SLC11A2
protein-codingsolute carrier family 11 member 2, the group of Solute carrier family 11
Gene summary
This gene encodes a member of the solute carrier family 11 protein family. The product of this gene transports divalent metals and is involved in iron absorption. Mutations in this gene are associated with hypochromic microcytic anemia with iron overload. A related solute carrier family 11 protein gene is located on chromosome 2. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Apr 2010]
- NRAMP2
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~49.2 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0008787
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0008787
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0008787
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0008787
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0008787
Submitter: ClinGen
Executive Summary SLC11A2: **SLC11A2, anemia, hypochromic microcytic with iron overload (MONDO:0000104), autosomal recessive** SLC11A2 was first described as an anemia, hypochromic microcytic, with iron overload 1-causing gene in 2005 (PMID: 15459009, Mims et al. 2005). The specific disease entity, Anemia, hypochromic microcytic, with iron overload 1 (MONDO:0000104, OMIM:600523), is one of at least two known forms of microcytic hypochromic anemia and twenty known forms of microcytic anemia. Some of the most common patient phenotypes are: Hypochromic microcytic anemia, Increased circulating iron concentration, Anemia, Elevated transferrin saturation, Elevated hepatic iron concentration, Microcytic anemia, Increased circulating ferritin concentration, Pallor, Decreased circulating ferritin concentration, Decreased mean corpuscular hemoglobin concentration, Reticulocytosis, Hypochromia. Twelve variants: (Missense (9), Splice Site (2) & Multi_Frame Deletion (1)) that have been reported in 9 probands in 8 publications (PMIDs: 16439678, 16160008, 15459009, 35457224, 21871825, 19553145, 23016933 and 29178181) are included in this curation. Many of the probands were diagnosed during childhood after experiencing symptoms including Hypochromic microcytic anemia, Increased circulating iron concentration, Anemia, Elevated transferrin saturation, Elevated hepatic iron concentration and Microcytic anemia. Family history tended to be unremarkable. Siblings of the probands were generally found to be unaffected although there were instances of asymptomatic carrier siblings, a brother who had a haematological phenotype similar to one of the probands and a previous sibling to a proband that died intrauterine at week 39 presenting cardiomegaly and fetal ascites. Overall, the mechanism of pathogenicity appears to be loss of function as shown in the probands. This gene-disease relationship is also supported by multiple forms of experimental evidence such as Model System: Mouse (Mus musculus) (Quantity: 1), Model System: Rat (Rattus norvegicus domestica) (Quantity: 1), BioChem B (Quantity: 1), (PMIDs: 15849611, 24795636 and 9448300). First, a mouse model that has anemia and elevated hepatic iron concentration recapitulates the anemia and elevated hepatic iron concentration found in the human probands (Gunshin et al. 2015, PMID: 15849611). Then, Veuthey et al. 2014 captured a rat model with the phenotypes of microcytosis, anisocytosis and poikilocytosis that recapitulates the phenotypes found in the human probands (PMID: 24795636). Lastly, Fleming et al. 1998 (PMID: 9448300) describes an experiment where the expressing wild-type SLC11A2 gives HEK293T cells the ability to transport iron. In conclusion, SLC11A2 is definitively associated with anemia, hypochromic microcytic, with iron overload 1-causing gene. This classification has been clearly demonstrated and confirmed through both experimental and genetic evidence and has been upheld over time. This classification was approved by the General IEM GCEP on April 25th, 2025 (SOP Version 11).
Inheritance Pattern: AR
Disease ID:MONDO:0008787
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Hematologic
Intervention: Hematologic
Rationale: Individuals can require RBC transfusions and erythropoietin treatment; As hepatic iron overload is common, awareness may allow monitoring and adjustment of treatments and surveillance accordingly
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to SLC11A2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000617.3. 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 | 6 | 16 | 22 | |||
| missense | 3 | 67 | 3 | 3 | 76 | |
| nonsense | 1 | 1 | ||||
| start loss | 0 | |||||
| frameshift | 1 | 1 | ||||
| splice donor/acceptor (+/-2bp) | 3 | 3 | ||||
| Total | 3 | 1 | 77 | 19 | 3 | 103 |
Highest pathogenic variant AF is 0.0000027365397
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000608.1 | 15 | MANE Select | |
| Ensembl | ENSP00000262052.5 | 15 | MANE Select | |
| RefSeq | NP_001167596.1 | 16 | Standard | |
| RefSeq | NP_001167597.1 | 16 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| slc11a2 | Danio rerio | Structure: erythroid lineage cell Quality: decreased amount abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Lysosome - Homo sapiens (human)
- Mineral absorption - Homo sapiens (human)
- Ferroptosis - Homo sapiens (human)
- Iron metabolism in placenta
- Copper homeostasis
Biological Process
- response to hypoxia
- heme biosynthetic process
- cobalt ion transport
- copper ion transport
- iron ion transport
Molecular Function
- copper ion transmembrane transporter activity
- iron ion transmembrane transporter activity
- manganese ion transmembrane transporter activity
- iron ion binding
- copper ion binding
Cellular Component
- nucleus
- cytoplasm
- mitochondrion
- mitochondrial outer membrane
- lysosomal membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000394904
- Coding exons
- 16
- Length
- 49166
- Individuals with no LoFs
- 125722
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 25
- Defined
- 125747
- p
- 0.0000994
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.23 | 213 | 326 | 0.653 | 0.0000174 | 3806 |
| Missense (PolyPhen) | 46 | 106.96 | 0.43007 | 1240 | ||
| Synonymous | -0.0107 | 119 | 119 | 1.00 | 0.00000615 | 1206 |
| Loss of Function | 3.63 | 10 | 32.3 | 0.310 | 0.00000163 | 371 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00012 | 0.00012 | rare |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.00016 | 0.00016 | rare |
| South Asian | 0.00013 | 0.00013 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Important in metal transport, in particular iron. Can also transport manganese, cobalt, cadmium, nickel, vanadium and lead. Involved in apical iron uptake into duodenal enterocytes. Involved in iron transport from acidified endosomes into the cytoplasm of erythroid precursor cells. May play an important role in hepatic iron accumulation and tissue iron distribution. May serve to import iron into the mitochondria. {ECO:0000269|PubMed:17109629, ECO:0000269|PubMed:24448823, ECO:0000269|PubMed:25326704, ECO:0000269|PubMed:25491917}.;
- Disease
- DISEASE: Anemia, hypochromic microcytic, with iron overload 1 (AHMIO1) [MIM:206100]: A hematologic disease characterized by abnormal hemoglobin content in the erythrocytes which are reduced in size. The disorder is due to an error of iron metabolism that results in high serum iron, massive hepatic iron deposition, and absence of sideroblasts and stainable bone marrow iron store. Despite adequate transferrin-iron complex, delivery of iron to the erythroid bone marrow is apparently insufficient for the demands of hemoglobin synthesis. {ECO:0000269|PubMed:15459009, ECO:0000269|PubMed:16160008, ECO:0000269|PubMed:16439678}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.382
Intolerance Scores
- LoFtool
- 0.697
- RVIS EVS
- 0.31
- RVIS percentile EVS
- 72.6
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.795
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |