hemochromatosis type 2A

Summary

hemochromatosis type 2A (MONDO:0011216) is a disease caused by HJV (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: HJV (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 147

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hemochromatosis type 2A
Mondo ID	MONDO:0011216
OMIM	602390
DOID	DOID:0111027
UMLS	C1865614
MedGen	356321
GARD	0024782
Is cancer (heuristic)	no

Also known as: hemochromatosis type 2 caused by mutation in HJV · hemochromatosis type 2A · hemochromatosis, type 2A · HFE2A · HJV hemochromatosis type 2

Data availability: 147 ClinVar variants · 4 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 2 › hemochromatosis type 2A

Related subtypes (1): 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

147 retrieved; paginated sample, class counts are floors:

60 uncertain significance, 20 likely pathogenic, 18 conflicting classifications of pathogenicity, 18 pathogenic, 15 pathogenic/likely pathogenic, 10 likely benign, 5 benign, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
583553	NC_000001.10:g.(?145414782)(145474819_?)del	ANKRD34A	Pathogenic	criteria provided, single submitter
1067426	NM_213653.4(HJV):c.295G>A (p.Gly99Arg)	HJV	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070644	NM_213653.4(HJV):c.59dup (p.Ser21fs)	HJV	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076870	NM_213653.4(HJV):c.984_985del (p.Arg329fs)	HJV	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1327996	NM_213653.4(HJV):c.187C>T (p.Arg63Ter)	HJV	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1327997	NM_213653.4(HJV):c.445del (p.Asp149fs)	HJV	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1428335	NM_213653.4(HJV):c.898del (p.Lys299_Val300insTer)	HJV	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1459917	NM_213653.4(HJV):c.703del (p.Val235fs)	HJV	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2084916	NM_213653.4(HJV):c.399del (p.Ala134fs)	HJV	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2176196	NM_213653.4(HJV):c.765_766del (p.Asp256fs)	HJV	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
2366	NM_213653.4(HJV):c.976C>T (p.Arg326Ter)	HJV	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2368	NM_213653.4(HJV):c.842T>C (p.Ile281Thr)	HJV	Pathogenic	criteria provided, multiple submitters, no conflicts
2369	NM_213653.4(HJV):c.238T>C (p.Cys80Arg)	HJV	Pathogenic	criteria provided, multiple submitters, no conflicts
2370	NM_213653.4(HJV):c.302T>C (p.Leu101Pro)	HJV	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2371	NM_213653.4(HJV):c.963C>A (p.Cys321Ter)	HJV	Pathogenic	no assertion criteria provided
2372	NM_213653.4(HJV):c.982_985del (p.Ser328fs)	HJV	Pathogenic	no assertion criteria provided
2373	NM_213653.4(HJV):c.160A>T (p.Arg54Ter)	HJV	Pathogenic	criteria provided, single submitter
2699564	NM_213653.4(HJV):c.391_403del (p.Arg131fs)	HJV	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2733975	NM_213653.4(HJV):c.196G>T (p.Gly66Ter)	HJV	Pathogenic	criteria provided, multiple submitters, no conflicts
2733977	NM_213653.4(HJV):c.960dup (p.Cys321fs)	HJV	Pathogenic	criteria provided, multiple submitters, no conflicts
2733978	NM_213653.4(HJV):c.962_963delinsAA (p.Cys321Ter)	HJV	Pathogenic	criteria provided, multiple submitters, no conflicts
2853350	NM_213653.4(HJV):c.81del (p.Leu28fs)	HJV	Pathogenic	criteria provided, multiple submitters, no conflicts
2918293	NM_213653.4(HJV):c.769C>T (p.Arg257Ter)	HJV	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2978830	NM_213653.4(HJV):c.143C>A (p.Ser48Ter)	HJV	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3068589	NM_213653.4(HJV):c.127_146del (p.Asn43fs)	HJV	Pathogenic	criteria provided, single submitter
3907280	NM_213653.4(HJV):c.509T>C (p.Phe170Ser)	HJV	Pathogenic	criteria provided, single submitter
417403	NC_000001.10:g.(?145414693)(145417545_?)del	HJV	Pathogenic	criteria provided, single submitter
560162	NM_213653.4(HJV):c.1006G>T (p.Gly336Ter)	HJV	Pathogenic	criteria provided, multiple submitters, no conflicts
590920	NM_213653.4(HJV):c.697del (p.Gln233fs)	HJV	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
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

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
HJV	HGNC:4887	ENSG00000168509	Q6ZVN8	Hemojuvelin	gencc,clinvar
ANKRD34A	HGNC:27639	ENSG00000272031	Q69YU3	Ankyrin repeat domain-containing protein 34A	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.

Protein-family classification

Druggable: 0 · Difficult: 1 · 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
Scaffold/PPI	1	8.6×	0.225
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HJV	Other/Unknown	no		RGM_C, RGM_N, RGM
ANKRD34A	Scaffold/PPI	no		Ankyrin_rpt, Ankyrin_rpt-contain_sf, AN34A/B/C

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gastrocnemius	1
hindlimb stylopod muscle	1
skeletal muscle tissue of rectus abdominis	1
cerebellar hemisphere	1
prefrontal cortex	1
right hemisphere of cerebellum	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
ANKRD34A	168	ubiquitous	yes	prefrontal cortex, right hemisphere of cerebellum, cerebellar hemisphere

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ANKRD34A	1,162
HJV	780

Intra-cohort edges

A	B	Sources
ANKRD34A	HJV	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HJV	Q6ZVN8	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ANKRD34A	Q69YU3	57.86

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 2 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
Netrin-1 signaling	1	439.2×	0.002	HJV

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
activin receptor signaling pathway	1	887.0×	0.004	HJV
protein autoprocessing	1	648.1×	0.004	HJV
multicellular organismal-level iron ion homeostasis	1	581.1×	0.004	HJV
cellular response to BMP stimulus	1	561.7×	0.004	HJV
negative regulation of BMP signaling pathway	1	290.6×	0.007	HJV
intracellular iron ion homeostasis	1	244.2×	0.007	HJV
BMP signaling pathway	1	200.6×	0.007	HJV
transcription by RNA polymerase II	1	70.5×	0.018	HJV
negative regulation of transcription by RNA polymerase II	1	17.7×	0.063	HJV
positive regulation of transcription by RNA polymerase II	1	14.9×	0.067	HJV

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 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
HJV	0	0
ANKRD34A	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	2	HJV, ANKRD34A

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
HJV	0	—
ANKRD34A	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.