Hemochromatosis type 2

Summary

Hemochromatosis type 2 (MONDO:0019257) is a disease with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 3
• ClinVar variants: 4
• Phenotypes (HPO): 15

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		74	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

15 HPO clinical features (Orphanet curated; top 15 by frequency):

HPO ID	Term	Frequency
HP:0002612	Congenital hepatic fibrosis	Very frequent (80-99%)
HP:0003281	Increased circulating ferritin concentration	Very frequent (80-99%)
HP:0011031	Abnormality of iron homeostasis	Very frequent (80-99%)
HP:0012463	Elevated transferrin saturation	Very frequent (80-99%)
HP:0000135	Hypogonadism	Frequent (30-79%)
HP:0000802	Impotence	Frequent (30-79%)
HP:0000819	Diabetes mellitus	Frequent (30-79%)
HP:0001254	Lethargy	Frequent (30-79%)
HP:0001324	Muscle weakness	Frequent (30-79%)
HP:0001644	Dilated cardiomyopathy	Frequent (30-79%)
HP:0002910	Elevated circulating hepatic transaminase concentration	Frequent (30-79%)
HP:0003040	Arthropathy	Frequent (30-79%)
HP:0007440	Generalized hyperpigmentation	Frequent (30-79%)
HP:0000939	Osteoporosis	Occasional (5-29%)
HP:0012093	Abnormality of endocrine pancreas physiology	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hemochromatosis type 2
Mondo ID	MONDO:0019257
MeSH	C537247
Orphanet	79230
DOID	DOID:0111034
SNOMED CT	50855007
UMLS	C0268060
MedGen	82769
GARD	0010092
NORD	1315
Is cancer (heuristic)	no

Also known as: hemochromatosis juvenile · iron overload disease juvenile · Juvenile Hemochromatosis · juvenile hemochromatosis

Data availability: 4 ClinVar variants · 2 GenCC gene-disease records.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › mineral metabolism disease › iron metabolism disease › hemosiderosis › hereditary hemochromatosis › hemochromatosis type 2

Related subtypes (7): neonatal hemochromatosis, African iron overload, hemochromatosis type 3, hemochromatosis type 4, hemochromatosis type 5, hemochromatosis type 1, digenic hemochromatosis

Subtypes (2): hemochromatosis type 2A, hemochromatosis type 2B

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:

1 pathogenic, 1 pathogenic/likely pathogenic, 1 conflicting classifications of pathogenicity, 1 conflicting classifications of pathogenicity; other; risk factor

ClinVar	Variant (HGVS)	Gene	Classification	Review
3075867	NM_000410.4(HFE):c.616+1G>A	HFE	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2365	NM_213653.4(HJV):c.959G>T (p.Gly320Val)	HJV	Pathogenic	criteria provided, multiple submitters, no conflicts
9	NM_000410.4(HFE):c.845G>A (p.Cys282Tyr)	HFE	Conflicting classifications of pathogenicity; other; risk factor	criteria provided, conflicting classifications
694655	NM_213653.4(HJV):c.950G>A (p.Cys317Tyr)	HJV	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 9 · 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
HAMP	Definitive	Autosomal recessive	hemochromatosis type 2B	5
HJV	Definitive	Autosomal recessive	hemochromatosis type 2A	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HJV	Orphanet:648581	Digenic hemochromatosis
HJV	Orphanet:79230	HJV or HAMP-related hemochromatosis
HAMP	Orphanet:648581	Digenic hemochromatosis
HAMP	Orphanet:79230	HJV or HAMP-related hemochromatosis
HFE	Orphanet:443057	Sporadic porphyria cutanea tarda
HFE	Orphanet:443062	Familial porphyria cutanea tarda
HFE	Orphanet:465508	Symptomatic form of HFE-related hemochromatosis
HFE	Orphanet:586	Cystic fibrosis
HFE	Orphanet:648581	Digenic hemochromatosis

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
HJV	HGNC:4887	ENSG00000168509	Q6ZVN8	Hemojuvelin	gencc,clinvar
HAMP	HGNC:15598	ENSG00000105697	P81172	Hepcidin	gencc
HFE	HGNC:4886	ENSG00000010704	Q30201	Hereditary hemochromatosis protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HJV	Hemojuvelin	Acts as a bone morphogenetic protein (BMP) coreceptor.
HAMP	Hepcidin	Liver-produced hormone that constitutes the main circulating regulator of iron absorption and distribution across tissues.
HFE	Hereditary hemochromatosis protein	Binds to transferrin receptor (TFR) and reduces its affinity for iron-loaded transferrin.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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
Antibody/Immunoglobulin	1	9.7×	0.199
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HJV	Other/Unknown	no		RGM_C, RGM_N, RGM
HAMP	Other/Unknown	no		Hepcidin
HFE	Antibody/Immunoglobulin	yes		MHC_I_a_a1/a2, Ig/MHC_CS, Ig_C1-set

Expression context

Cohort genes with no expression data: 0.

3 cohort genes 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gastrocnemius	1
hindlimb stylopod muscle	1
skeletal muscle tissue of rectus abdominis	1
cardiac atrium	1
right atrium auricular region	1
right lobe of liver	1
olfactory bulb	1
stromal cell of endometrium	1
type B pancreatic cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HJV	147	tissue_specific	marker	hindlimb stylopod muscle, skeletal muscle tissue of rectus abdominis, gastrocnemius
HAMP	223	broad	marker	right lobe of liver, right atrium auricular region, cardiac atrium
HFE	238	ubiquitous	marker	type B pancreatic cell, olfactory bulb, stromal cell of endometrium

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HAMP	1,580
HFE	1,569
HJV	780

Intra-cohort edges

A	B	Sources
HAMP	HFE	string_interaction
HAMP	HJV	string_interaction
HFE	HJV	string_interaction

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HAMP	P81172	6
HJV	Q6ZVN8	2
HFE	Q30201	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 3 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Netrin-1 signaling	1	219.6×	0.005	HJV
Transferrin endocytosis and recycling	1	184.2×	0.005	HFE

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
multicellular organismal-level iron ion homeostasis	3	581.1×	2e-07	HJV, HAMP, HFE
intracellular iron ion homeostasis	3	244.2×	1e-06	HJV, HAMP, HFE
response to iron ion	2	624.1×	4e-05	HAMP, HFE
BMP signaling pathway	2	133.8×	7e-04	HJV, HFE
negative regulation of iron ion transmembrane transport	1	5617.3×	9e-04	HAMP
negative regulation of iron export across plasma membrane	1	5617.3×	9e-04	HAMP
negative regulation of antigen processing and presentation of endogenous peptide antigen via MHC class I	1	5617.3×	9e-04	HFE
negative regulation of intestinal absorption	1	5617.3×	9e-04	HAMP
regulation of iron ion transport	1	2808.7×	0.002	HFE
response to iron ion starvation	1	1872.4×	0.002	HFE
negative regulation of CD8-positive, alpha-beta T cell activation	1	1404.3×	0.003	HFE
negative regulation of T cell cytokine production	1	802.5×	0.004	HFE
cellular response to iron ion	1	802.5×	0.004	HFE
regulation of protein localization to cell surface	1	561.7×	0.004	HFE
transferrin transport	1	510.7×	0.004	HFE
urate metabolic process	1	510.7×	0.004	HFE
positive regulation of peptide hormone secretion	1	510.7×	0.004	HFE
hormone biosynthetic process	1	468.1×	0.005	HFE
activin receptor signaling pathway	1	295.6×	0.007	HJV
negative regulation of ubiquitin-dependent protein catabolic process	1	280.9×	0.007	HFE
positive regulation of receptor-mediated endocytosis	1	267.5×	0.007	HFE
protein autoprocessing	1	216.1×	0.008	HJV
cellular response to BMP stimulus	1	187.2×	0.009	HJV
defense response to fungus	1	147.8×	0.011	HAMP
negative regulation of proteasomal ubiquitin-dependent protein catabolic process	1	133.8×	0.012	HFE
positive regulation of SMAD protein signal transduction	1	127.7×	0.012	HFE
negative regulation of transcription by RNA polymerase II	2	11.8×	0.013	HJV, HAMP
negative regulation of BMP signaling pathway	1	96.8×	0.014	HJV
killing of cells of another organism	1	90.6×	0.015	HAMP
receptor-mediated endocytosis	1	73.9×	0.018	HFE

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
HJV	0	0
HAMP	0	0
HFE	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
HAMP	9	Binding:9

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	1	HFE
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	HJV, HAMP

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
HJV	0	—
HAMP	9	—
HFE	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.