HAMP

Summary

HAMP (hepcidin antimicrobial peptide, HGNC:15598) is a protein-coding gene on chromosome 19q13.12, encoding Hepcidin (P81172). Liver-produced hormone that constitutes the main circulating regulator of iron absorption and distribution across tissues. It is a selective cancer dependency (DepMap: 29.3% of cell lines).

The product encoded by this gene is involved in the maintenance of iron homeostasis, and it is necessary for the regulation of iron storage in macrophages, and for intestinal iron absorption. The preproprotein is post-translationally cleaved into mature peptides of 20, 22 and 25 amino acids, and these active peptides are rich in cysteines, which form intramolecular bonds that stabilize their beta-sheet structures. These peptides exhibit antimicrobial activity against bacteria and fungi. Mutations in this gene cause hemochromatosis type 2B, also known as juvenile hemochromatosis, a disease caused by severe iron overload that results in cardiomyopathy, cirrhosis, and endocrine failure.

Source: NCBI Gene 57817 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hemochromatosis type 2B (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 9
• Clinical variants (ClinVar): 95 total — 4 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 27
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 29.3% of screened cell lines
• MANE Select transcript: NM_021175

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15598
Approved symbol	HAMP
Name	hepcidin antimicrobial peptide
Location	19q13.12
Locus type	gene with protein product
Status	Approved
Aliases	LEAP-1, HEPC, HFE2B, LEAP1
Ensembl gene	ENSG00000105697
Ensembl biotype	protein_coding
OMIM	606464
Entrez	57817

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 4 protein_coding, 1 retained_intron

ENST00000222304, ENST00000593580, ENST00000598398, ENST00000869748, ENST00000869749

RefSeq mRNA: 1 — MANE Select: NM_021175 NM_021175

CCDS: CCDS12454

Canonical transcript exons

ENST00000222304 — 3 exons

Exon	Start	End
ENSE00000700274	35284789	35284848
ENSE00000862778	35284938	35285143
ENSE00003197148	35282528	35282667

Expression profiles

Bgee: expression breadth ubiquitous, 223 present calls, max score 98.92.

FANTOM5 (CAGE): breadth broad, TPM avg 35.6317 / max 12311.3109, expressed in 359 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
175275	33.1152	306
175274	1.7190	232
175273	0.7363	154
175276	0.0611	11

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	98.92	gold quality
right atrium auricular region	UBERON:0006631	97.08	gold quality
cardiac atrium	UBERON:0002081	96.59	gold quality
liver	UBERON:0002107	96.42	gold quality
cardiac muscle of right atrium	UBERON:0003379	94.00	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	89.94	gold quality
spinal cord	UBERON:0002240	88.37	gold quality
myocardium	UBERON:0002349	87.02	gold quality
cranial nerve II	UBERON:0000941	84.74	gold quality
caput epididymis	UBERON:0004358	84.21	gold quality
body of pancreas	UBERON:0001150	84.02	gold quality
pancreatic ductal cell	CL:0002079	83.66	gold quality
buccal mucosa cell	CL:0002336	83.32	silver quality
medial globus pallidus	UBERON:0002477	80.42	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	80.12	silver quality
substantia nigra	UBERON:0002038	79.39	gold quality
tendon of biceps brachii	UBERON:0008188	78.79	silver quality
midbrain	UBERON:0001891	78.53	gold quality
globus pallidus	UBERON:0001875	78.04	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	78.00	silver quality
decidua	UBERON:0002450	77.57	gold quality
hypothalamus	UBERON:0001898	77.05	gold quality
vena cava	UBERON:0004087	77.00	silver quality
amygdala	UBERON:0001876	76.29	gold quality
CA1 field of hippocampus	UBERON:0003881	76.28	gold quality
pancreas	UBERON:0001264	75.97	gold quality
inferior olivary complex	UBERON:0002127	75.80	gold quality
caudate nucleus	UBERON:0001873	75.64	gold quality
Brodmann (1909) area 9	UBERON:0013540	75.46	gold quality
temporal lobe	UBERON:0001871	75.18	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-GEOD-75367	yes	75.40
E-ENAD-27	yes	30.71
E-MTAB-7249	no	4.25
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

4 targets.

