:0000269|PubMed:12542741, ECO:0000269|PubMed:12584229, ECO:0000269|PubMed:12737937, ECO:0000269|PubMed:14633868, ECO:0000269|PubMed:15046077, ECO:0000269|PubMed:15965644, ECO:0000269|PubMed:18157833, ECO:0000269|PubMed:8696333, ECO:0000269|PubMed:9024376, ECO:0000269|PubMed:9106528, ECO:0000269|PubMed:9620340, ECO:0000269|Ref.25}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Variegate porphyria (VP) [MIM:176200]: A form of porphyria. Porphyrias are inherited defects in the biosynthesis of heme, resulting in the accumulation and increased excretion of porphyrins or porphyrin precursors. They are classified as erythropoietic or hepatic, depending on whether the enzyme deficiency occurs in red blood cells or in the liver. Variegate porphyria is the most common form of porphyria in South Africa. It is characterized by skin hyperpigmentation and hypertrichosis, abdominal pain, tachycardia, hypertension and neuromuscular disturbances. High fecal levels of protoporphyrin and coproporphyrin, increased urine uroporphyrins and iron overload are typical markers of the disease. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Iron overload due to HFE variants is a precipitating or exacerbating factor in variegate porphyria.; DISEASE: Microvascular complications of diabetes 7 (MVCD7) [MIM:612635]: Pathological conditions that develop in numerous tissues and organs as a consequence of diabetes mellitus. They include diabetic retinopathy, diabetic nephropathy leading to end- stage renal disease, and diabetic neuropathy. Diabetic retinopathy remains the major cause of new-onset blindness among diabetic adults. It is characterized by vascular permeability and increased tissue ischemia and angiogenesis. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.730
Intolerance Scores
- LoFtool
- 0.406
- RVIS EVS
- 0.08
- RVIS percentile EVS
- 60.31
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.826
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |