Severe congenital hypochromic anemia with ringed sideroblasts

Summary

Severe congenital hypochromic anemia with ringed sideroblasts (MONDO:0014094) is a disease with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 1
• ClinVar variants: 4
• Phenotypes (HPO): 20

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		3	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

20 HPO clinical features (Orphanet curated; top 20 by frequency):

HPO ID	Term	Frequency
HP:0001896	Reticulocytopenia	Very frequent (80-99%)
HP:0001903	Anemia	Very frequent (80-99%)
HP:0003281	Increased circulating ferritin concentration	Very frequent (80-99%)
HP:0012464	Decreased transferrin saturation	Very frequent (80-99%)
HP:0000027	Azoospermia	Frequent (30-79%)
HP:0000135	Hypogonadism	Frequent (30-79%)
HP:0000864	Abnormality of the hypothalamus-pituitary axis	Frequent (30-79%)
HP:0000980	Pallor	Frequent (30-79%)
HP:0002910	Elevated circulating hepatic transaminase concentration	Frequent (30-79%)
HP:0003452	Increased serum iron	Frequent (30-79%)
HP:0004823	Anisopoikilocytosis	Frequent (30-79%)
HP:0012378	Fatigue	Frequent (30-79%)
HP:0012465	Elevated hepatic iron concentration	Frequent (30-79%)
HP:0025066	Decreased mean corpuscular volume	Frequent (30-79%)
HP:0000821	Hypothyroidism	Occasional (5-29%)
HP:0000846	Adrenal insufficiency	Occasional (5-29%)
HP:0000957	Cafe-au-lait spot	Occasional (5-29%)
HP:0001433	Hepatosplenomegaly	Occasional (5-29%)
HP:0001510	Growth delay	Occasional (5-29%)
HP:0012134	Dysplastic erythropoesis	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	severe congenital hypochromic anemia with ringed sideroblasts
Mondo ID	MONDO:0014094
OMIM	615234
Orphanet	300298
SNOMED CT	725463007
UMLS	C3808920
MedGen	815250
GARD	0017364
Is cancer (heuristic)	no

Also known as: AHMIO2 · anemia, hypochromic microcytic, with iron overload 2 · anemia, hypochromic microcytic, with iron overload type 2 · severe congenital hypochromic sideroblastic anaemia · severe congenital hypochromic sideroblastic anemia

Data availability: 4 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › hematologic disorder › anemia › microcytic anemia › hypochromic microcytic anemia › anemia, hypochromic microcytic with iron overload › severe congenital hypochromic anemia with ringed sideroblasts

Related subtypes (1): microcytic anemia with liver iron overload

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

4 retrieved; paginated sample, class counts are floors:

3 uncertain significance, 1 no classifications from unflagged records

ClinVar	Variant (HGVS)	Gene	Classification	Review
3892567	NM_182915.3(STEAP3):c.1215+2771C>G	STEAP3	Uncertain significance	criteria provided, single submitter
3892568	NM_182915.3(STEAP3):c.745T>C (p.Tyr249His)	STEAP3	Uncertain significance	criteria provided, single submitter
4082252	NM_182915.3(STEAP3):c.205C>T (p.Arg69Cys)	STEAP3	Uncertain significance	criteria provided, single submitter
50372	NM_182915.3(STEAP3):c.330C>A (p.Cys110Ter)	STEAP3	no classifications from unflagged records	no classifications from unflagged records

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
STEAP3	Moderate	Autosomal dominant	severe congenital hypochromic anemia with ringed sideroblasts	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
STEAP3	Orphanet:300298	Severe congenital hypochromic anemia with ringed sideroblasts

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
STEAP3	HGNC:24592	ENSG00000115107	Q658P3	Metalloreductase STEAP3	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
STEAP3	Metalloreductase STEAP3	Integral membrane protein that functions as a NADPH-dependent ferric-chelate reductase, using NADPH from one side of the membrane to reduce a Fe(3+) chelate that is bound on the other side of the membrane.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
STEAP3	Other/Unknown	no		Fe3_Rdtase_TM_dom, P5C_Rdtase_cat_N, NAD(P)-bd_dom_sf

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
dorsal root ganglion	1
liver	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
STEAP3	259	ubiquitous	marker	right lobe of liver, liver, dorsal root ganglion

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
STEAP3	1,479

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
STEAP3	Q658P3	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 18. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
TP53 Regulates Transcription of Cell Death Genes	1	543.8×	0.012	STEAP3
TP53 Regulates Transcription of Genes Involved in Cytochrome C Release	1	543.8×	0.012	STEAP3
Transferrin endocytosis and recycling	1	368.4×	0.012	STEAP3
Iron uptake and transport	1	346.1×	0.012	STEAP3
RHOF GTPase cycle	1	259.6×	0.012	STEAP3
RHOD GTPase cycle	1	203.9×	0.012	STEAP3
RHOJ GTPase cycle	1	200.3×	0.012	STEAP3
RHOQ GTPase cycle	1	181.3×	0.012	STEAP3
CDC42 GTPase cycle	1	72.3×	0.027	STEAP3
Transcriptional Regulation by TP53	1	62.1×	0.027	STEAP3
RHO GTPase cycle	1	60.1×	0.027	STEAP3
Signaling by Rho GTPases	1	34.2×	0.041	STEAP3
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	33.5×	0.041	STEAP3
Transport of small molecules	1	25.1×	0.051	STEAP3
RNA Polymerase II Transcription	1	22.5×	0.053	STEAP3
Gene expression (Transcription)	1	17.8×	0.063	STEAP3
Generic Transcription Pathway	1	15.1×	0.070	STEAP3
Signal Transduction	1	10.2×	0.098	STEAP3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
copper ion import	1	2407.4×	0.002	STEAP3
iron ion transport	1	887.0×	0.002	STEAP3
protein secretion	1	263.3×	0.005	STEAP3
apoptotic process	1	28.7×	0.035	STEAP3

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
STEAP3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	STEAP3

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
STEAP3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.