CYBRD1

Summary

CYBRD1 (cytochrome b reductase 1, HGNC:20797) is a protein-coding gene on chromosome 2q31.1, encoding Plasma membrane ascorbate-dependent reductase CYBRD1 (Q53TN4). Plasma membrane reductase that uses cytoplasmic ascorbate as an electron donor to reduce extracellular Fe(3+) into Fe(2+).

This gene is a member of the cytochrome b(561) family that encodes an iron-regulated protein. It highly expressed in the duodenal brush border membrane. It has ferric reductase activity and is believed to play a physiological role in dietary iron absorption.

Source: NCBI Gene 79901 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hereditary hemochromatosis (Strong, GenCC)
• GWAS associations: 16
• Clinical variants (ClinVar): 53 total — 1 pathogenic
• MANE Select transcript: NM_024843

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20797
Approved symbol	CYBRD1
Name	cytochrome b reductase 1
Location	2q31.1
Locus type	gene with protein product
Status	Approved
Aliases	DCYTB, FLJ23462, FRRS3, CYB561A2
Ensembl gene	ENSG00000071967
Ensembl biotype	protein_coding
OMIM	605745
Entrez	79901

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 5 protein_coding, 3 protein_coding_CDS_not_defined

ENST00000321348, ENST00000375252, ENST00000409484, ENST00000445146, ENST00000468308, ENST00000474182, ENST00000494587, ENST00000858692

RefSeq mRNA: 3 — MANE Select: NM_024843 NM_001127383, NM_001256909, NM_024843

CCDS: CCDS2244, CCDS46449, CCDS58736

Canonical transcript exons

ENST00000321348 — 4 exons

Exon	Start	End
ENSE00001718693	171554524	171558129
ENSE00003520500	171522474	171522738
ENSE00003526293	171541585	171541793
ENSE00003613147	171553346	171553500

Expression profiles

Bgee: expression breadth ubiquitous, 262 present calls, max score 99.75.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 72.3667 / max 964.8601, expressed in 1640 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
23662	56.1236	1611
23663	10.7049	1272
23661	2.9972	1129
23660	1.1439	672
202472	0.3975	195
23668	0.3089	155
23667	0.2254	85
23659	0.2059	73
23658	0.1651	65
23665	0.0944	30

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	99.75	gold quality
germinal epithelium of ovary	UBERON:0001304	99.49	gold quality
skin of hip	UBERON:0001554	99.43	gold quality
parietal pleura	UBERON:0002400	99.43	gold quality
jejunal mucosa	UBERON:0000399	99.40	gold quality
synovial joint	UBERON:0002217	99.35	gold quality
upper leg skin	UBERON:0004262	99.25	gold quality
superficial temporal artery	UBERON:0001614	99.13	gold quality
right coronary artery	UBERON:0001625	98.98	gold quality
mucosa of stomach	UBERON:0001199	98.93	gold quality
pericardium	UBERON:0002407	98.90	gold quality
stromal cell of endometrium	CL:0002255	98.81	gold quality
gall bladder	UBERON:0002110	98.80	gold quality
tibia	UBERON:0000979	98.78	gold quality
urethra	UBERON:0000057	98.70	gold quality
descending thoracic aorta	UBERON:0002345	98.67	gold quality
visceral pleura	UBERON:0002401	98.66	gold quality
vena cava	UBERON:0004087	98.60	gold quality
thoracic aorta	UBERON:0001515	98.56	gold quality
subcutaneous adipose tissue	UBERON:0002190	98.56	gold quality
ascending aorta	UBERON:0001496	98.55	gold quality
endocervix	UBERON:0000458	98.54	gold quality
aorta	UBERON:0000947	98.50	gold quality
left lobe of thyroid gland	UBERON:0001120	98.46	gold quality
mammary duct	UBERON:0001765	98.44	gold quality
popliteal artery	UBERON:0002250	98.44	gold quality
tibial artery	UBERON:0007610	98.44	gold quality
duodenum	UBERON:0002114	98.42	gold quality
adipose tissue	UBERON:0001013	98.40	gold quality
thyroid gland	UBERON:0002046	98.40	gold quality

Single-cell (SCXA)

Detected in 9 experiment(s), a significant marker in 9.

Experiment	Marker?	Max mean expression
E-GEOD-125970	yes	508.10
E-MTAB-8410	yes	53.25
E-MTAB-10287	yes	16.59
E-MTAB-9543	yes	14.63
E-MTAB-5061	yes	11.13
E-GEOD-81547	yes	7.99
E-ENAD-27	yes	6.26
E-GEOD-130148	yes	5.11
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): BMP6, SMAD4, SP1

miRNA regulators (miRDB)

211 targeting CYBRD1, 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-3163	100.00	77.23	8605
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-512-3P	99.97	67.35	1049
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502

Literature-anchored findings (GeneRIF, showing 14)

• In Africans with iron overload not related to the HFE gene, the possible involvement of the SLC40A1 and CYBRD1 genes was demonstrated for the first time. (PMID:15338274)
• Duodenal cytochrome b present in human erythrocytes may contribute to their ability to reduce extracellular monodehydroascorbate. (PMID:17068337)
• The current study concerns the recombinant expression, purification, and initial spectroscopic characterization of a recombinant form of the human ferric reductase. (PMID:18092813)
• Functional characterization of Cybrd1 heme groups and iron/ascorbate metabolism. (PMID:18194661)
• The results of this study confirm that Dcytb can act as a ferric reductase that stimulates iron uptake in Caco-2 cells. (PMID:18492824)
• Polymorphisms in CYBRD1 modulates iron phenotype in HFE p.C282Y homozygous hemochromatosis. (PMID:22773607)
• Letter: report mutations in CYBRD1 promoter in and possible role in iron hemostasis in patients with porphyria cutanea tarda. (PMID:23012398)
• CYBRD1 has an involvement in iron homeostasis in chronic hepatitis C. (PMID:27439017)
• DCYTB is an important predictor of outcome and is associated with response to therapy in breast cancer patients. (PMID:28270217)
• Single nucleotide polymorphism in CYBRD1 gene is associated with hemochromatosis. (PMID:28937159)
• Studied the effect of iron supplements containing Lactobacillus plantarum on ferric iron metabolism and upregulation of duodenal cytochrome b ferric-chelate reductase 3 (DCTYB) in Caco-2 and HT-29 MTX cell lines. (PMID:30544799)
• miR-423-3p activates FAK signaling pathway to drive EMT process and tumor growth in lung adenocarcinoma through targeting CYBRD1. (PMID:34714955)
• DDX17 induces epithelial-mesenchymal transition and metastasis through the miR-149-3p/CYBRD1 pathway in colorectal cancer. (PMID:36593242)
• EGFR upregulates miRNA subset to inhibit CYBRD1 and cause DDP resistance in gastric cancer. (PMID:39419238)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	cybrd1	ENSDARG00000095577
mus_musculus	Cybrd1	ENSMUSG00000027015
rattus_norvegicus	Cybrd1	ENSRNOG00000009620
drosophila_melanogaster	CG1275	FBGN0035321

Paralogs (2): CYB561 (ENSG00000008283), CYB561A3 (ENSG00000162144)

Protein

Protein identifiers

Plasma membrane ascorbate-dependent reductase CYBRD1 — Q53TN4 (reviewed: Q53TN4)

Alternative names: Cytochrome b reductase 1, Duodenal cytochrome b, Ferric-chelate reductase 3

All UniProt accessions (2): Q53TN4, C9JML1

UniProt curated annotations — full annotation on UniProt →

Function. Plasma membrane reductase that uses cytoplasmic ascorbate as an electron donor to reduce extracellular Fe(3+) into Fe(2+). Probably functions in dietary iron absorption at the brush border of duodenal enterocytes by producing Fe(2+), the divalent form of iron that can be transported into enterocytes. It is also able to reduce extracellular monodehydro-L-ascorbate and may be involved in extracellular ascorbate regeneration by erythrocytes in blood. May also act as a ferrireductase in airway epithelial cells. May also function as a cupric transmembrane reductase.

Subunit / interactions. Homodimer.

Subcellular location. Cell membrane. Apical cell membrane.

Tissue specificity. Present in erythrocyte membranes (at protein level). Also expressed in respiratory epithelium.

Activity regulation. Activated by chelators like citrate, malate, and oxalate specially at alkaline pH.

Cofactor. Binds 2 heme b groups non-covalently.

Induction. By iron deficiency (at protein level).

Polymorphism. Genetic variations in CYBRD1 may act as modifier of iron overload expression and account for the variance observed in serum ferritin levels in patients with hereditary hemochromatosis.

Isoforms (3)

UniProt ID	Names	Canonical?
Q53TN4-1	1	yes
Q53TN4-2	2
Q53TN4-3	3

RefSeq proteins (3): NP_001120855, NP_001243838, NP_079119* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006593	Cyt_b561/ferric_Rdtase_TM	Domain
IPR043205	CYB561/CYBRD1-like	Family

Pfam: PF03188

Enzyme classification (BRENDA):

• EC 7.2.1.3 — ascorbate ferrireductase (transmembrane) (BRENDA: 10 organisms, 25 substrates, 3 inhibitors, 26 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

4 substrates with measured Km, best-characterized 4. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
FERRICYTOCHROME B5	0.001–0.009	20
CU(II)-NITRILOTRIACETIC ACID[SIDE 2]	0.0152–0.0231	2
FE(III)-NITRILOTRIACETIC ACID[SIDE 2]	0.074–0.0921	2
L-ASCORBATE	12	1

Catalyzed reactions (Rhea), 3 shown:

• Fe(3+)(out) + L-ascorbate(in) = monodehydro-L-ascorbate radical(in) + Fe(2+)(out) + H(+) (RHEA:30403)
• monodehydro-L-ascorbate radical(out) + L-ascorbate(in) = monodehydro-L-ascorbate radical(in) + L-ascorbate(out) (RHEA:66524)
• Cu(2+)(out) + L-ascorbate(in) = Cu(+)(out) + monodehydro-L-ascorbate radical(in) + H(+) (RHEA:66656)

UniProt features (61 total): binding site 13, helix 12, mutagenesis site 10, topological domain 7, transmembrane region 6, sequence variant 3, modified residue 2, splice variant 2, chain 1, domain 1, region of interest 1, sequence conflict 1, strand 1, turn 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
5ZLE	X-RAY DIFFRACTION	2.6
5ZLG	X-RAY DIFFRACTION	2.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q53TN4-F1	87.19	0.78

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 (13): 50 (axial binding residue); 70; 79; 79; 83; 86 (axial binding residue); 108; 115–118; 120 (axial binding residue); 152; 159 (axial binding residue); 180 …

Post-translational modifications (2): 232, 285

Mutagenesis-validated functional residues (10):

Position	Phenotype
58	decreased transmembrane ascorbate ferrireductase activity.
79	decreased heme b reduction by ascorbate.
83	decreased heme b reduction by ascorbate.
107	decreased transmembrane ascorbate ferrireductase activity.
108	loss of transmembrane ascorbate ferrireductase activity.
108	loss of iron binding. loss of transmembrane ascorbate ferrireductase activity.
117	decreased transmembrane ascorbate ferrireductase activity.
131	decreased transmembrane ascorbate ferrireductase activity.
152	decreased heme b reduction by ascorbate.
184	decreased transmembrane ascorbate ferrireductase activity.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-917937	Iron uptake and transport

MSigDB gene sets: 245 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_DN, GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_DN, XU_GH1_AUTOCRINE_TARGETS_UP, GOCC_VACUOLAR_MEMBRANE, GOBP_TRANSITION_METAL_ION_TRANSPORT, GOBP_INTRACELLULAR_IRON_ION_HOMEOSTASIS, KYNG_DNA_DAMAGE_BY_4NQO, SARRIO_EPITHELIAL_MESENCHYMAL_TRANSITION_DN, GOBP_IRON_ION_TRANSPORT, AAAYRNCTG_UNKNOWN, CHANDRAN_METASTASIS_DN, GOBP_MONOATOMIC_CATION_TRANSPORT, LINDGREN_BLADDER_CANCER_CLUSTER_2A_DN, GOBP_RESPONSE_TO_METAL_ION, PICCALUGA_ANGIOIMMUNOBLASTIC_LYMPHOMA_UP

GO Biological Process (6): intracellular iron ion homeostasis (GO:0006879), response to iron ion (GO:0010039), reductive iron assimilation (GO:0033215), multicellular organismal-level iron ion homeostasis (GO:0060586), ascorbate homeostasis (GO:0140576), transmembrane transport (GO:0055085)

GO Molecular Function (7): oxidoreductase activity (GO:0016491), oxidoreductase activity, acting on metal ions (GO:0016722), identical protein binding (GO:0042802), metal ion binding (GO:0046872), transmembrane ascorbate ferrireductase activity (GO:0140571), transmembrane monodehydroascorbate reductase activity (GO:0140575), protein binding (GO:0005515)

GO Cellular Component (6): lysosomal membrane (GO:0005765), plasma membrane (GO:0005886), membrane (GO:0016020), apical plasma membrane (GO:0016324), brush border membrane (GO:0031526), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Transport of small molecules	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
inorganic ion homeostasis	2
oxidoreductase activity	2
intracellular monoatomic cation homeostasis	1
response to metal ion	1
ferric-chelate reductase activity	1
iron ion transmembrane transport	1
iron ion import across plasma membrane	1
monoatomic cation homeostasis	1
multicellular organismal-level chemical homeostasis	1
carbohydrate homeostasis	1
transport	1
cellular process	1
catalytic activity	1
protein binding	1
cation binding	1
oxidoreduction-driven active transmembrane transporter activity	1
oxidoreductase activity, acting on metal ions	1
binding	1
lysosome	1
lytic vacuole membrane	1
membrane	1
cell periphery	1
cellular anatomical structure	1
apical part of cell	1
plasma membrane region	1
brush border	1
apical plasma membrane	1
cell projection membrane	1
extracellular vesicle	1

Protein interactions and networks

STRING

720 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CYBRD1	SLC11A2	P49281	966
CYBRD1	SLC40A1	Q9NP59	941
CYBRD1	HAMP	P81172	926
CYBRD1	HFE	Q30201	908
CYBRD1	TFRC	P02786	852
CYBRD1	HEPH	Q9BQS7	829
CYBRD1	TFR2	Q9UP52	807
CYBRD1	SLC39A1	Q9NY26	789
CYBRD1	HJV	Q6ZVN8	788
CYBRD1	STEAP3	Q658P3	782
CYBRD1	ACO1	P21399	712
CYBRD1	TMPRSS6	Q8IU80	708
CYBRD1	SLC46A1	Q96NT5	676
CYBRD1	STEAP2	Q8NFT2	670
CYBRD1	STEAP1	Q9UHE8	667

IntAct

111 interactions, top by confidence:

A	B	Type	Score
STX4	CYBRD1	psi-mi:“MI:0915”(physical association)	0.780
CYBRD1	STX4	psi-mi:“MI:0915”(physical association)	0.780
LPAR3	CYBRD1	psi-mi:“MI:0915”(physical association)	0.560
SEC22A	CYBRD1	psi-mi:“MI:0915”(physical association)	0.560
STX7	CYBRD1	psi-mi:“MI:0915”(physical association)	0.560
SERP1	CYBRD1	psi-mi:“MI:0915”(physical association)	0.560
GIMAP5	CYBRD1	psi-mi:“MI:0915”(physical association)	0.560
VAPB	CYBRD1	psi-mi:“MI:0915”(physical association)	0.560
CYBRD1	TMEM65	psi-mi:“MI:0915”(physical association)	0.560
CYBRD1	TMEM120A	psi-mi:“MI:0915”(physical association)	0.560
GOSR2	CYBRD1	psi-mi:“MI:0915”(physical association)	0.560
CYBRD1	RABAC1	psi-mi:“MI:0915”(physical association)	0.560
CYBRD1	LPAR3	psi-mi:“MI:0915”(physical association)	0.560
PLP2	CYBRD1	psi-mi:“MI:0915”(physical association)	0.560
CYBRD1	SEC22A	psi-mi:“MI:0915”(physical association)	0.560
CYBRD1	VAPA	psi-mi:“MI:0915”(physical association)	0.560
CYBRD1	SERP2	psi-mi:“MI:0915”(physical association)	0.560
FKBP8	CYBRD1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (74): CYBRD1 (Two-hybrid), CYBRD1 (Two-hybrid), CYBRD1 (Two-hybrid), CYBRD1 (Affinity Capture-MS), CYBRD1 (Affinity Capture-MS), CYBRD1 (Affinity Capture-MS), CYBRD1 (Affinity Capture-MS), CYBRD1 (Affinity Capture-MS), CYBRD1 (Affinity Capture-MS), CYBRD1 (Affinity Capture-MS), CYBRD1 (Affinity Capture-MS), CYBRD1 (Affinity Capture-MS), CYBRD1 (Affinity Capture-MS), CYBRD1 (Affinity Capture-MS), CYBRD1 (Affinity Capture-MS)

ESM2 similar proteins: A3A9H6, A3KPR5, A5D9A7, C4IYS8, P0AEL1, P10897, P34465, P49447, Q04453, Q0WRW8, Q2Y9R4, Q3T130, Q497B2, Q4V8K1, Q503V1, Q53TN4, Q5CZL8, Q5RAJ4, Q5RCZ2, Q5RKJ2, Q5U2W7, Q5XGD7, Q60720, Q67ZF6, Q687X5, Q6DDR3, Q6I681, Q6INU7, Q6NS09, Q6P1H1, Q7XMK3, Q8L856, Q8NBI2, Q8VCZ2, Q8VYH6, Q91577, Q923B6, Q925G2, Q93ZH9, Q95204

Diamond homologs: A3A9H6, A3KPR5, A5D9A7, C4IYS8, P10897, P34465, P49447, Q503V1, Q53TN4, Q5CZL8, Q5RAJ4, Q5RCZ2, Q5RKJ2, Q5U2W7, Q60720, Q67ZF6, Q6DDR3, Q6I681, Q6P1H1, Q7XMK3, Q8L856, Q8NBI2, Q91577, Q925G2, Q95204, Q95245, Q9C540, Q9SWS1

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	33
Likely benign	7
Benign	1

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
58765	GRCh38/hg38 2q31.1(chr2:170444219-172050237)x1	Pathogenic

SpliceAI

830 predictions. Top by Δscore:

Variant	Effect	Δscore
2:171522732:GGCA:G	donor_gain	1.0000
2:171541584:GCC:G	acceptor_gain	1.0000
2:171541654:GGT:G	donor_gain	1.0000
2:171553345:GCT:G	acceptor_gain	1.0000
2:171553498:CCT:C	donor_gain	1.0000
2:171553499:CT:C	donor_gain	1.0000
2:171553501:G:GG	donor_gain	1.0000
2:171540488:T:TA	acceptor_gain	0.9900
2:171540493:T:G	acceptor_gain	0.9900
2:171541580:CCTA:C	acceptor_loss	0.9900
2:171541583:A:AG	acceptor_gain	0.9900
2:171541583:A:C	acceptor_loss	0.9900
2:171541584:G:GA	acceptor_gain	0.9900
2:171541584:GC:G	acceptor_gain	0.9900
2:171541789:TACAG:T	donor_loss	0.9900
2:171541790:ACAGG:A	donor_loss	0.9900
2:171541791:CAGG:C	donor_loss	0.9900
2:171541792:AG:A	donor_loss	0.9900
2:171541793:GGT:G	donor_loss	0.9900
2:171541794:GTC:G	donor_loss	0.9900
2:171541795:T:G	donor_loss	0.9900
2:171553344:A:AG	acceptor_gain	0.9900
2:171553345:G:GG	acceptor_gain	0.9900
2:171553345:GC:G	acceptor_gain	0.9900
2:171553345:GCTT:G	acceptor_gain	0.9900
2:171553345:GCTTC:G	acceptor_gain	0.9900
2:171553496:TCCCT:T	donor_gain	0.9900
2:171553497:CCCT:C	donor_gain	0.9900
2:171553498:CCTG:C	donor_loss	0.9900
2:171553499:CTGT:C	donor_loss	0.9900

