Microcytic anemia with liver iron overload

Summary

Microcytic anemia with liver iron overload (MONDO:0008787) is a disease caused by SLC11A2 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: SLC11A2 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 89

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

Identifiers

Disease identifiers

Field	Value
Canonical name	microcytic anemia with liver iron overload
Mondo ID	MONDO:0008787
OMIM	206100
Orphanet	83642
SNOMED CT	711161006
UMLS	C3806153
MedGen	812483
GARD	0012360
Is cancer (heuristic)	no

Also known as: AHMIO1 · anemia, hypochromic microcytic, with iron overload 1 · anemia, hypochromic microcytic, with iron overload type 1 · hypochromic microcytic anaemia with iron overload · hypochromic microcytic anemia with iron overload · microcytic anaemia and hepatic iron overload · microcytic anemia and hepatic iron overload

Data availability: 89 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 › microcytic anemia with liver iron overload

Related subtypes (1): severe congenital hypochromic anemia with ringed sideroblasts

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

89 retrieved; paginated sample, class counts are floors:

48 uncertain significance, 24 benign, 7 pathogenic, 5 conflicting classifications of pathogenicity, 3 likely benign, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
2446381	NM_000617.3(SLC11A2):c.675+35A>G	SLC11A2	Pathogenic	criteria provided, single submitter
800819	NM_000617.3(SLC11A2):c.223G>A (p.Gly75Arg)	SLC11A2	Pathogenic	criteria provided, single submitter
9074	NM_000617.3(SLC11A2):c.1197G>C (p.Glu399Asp)	SLC11A2	Pathogenic	no assertion criteria provided
9075	NM_000617.3(SLC11A2):c.310-5_310-3del	SLC11A2	Pathogenic	no assertion criteria provided
9076	NM_000617.3(SLC11A2):c.1246C>T (p.Arg416Cys)	SLC11A2	Pathogenic	no assertion criteria provided
9077	NM_000617.3(SLC11A2):c.341_343del (p.Val114del)	SLC11A2	Pathogenic	no assertion criteria provided
9078	NM_000617.3(SLC11A2):c.635G>T (p.Gly212Val)	SLC11A2	Pathogenic	no assertion criteria provided
309308	NM_000617.3(SLC11A2):c.1425C>T (p.Gly475=)	SLC11A2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
309311	NM_000617.3(SLC11A2):c.1258A>G (p.Ile420Val)	SLC11A2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
309320	NM_000617.3(SLC11A2):c.504A>G (p.Ser168=)	SLC11A2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
760771	NM_000617.3(SLC11A2):c.1032C>G (p.Leu344=)	SLC11A2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
882847	NM_000617.3(SLC11A2):c.828C>G (p.Val276=)	SLC11A2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1708493	NM_000617.3(SLC11A2):c.578C>T (p.Thr193Ile)	SLC11A2	Uncertain significance	criteria provided, single submitter
309277	NM_000617.3(SLC11A2):c.*2289G>T	SLC11A2	Uncertain significance	criteria provided, single submitter
309279	NM_000617.3(SLC11A2):c.*1949A>G	SLC11A2	Uncertain significance	criteria provided, single submitter
309280	NM_000617.3(SLC11A2):c.*1902C>G	SLC11A2	Uncertain significance	criteria provided, single submitter
309283	NM_000617.3(SLC11A2):c.*1599C>T	SLC11A2	Uncertain significance	criteria provided, single submitter
309284	NM_000617.3(SLC11A2):c.*1559G>T	SLC11A2	Uncertain significance	criteria provided, single submitter
309291	NM_000617.3(SLC11A2):c.*1007A>G	SLC11A2	Uncertain significance	criteria provided, single submitter
309292	NM_000617.3(SLC11A2):c.*986C>A	SLC11A2	Uncertain significance	criteria provided, single submitter
309293	NM_000617.3(SLC11A2):c.*985G>A	SLC11A2	Uncertain significance	criteria provided, single submitter
309297	NM_000617.3(SLC11A2):c.*420G>A	SLC11A2	Uncertain significance	criteria provided, single submitter
309298	NM_000617.3(SLC11A2):c.*415G>A	SLC11A2	Uncertain significance	criteria provided, single submitter
309302	NM_000617.3(SLC11A2):c.*32A>G	SLC11A2	Uncertain significance	criteria provided, single submitter
309303	NM_000617.3(SLC11A2):c.*11G>A	SLC11A2	Uncertain significance	criteria provided, single submitter
309304	NM_000617.3(SLC11A2):c.1663G>A (p.Ala555Thr)	SLC11A2	Uncertain significance	criteria provided, multiple submitters, no conflicts
309306	NM_000617.3(SLC11A2):c.1584A>G (p.Gln528=)	SLC11A2	Uncertain significance	criteria provided, single submitter
309309	NM_000617.3(SLC11A2):c.1421+8T>A	SLC11A2	Uncertain significance	criteria provided, single submitter
309313	NM_000617.3(SLC11A2):c.1206G>A (p.Leu402=)	SLC11A2	Uncertain significance	criteria provided, single submitter
309314	NM_000617.3(SLC11A2):c.932A>G (p.Asn311Ser)	SLC11A2	Uncertain significance	criteria provided, multiple submitters, no conflicts

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
SLC11A2	Strong	Autosomal recessive	microcytic anemia with liver iron overload	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC11A2	Orphanet:83642	Microcytic anemia with liver iron overload

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
SLC11A2	HGNC:10908	ENSG00000110911	P49281	Natural resistance-associated macrophage protein 2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC11A2	Natural resistance-associated macrophage protein 2	Proton-coupled metal ion symporter operating with a proton to metal ion stoichiometry of 1:1.

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)
SLC11A2	Other/Unknown	no		NRAMP_fam

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
buccal mucosa cell	1
caput epididymis	1
inferior vagus X ganglion	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC11A2	297	ubiquitous	marker	inferior vagus X ganglion, buccal mucosa cell, caput epididymis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SLC11A2	1,989

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SLC11A2	P49281	7

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. 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
Defective SLC11A2 causes hypochromic microcytic anemia, with iron overload 1 (AHMIO1)	1	11420.0×	3e-04	SLC11A2
Metal ion SLC transporters	1	601.0×	0.002	SLC11A2
Iron uptake and transport	1	346.1×	0.003	SLC11A2

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
vanadium ion transport	1	16852.0×	6e-04	SLC11A2
lead ion transport	1	16852.0×	6e-04	SLC11A2
nickel cation transport	1	8426.0×	7e-04	SLC11A2
detection of oxygen	1	5617.3×	7e-04	SLC11A2
iron import into cell	1	5617.3×	7e-04	SLC11A2
intracellular manganese ion homeostasis	1	3370.4×	9e-04	SLC11A2
cadmium ion transmembrane transport	1	3370.4×	9e-04	SLC11A2
cobalt ion transport	1	2407.4×	1e-03	SLC11A2
iron ion transmembrane transport	1	2407.4×	1e-03	SLC11A2
manganese ion transport	1	2106.5×	1e-03	SLC11A2
copper ion transport	1	1685.2×	0.001	SLC11A2
response to iron ion	1	936.2×	0.002	SLC11A2
iron ion transport	1	887.0×	0.002	SLC11A2
heme biosynthetic process	1	601.9×	0.002	SLC11A2
multicellular organismal-level iron ion homeostasis	1	581.1×	0.002	SLC11A2
erythrocyte development	1	526.6×	0.002	SLC11A2
dendrite morphogenesis	1	432.1×	0.003	SLC11A2
intracellular iron ion homeostasis	1	244.2×	0.005	SLC11A2
learning or memory	1	240.7×	0.005	SLC11A2
cellular response to oxidative stress	1	154.6×	0.007	SLC11A2
response to hypoxia	1	95.8×	0.010	SLC11A2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SLC11A2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
SLC11A2	10	Binding:10

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	SLC11A2

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)
SLC11A2	10	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.