HJV

Summary

HJV (hemojuvelin BMP co-receptor, HGNC:4887) is a protein-coding gene on chromosome 1q21.1, encoding Hemojuvelin (Q6ZVN8). Acts as a bone morphogenetic protein (BMP) coreceptor. It is a selective cancer dependency (DepMap: 17.7% of cell lines).

The product of this gene is involved in iron metabolism. It may be a component of the signaling pathway which activates hepcidin or it may act as a modulator of hepcidin expression. It could also represent the cellular receptor for hepcidin. Two uORFs in the 5’ UTR negatively regulate the expression and activity of the encoded protein. Alternatively spliced transcript variants encoding different isoforms have been identified for this gene. Defects in this gene are the cause of hemochromatosis type 2A, also called juvenile hemochromatosis (JH). JH is an early-onset autosomal recessive disorder due to severe iron overload resulting in hypogonadotrophic hypogonadism, hepatic fibrosis or cirrhosis and cardiomyopathy, occurring typically before age of 30.

Source: NCBI Gene 148738 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hemochromatosis type 2A (Definitive, ClinGen) — +1 more curated relationship
• Clinical variants (ClinVar): 478 total — 43 pathogenic, 23 likely-pathogenic
• Phenotypes (HPO): 30
• Cancer dependency (DepMap): dependent in 17.7% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_213653

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4887
Approved symbol	HJV
Name	hemojuvelin BMP co-receptor
Location	1q21.1
Locus type	gene with protein product
Status	Approved
Aliases	JH, HFE2A, RGMC, hemojuvelin, haemojuvelin
Ensembl gene	ENSG00000168509
Ensembl biotype	protein_coding
OMIM	608374
Entrez	148738

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 10 protein_coding

ENST00000336751, ENST00000357836, ENST00000421822, ENST00000475797, ENST00000497365, ENST00000634927, ENST00000636675, ENST00000884037, ENST00000884038, ENST00000945407

RefSeq mRNA: 6 — MANE Select: NM_213653 NM_001316767, NM_001379352, NM_145277, NM_202004, NM_213652, NM_213653

CCDS: CCDS72877, CCDS72878, CCDS72879

Canonical transcript exons

ENST00000336751 — 4 exons

Exon	Start	End
ENSE00001435872	146020135	146020320
ENSE00001825041	146017470	146018700
ENSE00001949269	146021587	146021735
ENSE00003651604	146019175	146019734

Expression profiles

Bgee: expression breadth ubiquitous, 147 present calls, max score 98.94.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 2.1946 / max 442.0888, expressed in 148 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
14194	1.8917	141
14193	0.2733	63
14192	0.0296	9

Top tissues by expression

243 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
hindlimb stylopod muscle	UBERON:0004252	98.94	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	98.92	gold quality
gastrocnemius	UBERON:0001388	98.88	gold quality
quadriceps femoris	UBERON:0001377	98.77	gold quality
vastus lateralis	UBERON:0001379	98.69	gold quality
tibialis anterior	UBERON:0001385	98.59	gold quality
skeletal muscle tissue	UBERON:0001134	98.50	gold quality
deltoid	UBERON:0001476	98.17	gold quality
biceps brachii	UBERON:0001507	98.06	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	97.59	gold quality
muscle of leg	UBERON:0001383	97.21	gold quality
right lobe of liver	UBERON:0001114	97.14	gold quality
liver	UBERON:0002107	96.36	gold quality
apex of heart	UBERON:0002098	95.93	gold quality
right atrium auricular region	UBERON:0006631	93.23	gold quality
cardiac atrium	UBERON:0002081	92.93	gold quality
muscle tissue	UBERON:0002385	92.93	gold quality
body of tongue	UBERON:0011876	91.81	gold quality
cardiac muscle of right atrium	UBERON:0003379	91.52	gold quality
myocardium	UBERON:0002349	90.53	gold quality
left ventricle myocardium	UBERON:0006566	90.10	gold quality
heart left ventricle	UBERON:0002084	89.45	gold quality
cardiac ventricle	UBERON:0002082	89.11	gold quality
tongue	UBERON:0001723	85.55	gold quality
heart	UBERON:0000948	84.54	gold quality
heart right ventricle	UBERON:0002080	83.59	gold quality
superior surface of tongue	UBERON:0007371	76.48	gold quality
vena cava	UBERON:0004087	74.20	gold quality
kidney epithelium	UBERON:0004819	71.46	gold quality
pharyngeal mucosa	UBERON:0000355	70.45	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

3 targets.

Target	Regulation
BMP6	Repression
HAMP	Activation
TFRC	Activation

Upstream regulators (CollecTRI, top): MAFB, MEF2C, MYOG, NR5A1

miRNA regulators (miRDB)

33 targeting HJV, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-3941	99.86	70.54	2735
HSA-MIR-4694-3P	99.79	69.53	2640
HSA-MIR-4679	99.76	69.19	1229
HSA-MIR-17-3P	99.55	66.77	1311
HSA-MIR-3923	99.52	69.21	446
HSA-MIR-6740-3P	99.48	68.49	1392
HSA-MIR-516A-3P	99.46	67.96	1378
HSA-MIR-516B-3P	99.46	67.96	1378
HSA-MIR-7162-5P	99.46	68.08	1368
HSA-MIR-519D-5P	99.41	69.30	2057
HSA-MIR-580-5P	99.28	70.94	1776
HSA-MIR-10522-5P	99.26	68.50	2087
HSA-MIR-485-5P	99.10	64.78	1889
HSA-MIR-6884-5P	99.10	64.50	1987
HSA-MIR-513B-3P	98.76	68.12	1577
HSA-MIR-3611	98.76	68.76	1290
HSA-MIR-6757-5P	98.08	65.50	724
HSA-MIR-4778-5P	97.96	68.06	1634
HSA-MIR-3652	97.71	65.43	1890
HSA-MIR-192-3P	97.52	67.66	1001
HSA-MIR-4430	97.47	65.61	1813
HSA-MIR-6781-3P	97.44	66.85	970
HSA-MIR-1225-3P	97.29	64.60	876
HSA-MIR-2682-3P	97.10	66.16	840
HSA-MIR-1288-3P	96.86	66.95	536
HSA-MIR-616-3P	96.82	66.99	784
HSA-MIR-4522	95.76	66.23	742

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 17.7% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• Here we report the positional cloning of the locus associated with juvenile hemochromatosis and the identification of a new gene crucial to iron metabolism. (PMID:14647275)
• Various amino acid substitutions identified in hemochromatosis. (PMID:14982867)
• 17 different (16 novel) mutations of HJV, both at the homozygous and at the compound heterozygous state in juvenile hemochromatosis (PMID:14982873)
• compound heterozygous mutations in hemojuvelin may have a role in juvenile hemochromatosis (PMID:15138164)
• Hemochromatosis in a consanguineous family linked to a mutation in the recently identified HJV gene. (PMID:15315789)
• Human HJV mRNA expression was detected in the liver, heart, esophagus, pancreas, descending colon, ileocecum and skeletal muscle. Its role in regulating iron allocation could be extended to other tissues beyond the liver. (PMID:15590393)
• nonsense mutation (G66X) causes severe juvenile hemochromatosis with fatal cardiomyopathy (PMID:15611318)
• Juvenile hereditary hemochromatosis is not a distinct monogenic disorder invariably due to hemojuvelin or hepcidin mutations: it may be genetically linked to the adult-onset form of hereditary hemochromatosis. (PMID:15685557)
• hemojuvelin may have a role in juvenile hemochromatosis [letter, case report] (PMID:15710580)
• soluble and cell-associated hemojuvelin reciprocally regulate hepcidin expression in response to changes in extracellular iron concentration (PMID:15998830)
• Hemojuvelin-induced increase in intracellular iron levels in human embryonic kidney 293 cells is dependent on the presence of neogenin in the cells, thus linking these two proteins to intracellular iron homeostasis (PMID:16103117)
• An HFE-independent pathway that seems to involve TFR2 and hemojuvelin can regulate HAMP expression under conditions of iron overload (PMID:16103673)
• Hjv & transferrin receptor type 2 were predominantly localized to the basolateral membrane domain of hepatocytes; localization of Hjv and TfR2 at the same membrane domain renders a functional interaction of these two proteins in iron homeostasis possible (PMID:16932966)
• The loss of HJV membrane export is central to the pathogenesis of juvenile hemochromatosis; HJV cleavage is essential for the export. (PMID:17264300)
• A novel R176C mutation in the juvenile hemochromatosis gene was found in exon 3. This substitution destabilizes a short helix made of the RSF residues (from 176 to 178). (PMID:17339196)
• Hemojuvelin missense mutation is associated with hemochromatosis. (PMID:17768121)
• interactive effect on serum ferritin level of rs235756 in BMP2 and a SNP in HJV, with a small additive effect of a SNP in BMP4 (PMID:17847004)
• s-hemojuvelin release is regulated by a proprotein convertase through the cleavage at a conserved polybasic RNRR site. (PMID:17869549)
• s-HJV originates from a furin cleavage at position 332-335 (PMID:17938254)
• results show that different isoforms of hemojuvlin may play unique physiological roles through defined interactions with distinct signaling proteins such as BMP2 and neogenin, and demonstrate that some of these interactions are defective. (PMID:18287331)
• HJV-mediated bone morphogenetic protein signaling and hepcidin regulation occur via a distinct subset of BMP ligands and BMP receptors, independently of neogenin (PMID:18326817)
• neogenin is part of a multiprotein complex at the hepatocyte membrane involving bone morphogenetic protein, its receptors, and hemojuvelin (PMID:18335997)
• These data uncover a missing link in the HFE2-mediated control of hepcidin expression and suggest that the BMP-responsive element controls hepcidin promoter activity mediated by HFE2 and inflammatory stimuli. (PMID:18421430)
• neogenin-mediated HJV release occurs after the HJV-neogenin complex is internalized from the cell surface (PMID:18445598)
• The researchers identified a nonsense Q312X mutation in the hemojuvelin gene that increases ferritin levels and leads to juvenile hemochromatosis that is associated with severe cardiomyopathy. (PMID:18725184)
• all hemojuvelin mutants tested showed no or minimal hepcidin activation (PMID:18827264)
• Our results support a model in which retrograde trafficking of HJV before cleavage is the predominant processing pathway (PMID:19029439)
• HAMP and hemojuvelin mutations are rare among Spanish HH patients, and their impact in this population is not significant (PMID:19214511)
• In this review, HJV plays an essential role in the regulation of hepcidin expression, specifically in the iron-sensing pathway, although through unknown mechanisms. (PMID:19287179)
• The results suggest that the HJV-neogenin interaction is required for the BMP-mediated induction of hepcidin expression when HJV is expressed. (PMID:19564337)
• identified mutations in HFE, SLC40A1, HAMP, HJV, TFR2, and FTL that could explain TRANSFERRIN SATURATION/SERUM FERRITIN heterogeneity in adults with previous HFE genotyping to detect C282Y and H63D; results were correlated with racial groups (PMID:19787796)
• c/hemojuvelin is a broad spectrum bone morphogenetic protein (BMP) antagonist and inhibits both BMP2- and BMP6-mediated signaling and gene expression (PMID:20530805)
• Case Report: Homozygous G320V mutation in the HJV gene causing juvenile hereditary haemochromatosis type A. (PMID:20593054)
• showed that it localizes to similar subcellular compartments as wild-type TMPRSS6 and binds HJV, but fails to auto-catalytically activate itself. (PMID:20704562)
• Data show that Patients with iron-refractory iron-deficiency anemia with a mutation in the TMPRSS6 gene were found to have lower levels of circulating hemojuvelin than those in healthy patients. (PMID:20713458)
• Matriptase-2- and proprotein convertase-cleaved forms of hemojuvelin have different roles in the down-regulation of hepcidin expression (PMID:20937842)
• these data indicate that HJV and HAMP functional mutations are not frequent in patients with iron overload. (PMID:21039223)
• possible involvement of hemojuvelin gene mutation in porphyria cutanea tarda (PMID:21088809)
• Downregulation of hemojuvelin prevents inhibitory effects of bone morphogenetic proteins on iron metabolism in hepatocellular carcinoma. (PMID:21863061)
• The expression of RGMA, RGMB and RGMC was evident in most examined prostate cancer cell lines, and also in the prostate cancer tissues (PMID:22076499)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	hjv	ENSDARG00000030494
mus_musculus	Hjv	ENSMUSG00000038403
rattus_norvegicus	Hjv	ENSRNOG00000021200
caenorhabditis_elegans	drag-1	WBGENE00022154

Paralogs (2): RGMB (ENSG00000174136), RGMA (ENSG00000182175)

Protein

Protein identifiers

Hemojuvelin — Q6ZVN8 (reviewed: Q6ZVN8)

Alternative names: Hemochromatosis type 2 protein, Hemojuvelin BMP coreceptor, RGM domain family member C

All UniProt accessions (4): Q6ZVN8, A0A0U1RR55, A8K466, F8W6J7

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a bone morphogenetic protein (BMP) coreceptor. Through enhancement of BMP signaling regulates hepcidin (HAMP) expression and regulates iron homeostasis.

Subunit / interactions. Interacts with BMP2 and BMP4. Interacts with BMP6. Interacts with BMPR1B. Interacts with TMPRSS6.

Subcellular location. Cell membrane.

Tissue specificity. Adult and fetal liver, heart, and skeletal muscle.

Post-translational modifications. Autocatalytically cleaved at low pH; the two chains remain linked via two disulfide bonds. Also proteolytically processed by TMPRSS6, several fragments being released in the extracellular space; regulates HJV activity in BMP signaling and thefore iron homeostasis.

Disease relevance. Hemochromatosis 2A (HFE2A) [MIM:602390] A juvenile form of hemochromatosis, a disorder of iron metabolism with excess deposition of iron in a variety of organs leading to their failure, bronze skin pigmentation, hepatic cirrhosis, arthropathy and diabetes. The most common symptoms of juvenile hemochromatosis at presentation are hypogonadism and cardiomyopathy. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the repulsive guidance molecule (RGM) family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q6ZVN8-1	a	yes
Q6ZVN8-2	b
Q6ZVN8-3	c

RefSeq proteins (6): NP_001303696, NP_001366281, NP_660320, NP_973733, NP_998817, NP_998818* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR009496	RGM_C	Domain
IPR010536	RGM_N	Domain
IPR040287	RGM	Family

Pfam: PF06534, PF06535

UniProt features (35 total): sequence variant 15, helix 4, glycosylation site 3, disulfide bond 2, splice variant 2, sequence conflict 2, signal peptide 1, chain 1, propeptide 1, region of interest 1, site 1, modified residue 1, lipid moiety-binding region 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
4UI1	X-RAY DIFFRACTION	2.35
6Z3L	X-RAY DIFFRACTION	2.51

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6ZVN8-F1	82.87	0.62

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 172–173 (cleavage; by autolysis)

Post-translational modifications (2): 46, 400

Disulfide bonds (2): 148–230, 167–317

Glycosylation sites (3): 118, 213, 372

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-373752	Netrin-1 signaling

MSigDB gene sets: 213 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_DN, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GCANCTGNY_MYOD_Q6, GOBP_INTRACELLULAR_IRON_ION_HOMEOSTASIS, GOCC_CELL_SURFACE, AP4_Q6, MEF2_02, CAGCTG_AP4_Q5, CEBP_Q2, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_PROTEIN_MATURATION, GOBP_REGULATION_OF_TRANSMEMBRANE_RECEPTOR_PROTEIN_SERINE_THREONINE_KINASE_SIGNALING_PATHWAY, WTGAAAT_UNKNOWN, GOBP_NEGATIVE_REGULATION_OF_BMP_SIGNALING_PATHWAY, GOBP_RESPONSE_TO_BMP

GO Biological Process (10): negative regulation of transcription by RNA polymerase II (GO:0000122), transcription by RNA polymerase II (GO:0006366), intracellular iron ion homeostasis (GO:0006879), protein autoprocessing (GO:0016540), BMP signaling pathway (GO:0030509), negative regulation of BMP signaling pathway (GO:0030514), activin receptor signaling pathway (GO:0032924), positive regulation of transcription by RNA polymerase II (GO:0045944), multicellular organismal-level iron ion homeostasis (GO:0060586), cellular response to BMP stimulus (GO:0071773)

GO Molecular Function (6): signaling receptor binding (GO:0005102), coreceptor activity (GO:0015026), BMP binding (GO:0036122), transferrin receptor binding (GO:1990459), protein binding (GO:0005515), BMP receptor activity (GO:0098821)

GO Cellular Component (8): obsolete extracellular space (GO:0005615), plasma membrane (GO:0005886), cell surface (GO:0009986), BMP receptor complex (GO:0070724), side of membrane (GO:0098552), plasma membrane protein complex (GO:0098797), HFE-transferrin receptor complex (GO:1990712), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Axon guidance	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
inorganic ion homeostasis	2
transforming growth factor beta receptor superfamily signaling pathway	2
BMP signaling pathway	2
membrane	2
plasma membrane signaling receptor complex	2
negative regulation of DNA-templated transcription	1
DNA-templated transcription	1
intracellular monoatomic cation homeostasis	1
protein processing	1
cellular response to BMP stimulus	1
regulation of BMP signaling pathway	1
negative regulation of transmembrane receptor protein serine/threonine kinase signaling pathway	1
negative regulation of cellular response to growth factor stimulus	1
positive regulation of DNA-templated transcription	1
monoatomic cation homeostasis	1
multicellular organismal-level chemical homeostasis	1
cellular response to growth factor stimulus	1
response to BMP	1
protein binding	1
signaling receptor activity	1
cytokine binding	1
signaling receptor binding	1
binding	1
transmembrane receptor protein serine/threonine kinase activity	1
cell periphery	1
leaflet of membrane bilayer	1
plasma membrane	1
membrane protein complex	1

Protein interactions and networks

STRING

766 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HJV	TFR2	Q9UP52	999
HJV	BMP6	P22004	998
HJV	HFE	Q30201	995
HJV	NEO1	Q92859	995
HJV	TMPRSS6	Q8IU80	994
HJV	HAMP	P81172	983
HJV	TFRC	P02786	982
HJV	SLC40A1	Q9NP59	904
HJV	BMP4	P12644	903
HJV	SLC11A2	P49281	804
HJV	CYBRD1	Q53TN4	788
HJV	BMP5	P22003	786
HJV	SMAD4	Q13485	756
HJV	BMPR1A	P36894	734
HJV	GDF15	P78360	688

IntAct

11 interactions, top by confidence:

A	B	Type	Score
HJV	TMPRSS6	psi-mi:“MI:0915”(physical association)	0.660
HJV	NEO1	psi-mi:“MI:0407”(direct interaction)	0.620
BMP2	HJV	psi-mi:“MI:0915”(physical association)	0.540
HJV	BMP2	psi-mi:“MI:0407”(direct interaction)	0.540
HJV	Tmprss6	psi-mi:“MI:0915”(physical association)	0.400
TMPRSS6	HJV	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (3): HFE2 (Two-hybrid), HFE2 (Negative Genetic), HFE2 (Positive Genetic)

ESM2 similar proteins: B2GUT4, O00744, O73864, O75173, O96014, P04426, P04628, P09531, P22724, P22727, P24257, P34820, P34821, P43446, P48614, P48615, P49339, P49340, P49893, P51891, P55103, P56705, P57110, P70701, Q28J82, Q5Q0T9, Q5RFQ8, Q5T4F7, Q641Q3, Q66II0, Q670P5, Q6ZVN8, Q7TQ32, Q7Z5Y6, Q801F7, Q8BNJ2, Q8C1Q4, Q8N7M5, Q91029, Q93097

Diamond homologs: G5EDE5, Q6NW40, Q6PCX7, Q6ZVN8, Q7TQ32, Q7TQ33, Q8JG54, Q8N7M5, Q96B86, Q9N0A6

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

478 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	43
Likely pathogenic	23
Uncertain significance	151
Likely benign	218
Benign	8

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1069657	NM_213653.4(HJV):c.552del (p.Cys185fs)	Pathogenic
1076582	NM_213653.4(HJV):c.7dup (p.Glu3fs)	Pathogenic
1377808	NM_213653.4(HJV):c.413_435del (p.Ala138fs)	Pathogenic
1390193	NM_213653.4(HJV):c.919del (p.Ala307fs)	Pathogenic
1390285	NM_213653.4(HJV):c.436del (p.Asp146fs)	Pathogenic
1393832	NM_213653.4(HJV):c.371del (p.Pro124fs)	Pathogenic
1398738	NM_213653.4(HJV):c.1093del (p.Val365fs)	Pathogenic
1423659	NM_213653.4(HJV):c.331G>T (p.Glu111Ter)	Pathogenic
1438656	NM_213653.4(HJV):c.494T>A (p.Leu165Ter)	Pathogenic
1452499	NM_213653.4(HJV):c.885del (p.Phe296fs)	Pathogenic
1452535	NM_213653.4(HJV):c.515del (p.Asp172fs)	Pathogenic
1455259	NM_213653.4(HJV):c.346C>T (p.Gln116Ter)	Pathogenic
2045832	NM_213653.4(HJV):c.433_434del (p.Pro145fs)	Pathogenic
2093487	NM_213653.4(HJV):c.657+1G>C	Pathogenic
2126171	NM_213653.4(HJV):c.8del (p.Glu3fs)	Pathogenic
2365	NM_213653.4(HJV):c.959G>T (p.Gly320Val)	Pathogenic
2368	NM_213653.4(HJV):c.842T>C (p.Ile281Thr)	Pathogenic
2369	NM_213653.4(HJV):c.238T>C (p.Cys80Arg)	Pathogenic
2371	NM_213653.4(HJV):c.963C>A (p.Cys321Ter)	Pathogenic
2372	NM_213653.4(HJV):c.982_985del (p.Ser328fs)	Pathogenic
2373	NM_213653.4(HJV):c.160A>T (p.Arg54Ter)	Pathogenic
2692104	NM_213653.4(HJV):c.526C>T (p.Arg176Cys)	Pathogenic
2733975	NM_213653.4(HJV):c.196G>T (p.Gly66Ter)	Pathogenic
2733977	NM_213653.4(HJV):c.960dup (p.Cys321fs)	Pathogenic
2733978	NM_213653.4(HJV):c.962_963delinsAA (p.Cys321Ter)	Pathogenic
2848556	NM_213653.4(HJV):c.357C>A (p.Cys119Ter)	Pathogenic
2853350	NM_213653.4(HJV):c.81del (p.Leu28fs)	Pathogenic
2907290	NM_213653.4(HJV):c.520dup (p.His174fs)	Pathogenic
3011379	NM_213653.4(HJV):c.934C>T (p.Gln312Ter)	Pathogenic
3068589	NM_213653.4(HJV):c.127_146del (p.Asn43fs)	Pathogenic

SpliceAI

421 predictions. Top by Δscore:

Variant	Effect	Δscore
1:146018699:G:GA	acceptor_gain	1.0000
1:146018699:GC:G	acceptor_gain	1.0000
1:146018699:GCT:G	acceptor_gain	1.0000
1:146018699:GCTC:G	acceptor_gain	1.0000
1:146018699:GCTCA:G	acceptor_gain	1.0000
1:146018700:A:AG	acceptor_gain	1.0000
1:146018700:A:AT	acceptor_loss	1.0000
1:146018701:C:G	acceptor_gain	1.0000
1:146018701:CAGC:C	acceptor_loss	1.0000
1:146018703:CACA:C	acceptor_loss	1.0000
1:146018702:A:AG	acceptor_gain	0.9900
1:146021584:G:GG	donor_gain	0.9900
1:146018709:T:TA	acceptor_gain	0.9800
1:146019733:GCTC:G	acceptor_gain	0.9800
1:146019907:G:GG	donor_gain	0.9800
1:146019463:GGCCC:G	donor_gain	0.9700
1:146019733:G:GG	acceptor_gain	0.9700
1:146019734:A:AG	acceptor_gain	0.9700
1:146019695:G:GG	donor_gain	0.9600
1:146021586:CA:C	donor_gain	0.9600
1:146021582:AA:A	donor_loss	0.9500
1:146021583:T:G	donor_loss	0.9500
1:146021585:AGTA:A	donor_loss	0.9500
1:146021586:CAGTA:C	donor_loss	0.9500
1:146021587:ACAGT:A	donor_loss	0.9500
1:146021588:AACAG:A	donor_loss	0.9500
1:146019733:GCT:G	acceptor_gain	0.9400
1:146021581:AGT:A	donor_loss	0.9400
1:146021587:ACA:A	donor_gain	0.9400
1:146019699:C:G	donor_gain	0.9300

AlphaMissense

2720 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:146019523:G:C	F103L	0.999
1:146019523:G:T	F103L	0.999
1:146019525:A:G	F103L	0.999
1:146019541:G:C	C97W	0.999
1:146019542:C:T	C97Y	0.999
1:146019695:T:C	Y46C	0.999
1:146019707:C:G	C42S	0.999
1:146019708:A:T	C42S	0.999
1:146018618:A:C	F247C	0.998
1:146019494:A:G	L113P	0.998
1:146019522:G:C	H104D	0.998
1:146019524:A:C	F103C	0.998
1:146019530:A:T	L101H	0.998
1:146019542:C:A	C97F	0.998
1:146019542:C:G	C97S	0.998
1:146019543:A:G	C97R	0.998
1:146019543:A:T	C97S	0.998
1:146019566:C:G	C89S	0.998
1:146019566:C:T	C89Y	0.998
1:146019567:A:G	C89R	0.998
1:146019567:A:T	C89S	0.998
1:146019707:C:A	C42F	0.998
1:146019707:C:T	C42Y	0.998
1:146019716:A:G	I39T	0.998
1:146019722:C:G	C37S	0.998
1:146019723:A:T	C37S	0.998
1:146018652:A:C	Y236D	0.997
1:146019475:G:C	C119W	0.997
1:146019476:C:G	C119S	0.997
1:146019476:C:T	C119Y	0.997

dbSNP variants (sampled 300 via entrez): RS1001494877 (1:146019167 T>C,G), RS1001841174 (1:146018918 T>C), RS1003112531 (1:146017090 C>T), RS1003572945 (1:146017410 C>T), RS1004430045 (1:146019812 T>A,C), RS1006962532 (1:146017529 T>C), RS1007013332 (1:146017919 T>A), RS1007152677 (1:146023732 A>G,T), RS1008106313 (1:146021495 G>A), RS1010480921 (1:146017866 G>A), RS1010637392 (1:146023245 G>A), RS1010959452 (1:146022884 C>G,T), RS1012002651 (1:146021964 G>A), RS1014012787 (1:146018949 C>T), RS1015760008 (1:146019838 C>T)

Disease associations

OMIM: gene MIM:608374 | disease phenotypes: MIM:602390, MIM:235200

GenCC curated gene-disease

Disease	Classification	Inheritance
hemochromatosis type 2A	Definitive	Autosomal recessive
hemochromatosis type 2	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
hemochromatosis type 2A	Definitive	AR

Mondo (3): hemochromatosis type 2A (MONDO:0011216), hemochromatosis type 2 (MONDO:0019257), hemochromatosis type 1 (MONDO:0021001)

Orphanet (3): HJV or HAMP-related hemochromatosis (Orphanet:79230), Symptomatic form of HFE-related hemochromatosis (Orphanet:465508), NON RARE IN EUROPE: Hemochromatosis type 1 (Orphanet:139498)

HPO phenotypes

30 total (30 of 30 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000027	Azoospermia
HP:0000044	Hypogonadotropic hypogonadism
HP:0000135	Hypogonadism
HP:0000141	Amenorrhea
HP:0000789	Infertility
HP:0000802	Impotence
HP:0000819	Diabetes mellitus
HP:0000939	Osteoporosis
HP:0000953	Hyperpigmentation of the skin
HP:0001254	Lethargy
HP:0001324	Muscle weakness
HP:0001369	Arthritis
HP:0001394	Cirrhosis
HP:0001635	Congestive heart failure
HP:0001638	Cardiomyopathy
HP:0001644	Dilated cardiomyopathy
HP:0001744	Splenomegaly
HP:0002240	Hepatomegaly
HP:0002612	Congenital hepatic fibrosis
HP:0002910	Elevated circulating hepatic transaminase concentration
HP:0003040	Arthropathy
HP:0003281	Increased circulating ferritin concentration
HP:0003452	Increased circulating iron concentration
HP:0007440	Generalized hyperpigmentation
HP:0011031	Abnormality of iron homeostasis
HP:0011462	Young adult onset
HP:0011675	Arrhythmia
HP:0012093	Abnormality of endocrine pancreas physiology
HP:0012463	Elevated transferrin saturation

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C537247	Hemochromatosis, type 2 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Aflatoxin B1	affects expression, decreases expression	3
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	2
Tetrachlorodibenzodioxin	affects cotreatment, decreases expression	2
Cyclosporine	decreases expression	2
lasiocarpine	decreases expression	1
methyleugenol	decreases expression	1
arsenite	increases methylation	1
sodium arsenite	decreases expression	1
rutecarpine	decreases expression	1
9-chloro-2-(2-furyl)-(1,2,4)triazolo(1,5-c)quinazolin-5-imine	decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
SU 9516	decreases expression	1
dorsomorphin	decreases expression	1
incobotulinumtoxinA	decreases expression	1
MT19c compound	decreases expression	1
Rosiglitazone	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Sunitinib	decreases expression	1
Acetaminophen	decreases expression	1
Doxorubicin	decreases expression	1
Endosulfan	decreases expression, affects cotreatment	1
Estradiol	decreases expression	1
N-Nitrosopyrrolidine	decreases expression	1
Plant Extracts	decreases expression, affects cotreatment	1
Rotenone	increases expression	1
Triclosan	decreases expression	1
Valproic Acid	decreases expression, decreases methylation	1
Okadaic Acid	decreases expression	1

Clinical trials (associated diseases)

24 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00122980	PHASE3	TERMINATED	Stroke With Transfusions Changing to Hydroxyurea
NCT00202436	PHASE3	COMPLETED	Haemochromatosis:Phlebotomy Versus Erythrocytapheresis Therapy
NCT00350662	PHASE3	COMPLETED	Study With Deferiprone and/or Desferrioxamine in Iron Overloaded Patients
NCT00000595	PHASE2	COMPLETED	Evaluation of Subcutaneous Desferrioxamine as Treatment for Transfusional Hemochromatosis
NCT00007150	PHASE2	ACTIVE_NOT_RECRUITING	Treatment of Hemochromatosis
NCT00349453	PHASE2	COMPLETED	Study Using Deferiprone Alone or in Combination With Desferrioxamine in Iron Overloaded Transfusion-dependent Patients
NCT01892644	PHASE2	WITHDRAWN	Treatment of Iron Overload With Deferasirox (Exjade) in Hereditary Hemochromatosis and Myelodysplastic Syndrome
NCT00712738	PHASE1	COMPLETED	Oral Nifedipine to Treat Iron Overload
NCT00001203	Not specified	COMPLETED	Deferoxamine for the Treatment of Hemochromatosis
NCT00001455	Not specified	COMPLETED	Iron Overload in African Americans
NCT00005541	Not specified	COMPLETED	Hemochromatosis and Iron Overload Screening Study (HEIRS)
NCT00005559	Not specified	COMPLETED	Statistical Basis for Hemochromatosis Screening
NCT00006312	Not specified	COMPLETED	Hemochromatosis–Genetic Prevalence and Penetrance
NCT00199628	Not specified	COMPLETED	Research Network for Neonatal Diseases Induced by Tissular Fetomaternal Alloimmunization
NCT00509652	Not specified	UNKNOWN	Erythrocyte Apheresis Versus Phlebotomy in Hemochromatosis
NCT00587535	Not specified	COMPLETED	Evaluation of a New MR Pulse Sequence to Quantify Liver Iron Concentration
NCT01524757	Not specified	UNKNOWN	Proton Pump Inhibitors in the Prevention of Iron Reaccumulation in Patient With Hereditary Hemochromatosis
NCT01810965	Not specified	COMPLETED	Impact of Bloodletting on Iron Metabolism in Type 1 Hemochromatosis
NCT02025543	Not specified	COMPLETED	Confounder-Corrected Quantitative MRI Biomarker of Hepatic Iron Content
NCT02099214	Not specified	COMPLETED	Estimation of Myocardial Iron Overload by 3 Tesla MRI in HFE Hereditary Haemochromatosis
NCT03654794	Not specified	COMPLETED	Study of the Cellular Diffusion of Tacrolimus Across the Membrane of Mononuclear Cells
NCT03743272	Not specified	COMPLETED	Repeatability and Reproducibility of Multiparametric MRI
NCT04631718	Not specified	COMPLETED	MRI QSM Imaging for Iron Overload
NCT06137079	Not specified	UNKNOWN	Iron Overload and Endocrinological Diseases