Target	Regulation
ATOH8	Repression
BMP6	Repression
ID1	Repression
SMAD7	Repression

Upstream regulators (CollecTRI, top): ACVR1, ACVR2A, ACVR2B, AP1, ATOH8, BMP2, BMP4, BMP6, BMPR1A, BMPR1B, BMPR2, CD81, CEBPA, CEBPB, CEBPG, CREB3L3, DDIT3, EPO, ESR1, GATA4, HJV, HNF4A, IL6, IRF6, KLF10, MTF1, NFKB, RELA, RGMA, SMAD1, SMAD4, SMAD7, STAT1, STAT3, TFR2, TP53, USF1, USF2, VDR, ZGPAT

miRNA regulators (miRDB)

11 targeting HAMP, 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-5692A	100.00	74.40	6850
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-486-3P	99.51	66.82	1901
HSA-MIR-6165	99.44	67.12	1389
HSA-MIR-548B-3P	99.38	67.26	1000
HSA-MIR-3978	99.24	68.39	2201
HSA-MIR-3619-5P	99.00	68.87	2308
HSA-MIR-214-3P	98.71	68.12	2128

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 29.3% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• A highly disulfide-bonded human antimicrobial protein, LEAP1, is reported. (PMID:11034317)
• The sequencing of the whole hepcidin coding region, intron-exon junctions, 5’ and partially 3’UTRs, did not reveal any alteration in the iron overload patients. (PMID:11836175)
• solution structures of the hepcidin-20 and -25 amino acid peptides determined by standard two-dimensional (1)H NMR spectroscopy (PMID:12138110)
• hepcidin plays a major, causative role in the anemia observed in a subgroup of patients with hepatic adenomas, and may be important in the pathogenesis of the anemia of chronic disease in general. (PMID:12393428)
• study of molecular basis of hepcidin regulation in patients with anemia of inflammation demonstrating that HEPC is a type II acute-phase protein, is regulated by iron stores, and is a key mediator of anemia of inflammation (PMID:12433676)
• Mutant antimicrobial peptide hepcidin is associated with severe juvenile hemochromatosis (PMID:12469120)
• data suggest a close relationship between the transferrin saturation and hepatic hepcidin expression in hereditary hemochromatosis (PMID:12637325)
• REVIEW of the role of hepcidin in iron metabolism and host defense (PMID:12663437)
• Mutations in hepcidin results in hemochromatosis (PMID:12915468)
• new mutation (C70R), which affects 1 of the 8 conserved cysteines that form the disulfide bonds and are critical for the stability of the polypeptide. (PMID:14630809)
• Association of heterozygous mutations in the HFE and HAMP genes could lead to an adult-onset form of primary iron overload. (PMID:14670915)
• HEPC is important in the pathogenesis of anemia of inflammation. (PMID:15124013)
• IL-6 mediates anemia of inflammation by inducing the synthesis of HEPC. (PMID:15124018)
• hepcidin has a role in inhibition of iron transport across human intestinal epithelial cells (PMID:15178582)
• a mutation in HAMP may play a role in familial hemochromatosis (PMID:15198949)
• hepcidin bound to ferroportin in tissue culture cells; after binding, ferroportin was internalized and degraded, leading to decreased export of cellular iron (PMID:15514116)
• urinary hepcidin in patients with iron overload diseases (PMID:15671438)
• Juvenile 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)
• REVIEW: hepcidin as the hormone that links the type II acute phase response to iron handling and erythropoiesis (PMID:15725899)
• hepcidin levels correlated with hepatic iron stores and hemoglobin levels and may also be affected by hepatic dysfunction (PMID:15797999)
• the Y64N and C326Y mutants of FPN are completely resistant to hepcidin inhibition and N144D and N144H are partially resistant. Hemochromatosis-associated FPN mutations, either reduce iron export or produce an FPN variant that is insensitive to hepcidin (PMID:15831700)
• hepcidin accumulated in the ferroportin-rich organs, liver, spleen, and proximal duodenum, highlighting the central role of the hepcidin-ferroportin interaction in iron homeostasis (PMID:15933050)
• soluble and cell-associated hemojuvelin reciprocally regulate hepcidin expression in response to changes in extracellular iron concentration (PMID:15998830)
• central pathogenetic step in HFE-related hemochromatosis is impaired basal expression of HAMP rather than a lack of HAMP upregulation in response to iron stores (PMID:16103673)
• defective hepcidin regulation played a role in iron overload (PMID:16204153)
• Hepcidin serves to decrease the export of iron from reticuloendothelial cells and absorptive enterocytes. (PMID:16315135)
• The crucial role of hepcidin in the control of macrophage iron homeostasis was shown. (PMID:16460831)
• alcohol metabolism-mediated oxidative stress regulates hepcidin transcription via C/EBPalpha, which in turn leads to increased duodenal iron transport (PMID:16737972)
• Hepcidin is the key regulator of systemic iron homeostasis and acts by binding to the cellular iron exporter ferroportin and causing its internalization and degradation. (PMID:16769573)
• central regulatory role in iron circulation and iron toxicity in patients with thalassemia. (PMID:16769583)
• Mechanism by which hepcidin can be regulated by inflammation or, in the absence of inflammatory stimuli, by alternative mechanisms leading to STAT3 activation. (PMID:16835372)
• A cross-sectional study was performed to assess hepcidin correlations with renal function, iron status, and C reactive protein in patients with chronic renal failure on conservative treatment. (PMID:16929540)
• Data show the presence of co-purified iron with 20 and 25 residue hepcidins, and present a new 3D structure that is completely different from the solved structure of the synthetic peptide. (PMID:16937259)
• A STAT3 binding motif located at position -64/-72 of the hepcidin promoter is required for hepcidin activation in Il6-treated human liver cells. (PMID:16946298)
• Hepcidin is a proinflammatory adipokine and may play an important role in hypoferremia of inflammation in obese condition. (PMID:16952548)
• Iron overload and hemochromatosis my be due to a deficiency in hepcidin. (PMID:16962038)
• Elevated hepcidin values in kidney allograft recipients may be due not only to impaired renal function, but also to a low-grade inflammatory state. (PMID:17112858)
• hypoxia lowers circulating prohepcidin concentrations in humans (PMID:17229646)
• an additional ATG in the 5’ untranslated region (UTR) of the HAMP is functional and prevents normal hepcidin production by inducing an aberrant translation initiation of the pre-hepcidin mRNA [case report] (PMID:17229647)
• alcohol loading down-regulates hepatic hepcidin expression and leads to the increase of iron absorption from the intestine (PMID:17331161)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	hamp	ENSDARG00000102175
mus_musculus	Hamp	ENSMUSG00000050440
mus_musculus	Hamp2	ENSMUSG00000056978
rattus_norvegicus	Hamp	ENSRNOG00000021029

Protein

Protein identifiers

Hepcidin — P81172 (reviewed: P81172)

Alternative names: Liver-expressed antimicrobial peptide 1, Putative liver tumor regressor

All UniProt accessions (1): P81172

UniProt curated annotations — full annotation on UniProt →

Function. Liver-produced hormone that constitutes the main circulating regulator of iron absorption and distribution across tissues. Acts by promoting endocytosis and degradation of ferroportin/SLC40A1, leading to the retention of iron in iron-exporting cells and decreased flow of iron into plasma. Controls the major flows of iron into plasma: absorption of dietary iron in the intestine, recycling of iron by macrophages, which phagocytose old erythrocytes and other cells, and mobilization of stored iron from hepatocytes. Has strong antimicrobial activity against E.coli ML35P N.cinerea and weaker against S.epidermidis, S.aureus and group b streptococcus bacteria. Active against the fungus C.albicans. No activity against P.aeruginosa.

Subunit / interactions. Interacts with SLC40A1; this interaction promotes SLC40A1 rapid ubiquitination.

Subcellular location. Secreted.

Tissue specificity. Highest expression in liver and to a lesser extent in heart and brain. Low levels in lung, tonsils, salivary gland, trachea, prostate gland, adrenal gland and thyroid gland. Secreted into the urine and blood. Expressed by hepatocytes.

Disease relevance. Hemochromatosis 2B (HFE2B) [MIM:613313] 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.

Induction. Expression in hepatocytes is induced by LPS stimulus and the induction is mediated by IL6. Expression is inhibited in presence of TNF.

Similarity. Belongs to the hepcidin family.

RefSeq proteins (1): NP_066998* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR010500	Hepcidin	Family

Pfam: PF06446

UniProt features (15 total): sequence variant 4, disulfide bond 4, strand 2, peptide 2, signal peptide 1, propeptide 1, sequence conflict 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
3H0T	X-RAY DIFFRACTION	1.89
4QAE	X-RAY DIFFRACTION	2.1
6WBV	ELECTRON MICROSCOPY	2.5
1M4E	SOLUTION NMR
1M4F	SOLUTION NMR
2KEF	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P81172-F1	62.16	0.10

Antibody-complex structures (SAbDab): 2 — 3H0T, 6WBV

Functional residue map

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

Disulfide bonds (4): 66–82, 69–72, 70–78, 73–81

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 249 (showing top): GSE45365_NK_CELL_VS_CD8_TCELL_UP, GOBP_DIGESTION, GOBP_NEGATIVE_REGULATION_OF_TRANSMEMBRANE_TRANSPORT, GOBP_REGULATION_OF_PROTEASOMAL_UBIQUITIN_DEPENDENT_PROTEIN_CATABOLIC_PROCESS, GOBP_ANTIMICROBIAL_HUMORAL_RESPONSE, GOBP_POSITIVE_REGULATION_OF_ENDOCYTOSIS, GNF2_GSTM1, GOBP_TRANSITION_METAL_ION_TRANSPORT, GNF2_HPN, GOBP_INTRACELLULAR_IRON_ION_HOMEOSTASIS, GOBP_POSITIVE_REGULATION_OF_PROTEIN_CATABOLIC_PROCESS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, DARWICHE_SKIN_TUMOR_PROMOTER_UP, DARWICHE_PAPILLOMA_RISK_LOW_UP, DARWICHE_PAPILLOMA_RISK_HIGH_UP

GO Biological Process (16): negative regulation of transcription by RNA polymerase II (GO:0000122), intracellular iron ion homeostasis (GO:0006879), immune response (GO:0006955), response to iron ion (GO:0010039), killing of cells of another organism (GO:0031640), positive regulation of proteasomal ubiquitin-dependent protein catabolic process (GO:0032436), negative regulation of iron ion transmembrane transport (GO:0034760), defense response to bacterium (GO:0042742), defense response to fungus (GO:0050832), multicellular organismal-level iron ion homeostasis (GO:0060586), negative regulation of iron export across plasma membrane (GO:1904039), negative regulation of intestinal absorption (GO:1904479), signal transduction (GO:0007165), monoatomic cation homeostasis (GO:0055080), inorganic ion homeostasis (GO:0098771), iron ion export across plasma membrane (GO:1903988)

GO Molecular Function (2): hormone activity (GO:0005179), transporter regulator activity (GO:0141108)

GO Cellular Component (2): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
inorganic ion homeostasis	2
iron ion transmembrane transport	2
defense response	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
intracellular monoatomic cation homeostasis	1
immune system process	1
response to stimulus	1
response to metal ion	1
cell killing	1
disruption of cell in another organism	1
regulation of proteasomal ubiquitin-dependent protein catabolic process	1
proteasome-mediated ubiquitin-dependent protein catabolic process	1
positive regulation of proteasomal protein catabolic process	1
positive regulation of ubiquitin-dependent protein catabolic process	1
negative regulation of iron ion transport	1
regulation of iron ion transmembrane transport	1
negative regulation of cation transmembrane transport	1
response to bacterium	1
response to fungus	1
monoatomic cation homeostasis	1
multicellular organismal-level chemical homeostasis	1
negative regulation of iron ion transmembrane transport	1
iron ion export across plasma membrane	1
regulation of iron export across plasma membrane	1
intestinal absorption	1
negative regulation of digestive system process	1
regulation of intestinal absorption	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
monoatomic ion homeostasis	1
chemical homeostasis	1
export across plasma membrane	1
receptor ligand activity	1
transporter activity	1
molecular function regulator activity	1

Protein interactions and networks

STRING

1574 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HAMP	SLC40A1	Q9NP59	999
HAMP	HJV	Q6ZVN8	983
HAMP	HFE	Q30201	965
HAMP	TMPRSS6	Q8IU80	961
HAMP	SLC11A2	P49281	942
HAMP	TFR2	Q9UP52	941
HAMP	TFRC	P02786	933
HAMP	IL6	P05231	927
HAMP	CYBRD1	Q53TN4	926
HAMP	LEAP2	Q969E1	917
HAMP	EPO	P01588	904
HAMP	BMP6	P22004	897
HAMP	A2M	P01023	885
HAMP	GDF15	P78360	875
HAMP	ERFE	Q4G0M1	840

IntAct

3 interactions, top by confidence:

A	B	Type	Score
HAMP	CKAP4	psi-mi:“MI:0915”(physical association)	0.370
HAMP		psi-mi:“MI:0915”(physical association)	0.370

BioGRID (3): HAMP (PCA), HAMP (Two-hybrid), HAMP (Two-hybrid)

ESM2 similar proteins: O00230, O00253, O14836, O46541, O62827, O77559, P01160, P01169, P07499, P0C8A3, P0C8S2, P0CG36, P0CG37, P13204, P16859, P18104, P23582, P24393, P35318, P47851, P49192, P51461, P53366, P55206, P55207, P56283, P56388, P56413, P56473, P81172, P81277, P84715, P97297, Q5CZK2, Q5NVR8, Q61839, Q62715, Q62716, Q6PAL1, Q7TNK8

Diamond homologs: P81172, Q5NVR8, Q5U9D2, Q80T19, Q8MJ80, Q99MH3, Q9EQ21, P61516, Q7T273, A1Z0M0, P82951, Q801Y3, Q9DFD6

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
CEBPA	“up-regulates quantity by expression”	HAMP	“transcriptional regulation”
GATA4	“up-regulates quantity by expression”	HAMP	“transcriptional regulation”
STAT3	“up-regulates quantity by expression”	HAMP	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	3
Uncertain significance	21
Likely benign	49
Benign	6

Top pathogenic / likely-pathogenic (7)

Variant ID	HGVS	Classification
4283	NM_021175.4(HAMP):c.95del (p.Gly32fs)	Pathogenic
4284	NM_021175.4(HAMP):c.166C>T (p.Arg56Ter)	Pathogenic
4285	NM_021175.4(HAMP):c.148_150+1del	Pathogenic
917401	NM_021175.4(HAMP):c.176G>C (p.Arg59Pro)	Pathogenic
1350113	NM_021175.4(HAMP):c.223C>T (p.Arg75Ter)	Likely pathogenic
2576337	NM_021175.4(HAMP):c.2T>C (p.Met1Thr)	Likely pathogenic
4075845	NM_021175.4(HAMP):c.185A>G (p.His62Arg)	Likely pathogenic

SpliceAI

569 predictions. Top by Δscore:

Variant	Effect	Δscore
19:35280925:AAG:A	donor_loss	0.9900
19:35280929:T:A	donor_loss	0.9900
19:35284936:A:AG	acceptor_gain	0.9900
19:35284937:G:GG	acceptor_gain	0.9900
19:35280889:C:T	donor_gain	0.9800
19:35280897:C:T	donor_gain	0.9800
19:35284787:A:AG	acceptor_gain	0.9800
19:35284787:AGAC:A	acceptor_gain	0.9800
19:35284788:G:GG	acceptor_gain	0.9800
19:35284788:GACG:G	acceptor_gain	0.9800
19:35284937:GC:G	acceptor_gain	0.9800
19:35284937:GCC:G	acceptor_gain	0.9800
19:35284937:GCCC:G	acceptor_gain	0.9800
19:35284937:GCCCA:G	acceptor_gain	0.9800
19:35283495:TCCC:T	donor_gain	0.9700
19:35284788:GAC:G	acceptor_gain	0.9700
19:35284934:ACAGC:A	acceptor_loss	0.9700
19:35284935:CA:C	acceptor_loss	0.9700
19:35284936:A:AT	acceptor_loss	0.9700
19:35280853:C:G	donor_gain	0.9600
19:35282663:AACAG:A	donor_loss	0.9600
19:35282664:ACAGG:A	donor_loss	0.9600
19:35282665:CAGGT:C	donor_loss	0.9600
19:35282666:AGGTG:A	donor_loss	0.9600
19:35282667:GGTGA:G	donor_loss	0.9600
19:35282668:G:GC	donor_loss	0.9600
19:35282669:T:G	donor_loss	0.9600
19:35284787:AGACG:A	acceptor_gain	0.9600
19:35284788:GACGG:G	acceptor_gain	0.9600
19:35282670:GAGA:G	donor_loss	0.9300

AlphaMissense

545 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:35284975:T:G	F63C	0.977
19:35284983:T:A	C66S	0.962
19:35284984:G:C	C66S	0.962
19:35285028:T:A	C81S	0.960
19:35285029:G:C	C81S	0.960
19:35285031:T:A	C82S	0.957
19:35285032:G:C	C82S	0.957
19:35284984:G:A	C66Y	0.956
19:35284983:T:C	C66R	0.953
19:35284996:G:A	C70Y	0.953
19:35285032:G:A	C82Y	0.947
19:35284995:T:A	C70S	0.944
19:35284996:G:C	C70S	0.944
19:35285028:T:C	C81R	0.944
19:35285001:T:A	C72S	0.943
19:35285002:G:C	C72S	0.943
19:35284993:G:A	C69Y	0.941
19:35284985:C:G	C66W	0.940
19:35284992:T:C	C69R	0.939
19:35284990:T:G	F68C	0.938
19:35284992:T:A	C69S	0.935
19:35284993:G:C	C69S	0.935
19:35284994:C:G	C69W	0.935
19:35284984:G:T	C66F	0.934
19:35285033:C:G	C82W	0.933
19:35284996:G:T	C70F	0.932
19:35285001:T:C	C72R	0.931
19:35284995:T:C	C70R	0.928
19:35285004:T:A	C73S	0.928
19:35285005:G:A	C73Y	0.928

dbSNP variants (sampled 300 via entrez): RS1000460229 (19:35285586 T>A,C), RS1000849603 (19:35284018 C>T), RS1001186196 (19:35285567 G>C,T), RS1001462184 (19:35284167 A>G), RS1002080024 (19:35283826 G>A), RS1002489151 (19:35282959 C>G,T), RS1002696757 (19:35285111 G>A), RS1002856335 (19:35281413 G>T), RS1002894821 (19:35282805 A>G), RS1004346002 (19:35282978 G>A), RS1004754714 (19:35281054 A>C), RS1005224729 (19:35283788 C>G), RS1005872820 (19:35280624 A>G), RS1006734234 (19:35283447 C>G), RS1007067543 (19:35284546 G>A)

Disease associations

OMIM: gene MIM:606464 | disease phenotypes: MIM:235200, MIM:613313

GenCC curated gene-disease

Disease	Classification	Inheritance
hemochromatosis type 2B	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 2B	Definitive	AR

Mondo (4): hereditary hemochromatosis (MONDO:0006507), hemochromatosis type 2B (MONDO:0013220), hemochromatosis type 1 (MONDO:0021001), hemochromatosis type 2 (MONDO:0019257)

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

27 total (27 of 27 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000135	Hypogonadism
HP:0000802	Impotence
HP:0000819	Diabetes mellitus
HP:0000869	Secondary amenorrhea
HP:0000939	Osteoporosis
HP:0000953	Hyperpigmentation of the skin
HP:0001254	Lethargy
HP:0001324	Muscle weakness
HP:0001394	Cirrhosis
HP:0001395	Hepatic fibrosis
HP:0001635	Congestive heart failure
HP:0001638	Cardiomyopathy
HP:0001644	Dilated cardiomyopathy
HP:0001744	Splenomegaly
HP:0001903	Anemia
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:0012093	Abnormality of endocrine pancreas physiology
HP:0012463	Elevated transferrin saturation

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST006535_7	Irritable bowel syndrome	5.000000e-06
GCST006804_165	Red cell distribution width	4.000000e-09
GCST90002390_653	Mean corpuscular hemoglobin	3.000000e-17
GCST90002390_654	Mean corpuscular hemoglobin	9.000000e-14
GCST90002390_655	Mean corpuscular hemoglobin	2.000000e-14
GCST90002391_115	Mean corpuscular hemoglobin concentration	3.000000e-10
GCST90002392_73	Mean corpuscular volume	3.000000e-09
GCST90002403_294	Red blood cell count	1.000000e-09
GCST90002404_529	Red cell distribution width	2.000000e-16

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0009188	Red cell distribution width
EFO:0004527	mean corpuscular hemoglobin
EFO:0004528	mean corpuscular hemoglobin concentration
EFO:0004305	erythrocyte count

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D006432	Hemochromatosis	C16.320.565.618.337; C18.452.565.500.480; C18.452.648.618.337
C566557	Hemochromatosis, Type 2B (supp.)
C537247	Hemochromatosis, type 2 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3989381 (SINGLE PROTEIN)

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

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.14	IC50	7.3	nM	CHEMBL5184000
7.55	IC50	28	nM	CHEMBL5199417
7.47	IC50	34	nM	CHEMBL5181536
7.24	IC50	58	nM	CHEMBL5186341

PubChem BioAssay actives

4 with measured affinity, of 4 total; 4 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
methyl (3R,5S)-3,5-dimethyl-4-[3-[6-[(3R)-3-methylpiperazin-1-yl]-3-pyridinyl]-1H-pyrazolo[4,3-d]pyrimidin-5-yl]piperazine-1-carboxylate	1870527: Inhibition of Hepcidin in human Huh-7 cells assessed as inhibition of BMP-7 induced hepcidin production incubated for 16 to 24 hrs by ELISA method	ic50	0.0073	uM
[(3S,5R)-3,5-dimethyl-4-[3-[6-[(3R)-3-methylpiperazin-1-yl]-3-pyridinyl]-1H-pyrazolo[4,3-d]pyrimidin-5-yl]piperazin-1-yl]-pyrrolidin-1-ylmethanone	1870527: Inhibition of Hepcidin in human Huh-7 cells assessed as inhibition of BMP-7 induced hepcidin production incubated for 16 to 24 hrs by ELISA method	ic50	0.0280	uM
methyl (3S,5R)-3,5-dimethyl-4-[3-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrazolo[4,3-d]pyrimidin-5-yl]piperazine-1-carboxylate	1870527: Inhibition of Hepcidin in human Huh-7 cells assessed as inhibition of BMP-7 induced hepcidin production incubated for 16 to 24 hrs by ELISA method	ic50	0.0340	uM
methyl (3S,5R)-3,5-dimethyl-4-[3-[6-(4-methylpiperazin-1-yl)-3-pyridinyl]-1H-pyrazolo[4,3-d]pyrimidin-5-yl]piperazine-1-carboxylate	1870527: Inhibition of Hepcidin in human Huh-7 cells assessed as inhibition of BMP-7 induced hepcidin production incubated for 16 to 24 hrs by ELISA method	ic50	0.0580	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, affects cotreatment, increases expression, decreases expression	4
Tetrachlorodibenzodioxin	increases expression	3
Aflatoxin B1	decreases expression	3
Acetaminophen	decreases expression, increases expression	2
Ethanol	decreases expression, decreases reaction	2
Estradiol	decreases reaction, decreases expression	2
Heparin	decreases reaction, increases expression, increases secretion, decreases expression, decreases secretion	2
Iron	decreases secretion, increases expression, affects reaction, increases uptake	2
Lipopolysaccharides	increases expression, increases secretion, affects reaction	2
Niclosamide	decreases expression, increases expression	2
Cyclosporine	decreases expression, increases expression	2
Particulate Matter	increases expression, affects expression, increases abundance	2
aristolochic acid I	increases expression	1
dicrotophos	increases expression	1
benzo(b)fluoranthene	increases expression	1
bisphenol A	affects expression	1
2,2’-methylenebis(4-methyl-6-tert-butylphenol)	affects expression, affects response to substance	1
tris(2-butoxyethyl) phosphate	affects expression	1
benzamil	decreases reaction, increases expression, decreases expression	1
ferric ammonium citrate	affects reaction, decreases reaction, increases expression, decreases expression, increases reaction	1
10-(alpha-diethylaminopropionyl)phenothiazine	decreases expression	1
2,4,5,2’,4’,5’-hexachlorobiphenyl	decreases expression	1
diethyl maleate	increases expression	1
cobaltous chloride	decreases reaction, increases expression, decreases expression	1
3,4,5,3’,4’-pentachlorobiphenyl	decreases expression	1
1,10-phenanthroline	decreases expression	1
1,2,5,6-dibenzanthracene	increases expression	1
rutecarpine	decreases reaction, increases expression, decreases expression	1
benazol P	affects expression	1
deacylketoconazole	decreases expression	1

ChEMBL screening assays

9 unique, capped per target: 9 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4418349	Binding	Inhibition of human hepcidin-stimulated recombinant C-terminal Halo-tagged human FPN internalization in MDCK cells incubated for 15 to 20 mins by Halo-tagged TMR based fluorescence assay	Novel Quinoline-Hepcidine Antagonists

Clinical trials (associated diseases)

37 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
NCT01810965	Not specified	COMPLETED	Impact of Bloodletting on Iron Metabolism in Type 1 Hemochromatosis
NCT02099214	Not specified	COMPLETED	Estimation of Myocardial Iron Overload by 3 Tesla MRI in HFE Hereditary Haemochromatosis