STEAP3
protein-codingSTEAP3 metalloreductase, the group of STEAP family
Gene summary
This gene encodes a multipass membrane protein that functions as an iron transporter. The encoded protein can reduce both iron (Fe3+) and copper (Cu2+) cations. This protein may mediate downstream responses to p53, including promoting apoptosis. Deficiency in this gene can cause anemia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2015]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~41.8 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0014094
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0014094
Submitter: LiferaOmics
ClinGen classification (AD context) ClinGen has curated STEAP3 – severe congenital hypochromic anemia with ringed sideroblasts under an AD model and classified it as Disputed (04/25/2025). This AD relationship is not scorable for our AR curation, but we note it as contradictory/uncertain monoallelic context. Genetic evidence – Published (AR scope) No scorable published cases of biallelic (autosomal recessive) STEAP3 variants causing a defined “hypochromic microcytic anemia with iron overload” phenotype were identified from the requested PMID. Published genetic evidence total = 0 / 12 Published (AD context; not scored for AR) PMID: 22031863 – Reports 3 siblings with transfusion-dependent hypochromic anemia and iron overload in whom a nonsense STEAP3/TSAP6 variant was identified in the heterozygous state, inherited from the father, with no second variant found in the mother. This is a monoallelic/AD-context report and is not scorable under an autosomal recessive model. AD-context evidence total (not scored for AR) = 0 Genetic evidence – Our case Family 1 – One proband. Case-level (biallelic predicted null in AR model; homozygous stop-gained; no consanguinity deduction applied) = 1.5; Segregation = 0; Case-control = 0 Family 1 total = 1.5 Total genetic evidence (published AR + our case) 1.5 / 12 Experimental evidence – Published (conservative and phenotype-aligned) No experimental evidence found at this time. Experimental evidence total = 0 / 6 Overall score Genetic evidence = 1.5 Experimental evidence = 0 Overall score = 1.5 / 18
Inheritance Pattern: AD
Disease ID:MONDO:0014094
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0014094
Submitter: ClinGen
*STEAP3*, also called *TSAP6*, was first reported in relation to autosomal dominant severe congenital hypochromic anemia with ringed sideroblasts in 2011 (Grandchamp B et al., PMID:22031863). The index family from the original report presented with transfusion-dependent, poorly regenerative anemia and iron overload with onset in early childhood asserted to be caused by a premature termination in *STEAP3* (p.Cys110Ter); the affected siblings also inherited a lowly expressed hypomorphic allele. In a 2015 report by Liu et al. (PMID:26675350) 33 heterozygotes carrying an early termination variant (p.Cys271Ter) were identified and none of them had any significant erythrocyte hematologic phenotype. This report also includes a family where the mother has a missense *STEAP3* variant and no phenotype, the father has a missense variant predicted to be a null variant after transfection in HeLa cells showed completely abrogated iron reduction but has no hematologic phenotype and the couple’s child carries both variants in a compound heterozygous state and has no hematologic phenotype. This gene-disease relationship is supported by expression studies, biochemical function assays and animal models. RNA-seq performed on 27 tissues from 95 individuals shows specific expression of *STEAP3* in the liver (PMID:24309898). Overexpression of *STEAP3* by plasmids in HEK-293T cells showed the ferrireductase activity of *STEAP3* (PMID:16609065). Lespagnol A et al. created a *TSAP6* knockdown mouse model where the mice presented with microcytic, hypochromic anemia (PMID:18617898). A mouse model (nm1054) known to have microcytic, hypochromic anemia was investigated and found to have *STEAP3* through a positional cloning approach. Ferrireductase activity was measured in reticulocytes harvested from the mice. Both mutant and null cells were both found to have reduced activity as compared to the wild-type (PMID:16227996). In summary, the evidence supporting the relationship between STEAP3 and autosomal dominant severe congenital hypochromic anemia has been disputed and no valid evidence remains to support the claim. More evidence is needed to either support or entirely refute the role *STEAP3* plays in this disease. This classification was approved by the ClinGen General Inborn Errors of Metabolism GCEP on the meeting date 25 April, 2025 (SOP Version 11).
Inheritance Pattern: AD
Disease ID:MONDO:0014094
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0014094
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: Unknown
Disease ID:MONDO:0014094
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Endocrine; Hematologic
Intervention: Endocrine; Hematologic
Rationale: Individuals have been described with transfusion-dependent anemia; The condition may involve primary endocrine anomalies, and surveillance for involvement (eg, adrenal failure or thyroid insufficiency) may benefit medical management
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to STEAP3 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_182915.3. 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 | 1 | 25 | 6 | 32 | ||
| missense | 119 | 17 | 4 | 140 | ||
| nonsense | 2 | 1 | 3 | |||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 0 | 0 | 122 | 43 | 10 | 175 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_878919.2 | 5 | MANE Select | |
| Ensembl | ENSP00000376822.2 | 5 | MANE Select | |
| RefSeq | NP_001008410.1 | 4 | Standard | |
| RefSeq | NP_060704.2 | 4 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- p53 signaling pathway - Homo sapiens (human)
- Ferroptosis - Homo sapiens (human)
- Iron metabolism in placenta
- Copper homeostasis
- TP53 Regulates Transcription of Cell Death Genes
Biological Process
- apoptotic process
- cell cycle
- protein secretion
- copper ion import
- transferrin transport
Molecular Function
- protein binding
- cupric reductase activity
- oxidoreductase activity, oxidizing metal ions, NAD or NADP as acceptor
- metal ion binding
- ferric-chelate reductase (NADPH) activity
Cellular Component
- cytoplasm
- endosome
- multivesicular body
- plasma membrane
- endosome membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000393110
- Coding exons
- 5
- Length
- 41845
- Individuals with no LoFs
- 125609
- Homozygous LoFs
- 1
- Heterozygous LoFs
- 138
- Defined
- 125748
- p
- 0.000553
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.224 | 330 | 319 | 1.04 | 0.0000219 | 3176 |
| Missense (PolyPhen) | 147 | 135.66 | 1.0836 | 1350 | ||
| Synonymous | -0.162 | 154 | 151 | 1.02 | 0.0000111 | 1081 |
| Loss of Function | 0.524 | 14 | 16.3 | 0.860 | 6.99e-7 | 180 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00050 | 0.00049 | rare |
| Latino/Admixed American | 0.000087 | 0.000087 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.0038 | 0.0038 | notable |
| Finnish | 0.00057 | 0.00051 | rare |
| European (Non-Finnish) | 0.00026 | 0.00025 | rare |
| South Asian | 0.00049 | 0.00049 | rare |
| Other | 0.00066 | 0.00065 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Endosomal ferrireductase required for efficient transferrin-dependent iron uptake in erythroid cells. Participates in erythroid iron homeostasis by reducing Fe(3+) to Fe(2+). Can also reduce of Cu(2+) to Cu(1+), suggesting that it participates in copper homeostasis. Uses NADP(+) as acceptor. May play a role downstream of p53/TP53 to interface apoptosis and cell cycle progression. Indirectly involved in exosome secretion by facilitating the secretion of proteins such as TCTP. {ECO:0000269|PubMed:15319436, ECO:0000269|PubMed:16651434}.;
- Disease
- DISEASE: Anemia, hypochromic microcytic, with iron overload 2 (AHMIO2) [MIM:615234]: A hematologic disease characterized by abnormal hemoglobin content in the erythrocytes which are reduced in size, severe anemia, erythropoietic hyperplasia of bone marrow, massive hepatic iron deposition, and hepatosplenomegaly. {ECO:0000269|PubMed:22031863}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Intolerance Scores
- LoFtool
- 0.151
- RVIS EVS
- -0.1
- RVIS percentile EVS
- 45.65
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.788
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |