HEPH

Summary

HEPH (hephaestin, HGNC:4866) is a protein-coding gene on chromosome Xq12, encoding Hephaestin (Q9BQS7). Plasma membrane ferroxidase that mediates the extracellular conversion of ferrous/Fe(2+) iron into its ferric/Fe(3+) form.

This gene encodes a member of the multicopper oxidase protein family. The encoded protein is involved in the transport of dietary iron from epithelial cells of the intestinal lumen into the circulatory system, and may be involved in copper transport and homeostasis. In mouse, defects in this gene can lead to severe microcytic anemia. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 9843 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hereditary hemochromatosis (Moderate, GenCC)
• GWAS associations: 5
• Clinical variants (ClinVar): 278 total
• MANE Select transcript: NM_001367233

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4866
Approved symbol	HEPH
Name	hephaestin
Location	Xq12
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0698, CPL
Ensembl gene	ENSG00000089472
Ensembl biotype	protein_coding
OMIM	300167
Entrez	9843

Gene structure

Transcript identifiers

Ensembl transcripts: 75 — 65 protein_coding, 7 nonsense_mediated_decay, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000336279, ENST00000343002, ENST00000419594, ENST00000425114, ENST00000429547, ENST00000441993, ENST00000458621, ENST00000471121, ENST00000519389, ENST00000682362, ENST00000682927, ENST00000683049, ENST00000683420, ENST00000684042, ENST00000684071, ENST00000684603, ENST00000684625, ENST00000887518, ENST00000887519, ENST00000887520, ENST00000887521, ENST00000887522, ENST00000887523, ENST00000887524, ENST00000887525, ENST00000887526, ENST00000887527, ENST00000887528, ENST00000887529, ENST00000887530, ENST00000887531, ENST00000887532, ENST00000887533, ENST00000887534, ENST00000887535, ENST00000887536, ENST00000887537, ENST00000887538, ENST00000887539, ENST00000887540, ENST00000887541, ENST00000887542, ENST00000887543, ENST00000887544, ENST00000887545, ENST00000887546, ENST00000887547, ENST00000887548, ENST00000887549, ENST00000887550, ENST00000887551, ENST00000887552, ENST00000887553, ENST00000887554, ENST00000931787, ENST00000931788, ENST00000931789, ENST00000931790, ENST00000931791, ENST00000931792, ENST00000931793, ENST00000931794, ENST00000956604, ENST00000956605, ENST00000956606, ENST00000956607, ENST00000956608, ENST00000956609, ENST00000956610, ENST00000956611, ENST00000956612, ENST00000956613, ENST00000956614, ENST00000956615, ENST00000956616

RefSeq mRNA: 14 — MANE Select: NM_001367233 NM_001130860, NM_001282141, NM_001367232, NM_001367233, NM_001367234, NM_001367236, NM_001367238, NM_001367239, NM_001367240, NM_001367241, NM_001367242, NM_001367243, NM_014799, NM_138737

CCDS: CCDS14384, CCDS14385, CCDS48133, CCDS65277, CCDS94623

Canonical transcript exons

ENST00000343002 — 21 exons

Exon	Start	End
ENSE00000363852	66197683	66197894
ENSE00000671993	66195098	66195229
ENSE00000671996	66200540	66200752
ENSE00000869155	66198878	66199028
ENSE00000869158	66193502	66193638
ENSE00000869159	66192130	66192298
ENSE00000869160	66189684	66189938
ENSE00001592865	66256105	66256330
ENSE00001688447	66260100	66260262
ENSE00001694267	66258840	66258979
ENSE00001779033	66263644	66263688
ENSE00001793052	66255035	66255141
ENSE00003490948	66172355	66172599
ENSE00003498066	66170558	66170737
ENSE00003527357	66188359	66188541
ENSE00003548610	66173589	66173801
ENSE00003550523	66203364	66203577
ENSE00003623053	66207195	66207334
ENSE00003785575	66208115	66208246
ENSE00003916168	66164247	66164470
ENSE00003918881	66266440	66267389

Expression profiles

Bgee: expression breadth ubiquitous, 255 present calls, max score 98.98.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 11.0330 / max 536.7850, expressed in 957 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
196576	4.5660	887
196577	3.1330	689
196571	1.5399	80
196570	0.6202	68
196567	0.3083	73
196573	0.2493	30
196569	0.2060	57
196575	0.1487	57
196572	0.1046	43
196568	0.0933	40

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
jejunal mucosa	UBERON:0000399	98.98	gold quality
mucosa of sigmoid colon	UBERON:0004993	98.55	gold quality
colonic mucosa	UBERON:0000317	98.50	gold quality
ileal mucosa	UBERON:0000331	97.90	gold quality
rectum	UBERON:0001052	96.99	gold quality
duodenum	UBERON:0002114	96.40	gold quality
transverse colon	UBERON:0001157	95.49	gold quality
blood vessel layer	UBERON:0004797	95.40	gold quality
large intestine	UBERON:0000059	95.34	gold quality
descending thoracic aorta	UBERON:0002345	95.26	gold quality
sigmoid colon	UBERON:0001159	95.24	gold quality
colon	UBERON:0001155	95.23	gold quality
cranial nerve II	UBERON:0000941	95.20	gold quality
intestine	UBERON:0000160	94.81	gold quality
mucosa of transverse colon	UBERON:0004991	94.79	gold quality
thoracic aorta	UBERON:0001515	94.60	gold quality
smooth muscle tissue	UBERON:0001135	94.59	gold quality
ascending aorta	UBERON:0001496	94.50	gold quality
muscle layer of sigmoid colon	UBERON:0035805	94.50	gold quality
right coronary artery	UBERON:0001625	94.38	gold quality
gall bladder	UBERON:0002110	93.87	gold quality
aorta	UBERON:0000947	93.76	gold quality
saphenous vein	UBERON:0007318	93.61	gold quality
small intestine	UBERON:0002108	93.11	gold quality
popliteal artery	UBERON:0002250	93.11	gold quality
tibial artery	UBERON:0007610	93.09	gold quality
endothelial cell	CL:0000115	93.03	gold quality
small intestine Peyer’s patch	UBERON:0003454	92.96	gold quality
periodontal ligament	UBERON:0008266	92.21	gold quality
coronary artery	UBERON:0001621	90.61	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.30

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CDX2

miRNA regulators (miRDB)

33 targeting HEPH, 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-1252-5P	100.00	69.80	2774
HSA-MIR-10401-5P	99.99	65.79	948
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-6793-5P	99.97	65.95	758
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-8067	99.86	69.59	2260
HSA-MIR-4658	99.77	64.94	514
HSA-MIR-6790-5P	99.77	65.24	505
HSA-MIR-1200	99.71	70.42	1838
HSA-MIR-12124	99.68	69.17	2700
HSA-MIR-3609	99.52	69.89	2587
HSA-MIR-548AH-5P	99.52	69.73	2626
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-6878-3P	99.24	64.23	920
HSA-MIR-100-3P	99.20	67.33	672
HSA-MIR-544B	99.18	67.41	1632
HSA-MIR-4324	99.04	70.14	1569
HSA-MIR-4744	99.01	69.91	1581
HSA-MIR-6876-3P	98.97	65.69	765
HSA-MIR-6770-5P	98.97	66.76	1853
HSA-MIR-520G-3P	98.91	67.38	1914
HSA-MIR-520H	98.91	67.38	1914
HSA-MIR-626	98.89	66.21	762
HSA-MIR-4716-5P	98.82	68.57	1168
HSA-MIR-4724-3P	97.57	67.31	785
HSA-MIR-6890-3P	97.50	65.71	997

Literature-anchored findings (GeneRIF, showing 16)

• location was observed on or near the cell surface suggesting it might participate in surface membrane transport of iron (PMID:11891802)
• The gene structure, spanning approximately 100 kb, was assembled from the cDNA clones and the chromosome X genomic sequence data. Modelling supports its role as a membrane-tethered ferroxidase. (PMID:11932491)
• The hephaestin protein mRNA expression is not significantly altered by variations in iron homeostasis. The effect of phlebotomy-induced erythropoiesis did not alter either gene transcript mRNA expression. (PMID:16137899)
• Reombinant hephaestin was shown to have both multicopper oxidase and ferroxidase activity. (PMID:16274220)
• Results suggest the possibility that FPN-1 might associate and interact with Heph in the process of iron exit across the basolateral membrane of intestinal absorptive cell. (PMID:17486601)
• stable complex between these Cp and Hp and Tf does not occur under the experimental conditions used (PMID:18022819)
• Repletion of copper in Caco2 cells leads to reconstitution of hephaestin protein expression, activity, and transepithelial iron transport. (PMID:19452451)
• Hephaestin is expressed in enterocytes, in the antral portion of the stomach, in the myenteric and submucous plexi, and in pancreatic beta-cells. (PMID:20019163)
• In contrast to ceruloplasmin, hephaestin was incapable of direct oxidation of adrenaline and dopamine implying a difference in biological substrate specificities between these two homologous ferroxidases. (PMID:21802403)
• Heph is active in placenta but may not play a key role in placental iron transport. (PMID:22170436)
• These results support the hypothesis that hephaestin is involved in iron mobilization of iron from the intestine to circulation. (PMID:22503983)
• Iron efflux from human brain microvasculature endothelial cells ferroportin requires the action of an exocytoplasmic ferroxidase which can be either endogenous hephaestin or extracellular ceruloplasmin. (PMID:23640881)
• This review describes function of hephaestin as ferroxidase is essential for iron binding to apotransferrin in the lamina propria of the intestinal mucosa, a process that is important for further transport of iron to the liver by the portal vein. (PMID:24988611)
• Iron supplementation increased surface expression of the iron-efflux complex, and copper depletion knocked down hephaestin (Heph) activity and decreased ferroportin (Fpn) membrane localization. (PMID:30647129)
• Zinc induces iron egress from intestinal Caco-2 cells via induction of Hephaestin: A role for PI3K in intestinal iron absorption. (PMID:31973819)
• Association between iron metabolism and SARS-COV-2 infection, determined by ferritin, hephaestin and hypoxia-induced factor-1 alpha levels in COVID-19 patients. (PMID:36600108)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	hephl1b	ENSDARG00000026403
mus_musculus	Heph	ENSMUSG00000031209
rattus_norvegicus	Heph	ENSRNOG00000012294

Paralogs (35): NRXN3 (ENSG00000021645), TLL1 (ENSG00000038295), CP (ENSG00000047457), DCBLD2 (ENSG00000057019), TLL2 (ENSG00000095587), NRP1 (ENSG00000099250), PCOLCE (ENSG00000106333), CNTNAP3 (ENSG00000106714), CUBN (ENSG00000107611), CNTNAP1 (ENSG00000108797), NRXN2 (ENSG00000110076), MEP1A (ENSG00000112818), NRP2 (ENSG00000118257), CUZD1 (ENSG00000138161), MFGE8 (ENSG00000140545), MEP1B (ENSG00000141434), PDGFC (ENSG00000145431), CNTNAP4 (ENSG00000152910), CNTNAP3B (ENSG00000154529), CNTNAP5 (ENSG00000155052), CDCP2 (ENSG00000157211), PCOLCE2 (ENSG00000163710), EDIL3 (ENSG00000164176), NETO1 (ENSG00000166342), BMP1 (ENSG00000168487), PDGFD (ENSG00000170962), NETO2 (ENSG00000171208), CNTNAP2 (ENSG00000174469), NRXN1 (ENSG00000179915), HEPHL1 (ENSG00000181333), F8 (ENSG00000185010), ASTL (ENSG00000188886), F5 (ENSG00000198734), MFRP (ENSG00000235718), CNTNAP3C (ENSG00000283378)

Protein

Protein identifiers

Hephaestin — Q9BQS7 (reviewed: Q9BQS7)

All UniProt accessions (12): Q9BQS7, A0A0C4DG76, A0A804HIE6, A0A804HJ33, A0A804HJ98, A0A804HK72, A0A804HKF4, E7ES21, F8WBZ8, Q1HE23, Q5JZ07, Q5JZ08

UniProt curated annotations — full annotation on UniProt →

Function. Plasma membrane ferroxidase that mediates the extracellular conversion of ferrous/Fe(2+) iron into its ferric/Fe(3+) form. Couples ferroportin which specifically exports ferrous/Fe(2+) iron from cells to transferrin that only binds and shuttles extracellular ferric/Fe(3+) iron throughout the body. By helping iron transfer from cells to blood mainly contributes to dietary iron absorption by the intestinal epithelium and more generally regulates iron levels in the body.

