SLC40A1
protein-codingsolute carrier family 40 member 1, the group of Solute carrier family 40
Gene summary
The protein encoded by this gene is a cell membrane protein that may be involved in iron export from duodenal epithelial cells. Defects in this gene are a cause of hemochromatosis type 4 (HFE4). [provided by RefSeq, Jul 2008]
- SLC11A3
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~23.2 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0011631
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0011631
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0011631
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0011631
Submitter: ClinGen
*SLC40A1* (a.k.a FPN1, MTP1, and IREG1) was first reported in relation to autosomal dominant hemochromatosis type 4 in 2001 (Njajou et al., PMID:11431687). Hemochromatosis type 4 is an iron overload disorder where patients present with a clinical manifestation classified into one of groups: (1) an early onset rise in ferritin levels with low to normal transferrin saturation and iron accumulations, particularly in macrophages; (2) high ferritin levels with high transferrin saturation and prominent parenchymal iron loading (OMIM:#606069). 25 variants (24 missense, 1 in frame deletion) that have been reported in 21 probands in nine publications (PMIDs: 12857562, 12730114, 38886778, 16111902, 11518736, 25744502, 33385755, 24714983, 11431687, 29237594) are included in this curation. No predicted or proven null variants are included in this curation, but functional evidence showing a loss of protein function and a mislocalization of the gene product has been demonstrated for several variants (PMIDs: 24714983, 33385755, 29237594). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss of function, with some variants contributing a hypothesized gain-of-function effect (PMID: 24714983). This gene-disease relationship is also supported by animal models, model rescues, expression studies, protein interaction, and biochemical function (PMIDs: 10747949, 38508867, 38508867, 10693807, 16054062). The human phenotype has been recapitulated in a mouse model with targeted mutagenesis (PMID: 16054062). A hypochromic phenotype has been rescued in deficient zebrafish with treatment with a plasmid expressing the gene (PMID: 10693807). This gene’s protein product binds to HAMP as a part of its regulation, which has been curated by this group to have a definitive relationship with a hemochromatosis phenotype (PMID: 38508867). This protein is expressed in the relevant tissues to the disease (PMID: 38508867). The biochemical function, cellular iron export, is consistent with the disease phenotype, iron accumulation in cells (PMID:10747949). In summary, there is definitive evidence supporting the relationship between *SLC40A1* and autosomal dominant hemochromatosis type 4. This 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 GCEP on the meeting date March 27, 2026 (SOP Version 12).
Inheritance Pattern: AD
Disease ID:MONDO:0011631
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0011631
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Biochemical; Cardiovascular; Endocrine; Gastrointestinal; Hematologic
Intervention: Biochemical; Gastrointestinal; Hematologic
Rationale: Phlebotomy may be beneficial in some individuals, but genetic diagnosis may be useful to direct treatment regimens, as some indviduals may have reduced tolerance to phlebotomy and can become anemic on therapy despite persistently elevated serum ferritin
Comments: Biallelic variants (with other hemochromatosis-related genes, such as HFE) have been reported
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to SLC40A1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_014585.6. 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 | 69 | 5 | 75 | ||
| missense | 18 | 23 | 120 | 19 | 2 | 182 |
| nonsense | 3 | 2 | 5 | |||
| start loss | 0 | |||||
| frameshift | 2 | 2 | ||||
| splice donor/acceptor (+/-2bp) | 6 | 6 | ||||
| Total | 18 | 28 | 129 | 88 | 7 | 270 |
Highest pathogenic variant AF is 0.000097889184
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_055400.1 | 8 | MANE Select | |
| Ensembl | ENSP00000261024.3 | 8 | MANE Select | |
| Ensembl | ENSP00000390005.1 | 6 | Standard | |
| Ensembl | ENSP00000392730.1 | 2 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| slc40a1 | Danio rerio | Structure: nucleate erythrocyte Quality: decreased amount abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Mineral absorption - Homo sapiens (human)
- Ferroptosis - Homo sapiens (human)
- Iron metabolism in placenta
- Transport of bile salts and organic acids, metal ions and amine compounds
- SLC-mediated transmembrane transport
Biological Process
- lymphocyte homeostasis
- endothelium development
- cellular iron ion homeostasis
- regulation of transcription from RNA polymerase II promoter in response to iron
- iron ion transmembrane transport
Molecular Function
- iron ion transmembrane transporter activity
- protein binding
- ferrous iron transmembrane transporter activity
- peptide hormone binding
- identical protein binding
Cellular Component
- nucleoplasm
- cytoplasm
- cytosol
- plasma membrane
- integral component of plasma membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000261024
- Coding exons
- 8
- Length
- 23180
- Individuals with no LoFs
- 125743
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 5
- Defined
- 125748
- p
- 0.0000199
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.92 | 213 | 308 | 0.692 | 0.0000158 | 3698 |
| Missense (PolyPhen) | 33 | 93.106 | 0.35443 | 1174 | ||
| Synonymous | 1.17 | 100 | 116 | 0.862 | 0.00000635 | 1191 |
| Loss of Function | 4.25 | 3 | 26.7 | 0.113 | 0.00000167 | 271 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000035 | 0.000035 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: May be involved in iron export from duodenal epithelial cell and also in transfer of iron between maternal and fetal circulation. Mediates iron efflux in the presence of a ferroxidase (hephaestin and/or ceruloplasmin).;
Recessive Scores
- pRec
- 0.258
Intolerance Scores
- LoFtool
- 0.0890
- RVIS EVS
- 0.33
- RVIS percentile EVS
- 73.41
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.812
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |