Hemochromatosis type 4

Summary

Hemochromatosis type 4 (MONDO:0011631) is a disease caused by SLC40A1 (GenCC Definitive), with 1 cohort gene and 1 clinical trial. Top therapeutic interventions include ferrous fumarate.

At a glance

• Causal gene: SLC40A1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 276
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hemochromatosis type 4
Mondo ID	MONDO:0011631
MeSH	C537249
OMIM	606069
Orphanet	139491, 647834, 648562
DOID	DOID:0111028
SNOMED CT	719975002
UMLS	C1853733
MedGen	340044
GARD	0010094
NORD	1137
Is cancer (heuristic)	no

Also known as: Ferroportin Disease · ferroportin disease · hemochromatosis, type 4 · hereditary hemochromatosis caused by mutation in SLC40A1 · HFE4 · SLC40A1 hereditary hemochromatosis

Data availability: 276 ClinVar variants · 6 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › mineral metabolism disease › iron metabolism disease › hemosiderosis › hereditary hemochromatosis › hemochromatosis type 4

Related subtypes (7): neonatal hemochromatosis, African iron overload, hemochromatosis type 3, hemochromatosis type 5, hemochromatosis type 2, hemochromatosis type 1, digenic hemochromatosis

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

276 retrieved; paginated sample, class counts are floors:

102 likely benign, 86 uncertain significance, 24 benign, 19 pathogenic, 17 likely pathogenic, 15 conflicting classifications of pathogenicity, 7 pathogenic/likely pathogenic, 6 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
208986	NP_055400.1(SLC40A1):p.Gln248His	SLC40A1	Pathogenic	no assertion criteria provided
240918	NM_014585.6(SLC40A1):c.430A>T (p.Asn144Tyr)	SLC40A1	Pathogenic	criteria provided, single submitter
2580954	NM_014585.6(SLC40A1):c.977G>A (p.Cys326Tyr)	SLC40A1	Pathogenic	criteria provided, multiple submitters, no conflicts
381730	NM_014585.6(SLC40A1):c.263G>C (p.Arg88Thr)	SLC40A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
406376	NM_014585.6(SLC40A1):c.1469G>A (p.Gly490Asp)	SLC40A1	Pathogenic	criteria provided, multiple submitters, no conflicts
488151	NM_014585.6(SLC40A1):c.479T>C (p.Val160Ala)	SLC40A1	Pathogenic	no assertion criteria provided
488152	NM_014585.6(SLC40A1):c.541G>A (p.Asp181Asn)	SLC40A1	Pathogenic	no assertion criteria provided
488154	NM_014585.6(SLC40A1):c.1049C>A (p.Ala350Asp)	SLC40A1	Pathogenic	no assertion criteria provided
488155	NM_014585.6(SLC40A1):c.544C>G (p.Gln182Glu)	SLC40A1	Pathogenic	no assertion criteria provided
488156	NM_014585.6(SLC40A1):c.-205A>C	SLC40A1	Pathogenic	no assertion criteria provided
5410	NM_014585.6(SLC40A1):c.430A>C (p.Asn144His)	SLC40A1	Pathogenic	criteria provided, single submitter
5411	NM_014585.6(SLC40A1):c.230C>A (p.Ala77Asp)	SLC40A1	Pathogenic	no assertion criteria provided
5413	NM_014585.6(SLC40A1):c.546G>T (p.Gln182His)	SLC40A1	Pathogenic	no assertion criteria provided
5414	NM_014585.6(SLC40A1):c.476TTG[3] (p.Val162del)	SLC40A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
5415	NM_014585.6(SLC40A1):c.968G>T (p.Gly323Val)	SLC40A1	Pathogenic	no assertion criteria provided
5416	NM_014585.6(SLC40A1):c.542A>T (p.Asp181Val)	SLC40A1	Pathogenic	no assertion criteria provided
5417	NM_014585.6(SLC40A1):c.239G>T (p.Gly80Val)	SLC40A1	Pathogenic	no assertion criteria provided
5418	NM_014585.6(SLC40A1):c.800G>A (p.Gly267Asp)	SLC40A1	Pathogenic	criteria provided, single submitter
56155	NM_014585.6(SLC40A1):c.262A>G (p.Arg88Gly)	SLC40A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
56158	NM_014585.6(SLC40A1):c.610G>A (p.Gly204Ser)	SLC40A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
568628	NM_014585.6(SLC40A1):c.474G>T (p.Trp158Cys)	SLC40A1	Pathogenic	criteria provided, single submitter
801843	NM_014585.6(SLC40A1):c.430A>G (p.Asn144Asp)	SLC40A1	Pathogenic	criteria provided, multiple submitters, no conflicts
839124	NM_014585.6(SLC40A1):c.533G>A (p.Arg178Gln)	SLC40A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
917398	NM_014585.6(SLC40A1):c.1592T>C (p.Val531Ala)	SLC40A1	Pathogenic	no assertion criteria provided
951489	NM_014585.6(SLC40A1):c.626C>T (p.Ser209Leu)	SLC40A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
986324	NM_014585.6(SLC40A1):c.238G>A (p.Gly80Ser)	SLC40A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1209853	NM_014585.6(SLC40A1):c.1250_1251insGACAAGAACAGTTTGACAGTCAGAAGGTGCCACAAATCCTGCATTCAAGGAGAGTC (p.Ser417_Ile418insThrArgThrValTer)	SLC40A1	Likely pathogenic	criteria provided, single submitter
1209854	NM_014585.6(SLC40A1):c.1263_1264insGTGAGATTGACAAGAACAGTTTGACAGTCAGAAGGTGCCACAAATCCTGCATTCAAGGAGAGTCAATTACACCTACC (p.Lys422delinsValArgLeuThrArgThrValTer)	SLC40A1	Likely pathogenic	criteria provided, single submitter
2203235	NM_014585.6(SLC40A1):c.977G>T (p.Cys326Phe)	SLC40A1	Likely pathogenic	criteria provided, single submitter
406375	NM_014585.6(SLC40A1):c.524C>A (p.Ala175Asp)	SLC40A1	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 2 · 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
SLC40A1	Definitive	Autosomal dominant	hemochromatosis type 4	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC40A1	Orphanet:647834	SLC40A1-related hemochromatosis
SLC40A1	Orphanet:648562	Ferroportin disease

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
SLC40A1	HGNC:10909	ENSG00000138449	Q9NP59	Ferroportin	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC40A1	Ferroportin	Transports Fe(2+) from the inside of a cell to the outside of the cell, playing a key role for maintaining systemic iron homeostasis.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Transporter	1	77.8×	0.013

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC40A1	Transporter	yes		Ferroportin-1, MFS_trans_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
epithelial cell of pancreas	1
oviduct epithelium	1
pancreatic ductal cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC40A1	260	ubiquitous	marker	pancreatic ductal cell, epithelial cell of pancreas, oviduct epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SLC40A1	1,387

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SLC40A1	Q9NP59	8

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. 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 SLC40A1 causes hemochromatosis 4 (HFE4) (macrophages)	1	5710.0×	6e-04	SLC40A1
Defective CP causes aceruloplasminemia (ACERULOP)	1	5710.0×	6e-04	SLC40A1
Defective SLC40A1 causes hemochromatosis 4 (HFE4) (duodenum)	1	5710.0×	6e-04	SLC40A1
Metal ion SLC transporters	1	601.0×	0.005	SLC40A1
Iron uptake and transport	1	346.1×	0.006	SLC40A1
SLC transporter disorders	1	203.9×	0.009	SLC40A1
R-HSA-425366	1	181.3×	0.009	SLC40A1
Disorders of transmembrane transporters	1	139.3×	0.010	SLC40A1
SLC-mediated transmembrane transport	1	59.2×	0.021	SLC40A1
Transport of small molecules	1	25.1×	0.044	SLC40A1
Disease	1	13.1×	0.076	SLC40A1

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
spleen trabecula formation	1	16852.0×	4e-04	SLC40A1
iron ion export across plasma membrane	1	16852.0×	4e-04	SLC40A1
iron ion transmembrane transport	1	2407.4×	0.002	SLC40A1
lymphocyte homeostasis	1	1872.4×	0.002	SLC40A1
endothelium development	1	1296.3×	0.002	SLC40A1
multicellular organismal-level iron ion homeostasis	1	581.1×	0.003	SLC40A1
intracellular iron ion homeostasis	1	244.2×	0.007	SLC40A1
establishment of localization in cell	1	160.5×	0.009	SLC40A1
transcription by RNA polymerase II	1	70.5×	0.019	SLC40A1
negative regulation of apoptotic process	1	34.8×	0.035	SLC40A1
apoptotic process	1	28.7×	0.038	SLC40A1
positive regulation of transcription by RNA polymerase II	1	14.9×	0.067	SLC40A1

Therapeutics

Drug target analysis

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

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
SLC40A1	1	1

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VAMIFEPORT HYDROCHLORIDE	1	SLC40A1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SLC40A1	14	Binding:14

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

1 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.

Compound	Max phase	Cohort target (bioactivity)
VAMIFEPORT HYDROCHLORIDE	1	SLC40A1

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	1	SLC40A1
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01949467	PHASE2	COMPLETED	Analysis of the Modulation of Serum Hepcidin Level in Response to Iron Oral Intake: Potential Interest for the Differential Diagnosis Between Ferroportin Disease and Dysmetabolic Hepatosiderosis.

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
FERROUS FUMARATE	4	1