Subunit / interactions. Part of a complex composed of SLC40A1/ferroportin, TF/transferrin and HEPH/hephaestin that transfers iron from cells to transferrin.

Subcellular location. Basolateral cell membrane.

Tissue specificity. Expressed by intestinal absorptive cells (at protein level). Also detected in breast, colon, bone trabecular cells and fibroblasts.

Cofactor. Binds 6 Cu cations per monomer.

Similarity. Belongs to the multicopper oxidase family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q9BQS7-1	1	yes
Q9BQS7-2	2
Q9BQS7-3	3
Q9BQS7-4	4

RefSeq proteins (14): NP_001124332, NP_001269070, NP_001354161, NP_001354162, NP_001354163, NP_001354165, NP_001354167, NP_001354168, NP_001354169, NP_001354170, NP_001354171, NP_001354172, NP_055614, NP_620074 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002355	Cu_oxidase_Cu_BS	Binding_site
IPR008972	Cupredoxin	Homologous_superfamily
IPR011706	Cu-oxidase_C	Domain
IPR011707	Cu-oxidase-like_N	Domain
IPR033138	Cu_oxidase_CS	Conserved_site
IPR045087	Cu-oxidase_fam	Family
IPR048236	Ceruloplasmin-like_CuRO_5	Domain

Pfam: PF07731, PF07732

Catalyzed reactions (Rhea), 1 shown:

• 4 Fe(2+) + O2 + 4 H(+) = 4 Fe(3+) + 2 H2O (RHEA:11148)

UniProt features (75 total): binding site 36, glycosylation site 8, domain 6, mutagenesis site 6, disulfide bond 5, modified residue 3, splice variant 3, topological domain 2, sequence conflict 2, signal peptide 1, chain 1, transmembrane region 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BQS7-F1	89.09	0.76

Functional residue map

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

Ligand- & substrate-binding residues (36): 70; 73; 126 (type 2 copper site); 126; 128 (type 3 copper site); 134; 152; 153; 186 (type 3 copper site); 186; 188 (type 3 copper site); 265 …

Post-translational modifications (3): 1145, 1150, 1155

Disulfide bonds (5): 180–206, 285–366, 534–560, 637–718, 877–903

Glycosylation sites (8): 164, 236, 588, 714, 758, 829, 873, 931

Mutagenesis-validated functional residues (6):

Position	Phenotype
264	decreased affinity for fe(2+) and decreased ferroxidase activity; when associated with a-269, a-616 and a-621. loss of a
269	decreased affinity for fe(2+) and decreased ferroxidase activity; when associated with a-264, a-616 and a-621. loss of a
616	decreased affinity for fe(2+) and decreased ferroxidase activity; when associated with a-264, a-269 and a-621.
621	decreased affinity for fe(2+) and decreased ferroxidase activity; when associated with a-264, a-269 and a-616.
960	loss of affinity for fe(2+) and loss of ferroxidase activity; when associated with a-264, a-269 and a-965.
965	loss of affinity for fe(2+) and loss of ferroxidase activity; when associated with a-264, a-269 and a-960.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-425410	Metal ion SLC transporters
R-HSA-5655799	Defective SLC40A1 causes hemochromatosis 4 (HFE4) (duodenum)
R-HSA-917937	Iron uptake and transport

MSigDB gene sets: 155 (showing top): MORF_ITGA2, GOBP_DIGESTION, AP1_01, GOBP_TRANSITION_METAL_ION_TRANSPORT, AREB6_01, GOBP_IRON_ION_TRANSPORT, GOBP_POSITIVE_REGULATION_OF_TRANSMEMBRANE_TRANSPORT, MORF_RAD51L3, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_POSITIVE_REGULATION_OF_MONOATOMIC_ION_TRANSPORT, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM2, BLALOCK_ALZHEIMERS_DISEASE_UP, RIGGI_EWING_SARCOMA_PROGENITOR_DN, MORF_PRKCA, OCT1_07

GO Biological Process (5): iron ion transport (GO:0006826), multicellular organismal-level iron ion homeostasis (GO:0060586), intestinal iron absorption (GO:0160179), positive regulation of iron export across plasma membrane (GO:1904040), monoatomic ion transport (GO:0006811)

GO Molecular Function (6): ferroxidase activity (GO:0004322), copper ion binding (GO:0005507), protein binding (GO:0005515), oxidoreductase activity (GO:0016491), oxidoreductase activity, acting on metal ions (GO:0016722), metal ion binding (GO:0046872)

GO Cellular Component (6): plasma membrane (GO:0005886), basolateral plasma membrane (GO:0016323), perinuclear region of cytoplasm (GO:0048471), extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
SLC-mediated transmembrane transport	1
SLC transporter disorders	1
Transport of small molecules	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
transition metal ion transport	1
monoatomic cation homeostasis	1
inorganic ion homeostasis	1
multicellular organismal-level chemical homeostasis	1
intestinal absorption	1
positive regulation of iron ion transmembrane transport	1
iron ion export across plasma membrane	1
regulation of iron export across plasma membrane	1
transport	1
oxidoreductase activity, acting on metal ions, oxygen as acceptor	1
transition metal ion binding	1
binding	1
catalytic activity	1
oxidoreductase activity	1
cation binding	1
membrane	1
cell periphery	1
basal plasma membrane	1
plasma membrane region	1
cytoplasm	1

Protein interactions and networks

STRING

1522 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HEPH	SLC40A1	Q9NP59	925
HEPH	CYBRD1	Q53TN4	829
HEPH	SLC11A2	P49281	817
HEPH	HAMP	P81172	789
HEPH	TFR2	Q9UP52	718
HEPH	HJV	Q6ZVN8	665
HEPH	TFRC	P02786	657
HEPH	HFE	Q30201	649
HEPH	FTL	P02792	592
HEPH	PNLIP	P16233	585
HEPH	IREB2	P48200	534
HEPH	STEAP3	Q658P3	527
HEPH	ACO1	P21399	513
HEPH	FTH1	P02794	489
HEPH	SLC46A1	Q96NT5	489

IntAct

1 interactions, top by confidence:

BioGRID (5): HEPH (Proximity Label-MS), HEPH (Proximity Label-MS), HEPH (Proximity Label-MS), HEPH (Affinity Capture-MS), HEPH (Affinity Capture-MS)

ESM2 similar proteins: A2Y9C2, A2Y9C5, A2ZNT5, B3EWZ9, P00450, P13635, P29162, P33434, P33436, P56193, P83388, Q00624, Q02075, Q02079, Q06K61, Q08CS6, Q0IQU1, Q0JHP8, Q2QZ80, Q2R0L0, Q2R0L2, Q2VQV9, Q3V1H3, Q4PIF8, Q4WQY8, Q58L90, Q58L91, Q593B6, Q61147, Q6MZM0, Q7SZN0, Q84J37, Q8VXX5, Q8VZA1, Q90611, Q920H8, Q966W3, Q96WT3, Q9AWU4, Q9BQS7

Diamond homologs: A0A067XMP2, A0A0B2WJN5, A0A0B4F1I0, A0A0B4F5S2, A0A0B4GLB5, A0A0B4HQH6, A0A1S7IUL2, A0A2G5I8N8, A0A443HK79, A0A4Y6F0M8, C3SAH7, D0VWU3, D4APX3, E9E686, E9F648, E9RBR0, I1RF62, I6WZK7, O59896, P17489, Q01679, Q02081, Q0UHZ8, Q12570, Q12717, Q12718, Q12719, Q96WM9, Q99046, Q99049, Q99055, Q99056, Q9BQS7, Q9SU40, S8FIE4, W3X732, W3X7K0, A0A067XMP0, A0A5B8YWJ2, C0HLV7

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	130
Likely benign	11
Benign	6

Top pathogenic / likely-pathogenic (0)

SpliceAI

3528 predictions. Top by Δscore:

Variant	Effect	Δscore
X:66170738:G:GG	donor_gain	1.0000
X:66172353:A:AG	acceptor_gain	1.0000
X:66172353:AGAGT:A	acceptor_gain	1.0000
X:66172354:G:GG	acceptor_gain	1.0000
X:66172354:GA:G	acceptor_gain	1.0000
X:66172354:GAGT:G	acceptor_gain	1.0000
X:66172354:GAGTG:G	acceptor_gain	1.0000
X:66172596:GAAG:G	donor_gain	1.0000
X:66172600:G:A	donor_loss	1.0000
X:66172601:T:G	donor_loss	1.0000
X:66188537:GCATG:G	donor_gain	1.0000
X:66188539:ATGG:A	donor_loss	1.0000
X:66188540:TG:T	donor_gain	1.0000
X:66188541:GG:G	donor_gain	1.0000
X:66188541:GGTG:G	donor_loss	1.0000
X:66188542:G:GC	donor_loss	1.0000
X:66188543:T:G	donor_loss	1.0000
X:66189678:TTGCA:T	acceptor_loss	1.0000
X:66189679:TGCAG:T	acceptor_loss	1.0000
X:66189680:GCA:G	acceptor_loss	1.0000
X:66189681:CAG:C	acceptor_loss	1.0000
X:66189682:A:AG	acceptor_gain	1.0000
X:66189682:AGCA:A	acceptor_loss	1.0000
X:66189683:G:A	acceptor_loss	1.0000
X:66189683:G:GA	acceptor_gain	1.0000
X:66189683:GC:G	acceptor_gain	1.0000
X:66189683:GCA:G	acceptor_gain	1.0000
X:66189683:GCAA:G	acceptor_gain	1.0000
X:66189683:GCAAT:G	acceptor_gain	1.0000
X:66189936:GAGG:G	donor_loss	1.0000

AlphaMissense

7698 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:66172563:C:G	H126D	0.996
X:66172538:T:A	N117K	0.995
X:66172538:T:G	N117K	0.995
X:66172599:G:C	G138R	0.995
X:66173729:T:G	Y185D	0.995
X:66173736:C:T	S187F	0.995
X:66260201:C:G	C1046W	0.995
X:66173669:T:A	W165R	0.993
X:66173669:T:C	W165R	0.993
X:66189691:T:A	N272K	0.993
X:66189691:T:G	N272K	0.993
X:66260199:T:C	C1046R	0.993
X:66258847:T:A	N968K	0.992
X:66258847:T:G	N968K	0.992
X:66260187:T:A	W1042R	0.992
X:66260187:T:C	W1042R	0.992
X:66173736:C:A	S187Y	0.991
X:66188445:A:C	S238R	0.991
X:66188447:C:A	S238R	0.991
X:66188447:C:G	S238R	0.991
X:66200605:T:A	W644R	0.991
X:66200605:T:C	W644R	0.991
X:66260189:G:C	W1042C	0.991
X:66260189:G:T	W1042C	0.991
X:66173784:T:C	L203P	0.990
X:66260200:G:A	C1046Y	0.990
X:66172598:A:C	E137D	0.989
X:66172598:A:T	E137D	0.989
X:66173735:T:C	S187P	0.989
X:66173756:G:C	D194H	0.989

dbSNP variants (sampled 300 via entrez): RS1000033768 (X:66200399 G>A,C), RS1000050934 (X:66254247 A>T), RS1000099804 (X:66252310 G>C,T), RS1000110123 (X:66200812 C>G,T), RS1000143440 (X:66209322 G>A), RS1000162506 (X:66216513 G>A), RS1000169632 (X:66259186 G>A), RS1000193347 (X:66172888 C>T), RS1000196558 (X:66233757 A>G), RS1000210751 (X:66211113 T>C,G), RS1000240188 (X:66246512 A>G), RS1000252660 (X:66225384 C>A,T), RS1000297864 (X:66216207 G>A,T), RS1000298853 (X:66162687 C>A,G,T), RS1000336715 (X:66209808 C>T)

Disease associations

OMIM: gene MIM:300167 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
hereditary hemochromatosis	Moderate	X-linked

Mondo (1): hereditary hemochromatosis (MONDO:0006507)

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST000824_21	Erectile dysfunction and prostate cancer treatment	6.000000e-06
GCST006661_1	Male-pattern baldness	3.000000e-15
GCST006661_217	Male-pattern baldness	5.000000e-178
GCST006661_271	Male-pattern baldness	1.000000e-44
GCST006661_316	Male-pattern baldness	5.000000e-20

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D006432	Hemochromatosis	C16.320.565.618.337; C18.452.565.500.480; C18.452.648.618.337

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

41 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases methylation, increases expression, affects expression, decreases expression	6
entinostat	decreases expression, affects cotreatment	2
Nickel	decreases expression	2
testosterone enanthate	affects expression	1
methylmercuric chloride	decreases expression	1
methylselenic acid	increases expression	1
zinc chloride	decreases expression	1
sodium arsenite	affects methylation	1
manganese chloride	increases expression	1
tebuconazole	decreases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
incobotulinumtoxinA	increases expression	1
Dasatinib	increases expression	1
Sunitinib	decreases expression	1
Asbestos	affects response to substance	1
Ascorbic Acid	affects cotreatment, decreases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Bilirubin	decreases expression	1
Cadmium	decreases expression, increases abundance	1
Demecolcine	increases expression	1
Diethylhexyl Phthalate	decreases expression	1
Dimethyl Sulfoxide	increases expression	1
Doxorubicin	increases expression	1
Etoposide	affects response to substance	1
Hydrogen Peroxide	affects expression	1
Manganese	increases expression	1
Mercury	increases expression	1
Methyl Methanesulfonate	decreases expression	1

Clinical trials (associated diseases)

35 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
NCT01398644	PHASE3	UNKNOWN	Erythrocytapheresis Versus Phlebotomy as Maintenance Therapy in Hereditary Hemochromatosis (HH) 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
NCT03203850	PHASE2	TERMINATED	Study to Evaluate the Efficacy and Safety of Deferasirox Film-coated Tablet Versus Phlebotomy in Patients With Hereditary Hemochromatosis (HH)
NCT03395704	PHASE2	COMPLETED	A Study of LJPC-401 for the Treatment of Iron Overload in Adult Patients With Hereditary Hemochromatosis
NCT04202965	PHASE2	COMPLETED	PTG-300 in Subjects With Hereditary Hemochromatosis
NCT00712738	PHASE1	COMPLETED	Oral Nifedipine to Treat Iron Overload
NCT05238207	PHASE1	TERMINATED	A Study to Evaluate BBI-001 in Hereditary Haemochromatosis (HH) Patients and Iron Deficient Volunteers
NCT00440986	PHASE2/PHASE3	COMPLETED	Clinical Management of Hereditary Hemochromatosis: Phlebotomy vs. Erythrocytoapheresis
NCT00395629	PHASE1/PHASE2	COMPLETED	Safety and Efficacy of Deferasirox (ICL670) in Patients With Iron Overload Resulting From Hereditary Hemochromatosis
NCT07371793	PHASE1/PHASE2	RECRUITING	A Study to Evaluate BBI-001 in Healthy Volunteers and in Patients With Hereditary Hemochromatosis
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
NCT00068159	Not specified	COMPLETED	Cardiac Function in Patients With Hereditary Hemochromatosis
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
NCT01631708	Not specified	COMPLETED	Mi-iron - Moderately Increased Iron - is Reducing Iron Overload Necessary?
NCT01991925	Not specified	WITHDRAWN	Implications for Quality of Life and Quality of Care in Patients With Hereditary Haemochromatosis
NCT02025543	Not specified	COMPLETED	Confounder-Corrected Quantitative MRI Biomarker of Hepatic Iron Content
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
NCT04779593	Not specified	RECRUITING	Impact of Transferrin Saturation Guided Maintenance Treatment on Quality of Life in HFE Haemochromatosis
NCT05742035	Not specified	UNKNOWN	Quality and Biologic Characteristics of Red Blood Concentrates Obtained From Individuals With Elevated Ferritin.
NCT06137079	Not specified	UNKNOWN	Iron Overload and Endocrinological Diseases