AlphaMissense

1851 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:171522732:G:C	G63R	0.996
2:171522603:G:C	G20R	0.994
2:171541743:A:C	S118R	0.994
2:171541745:T:A	S118R	0.994
2:171541745:T:G	S118R	0.994
2:171522604:G:A	G20D	0.992
2:171541647:C:G	H86D	0.992
2:171554636:T:A	W224R	0.992
2:171554636:T:C	W224R	0.992
2:171522714:G:C	G57R	0.991
2:171522733:G:A	G63D	0.991
2:171541640:A:C	K83N	0.991
2:171541640:A:T	K83N	0.991
2:171522690:T:A	W49R	0.990
2:171522690:T:C	W49R	0.990
2:171553367:T:C	F142L	0.990
2:171553369:T:A	F142L	0.990
2:171553369:T:G	F142L	0.990
2:171522684:T:C	F47L	0.989
2:171522686:T:A	F47L	0.989
2:171522686:T:G	F47L	0.989
2:171541649:T:A	H86Q	0.989
2:171541649:T:G	H86Q	0.989
2:171541752:A:C	S121R	0.989
2:171541754:C:A	S121R	0.989
2:171541754:C:G	S121R	0.989
2:171554600:G:A	G212R	0.989
2:171554600:G:C	G212R	0.989
2:171522633:T:A	W30R	0.988
2:171522633:T:C	W30R	0.988

dbSNP variants (sampled 300 via entrez): RS1000065603 (2:171550947 C>G), RS1000068065 (2:171532889 G>A), RS1000245864 (2:171531541 G>A,C,T), RS1000433855 (2:171545748 T>A,C), RS1000472219 (2:171538321 T>G), RS1000510240 (2:171555864 T>A), RS1000555681 (2:171520862 G>A,T), RS1000630656 (2:171521139 G>T), RS1000720983 (2:171552642 C>G,T), RS1000776791 (2:171524853 C>T), RS1000782606 (2:171538528 C>T), RS1000917488 (2:171540264 C>T), RS1000963106 (2:171527716 T>C), RS1001002707 (2:171549336 G>A), RS1001068499 (2:171534270 C>G,T)

Disease associations

OMIM: gene MIM:605745 | disease phenotypes: MIM:261800

GenCC curated gene-disease

Disease	Classification	Inheritance
hereditary hemochromatosis	Strong	Autosomal recessive

Mondo (3): breast ductal adenocarcinoma (MONDO:0005590), isolated Pierre-Robin syndrome (MONDO:0009869), hereditary hemochromatosis (MONDO:0006507)

Orphanet (1): Isolated Pierre Robin sequence (Orphanet:718)

HPO phenotypes

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

GWAS associations

16 associations (top):

Study	Trait	p-value
GCST006629_83	Pulse pressure	4.000000e-13
GCST006979_44	Heel bone mineral density	2.000000e-11
GCST007293_122	Body fat distribution (arm fat ratio)	1.000000e-09
GCST007293_88	Body fat distribution (arm fat ratio)	3.000000e-12
GCST012429_1	Asthma (childhood onset)	2.000000e-08
GCST012489_158	Heel bone mineral density x serum urate levels interaction	4.000000e-08
GCST90000025_826	Appendicular lean mass	3.000000e-73
GCST90020025_1714	Waist-to-hip ratio adjusted for BMI	2.000000e-09
GCST90020025_1715	Waist-to-hip ratio adjusted for BMI	1.000000e-12
GCST90020027_437	Waist-hip index	2.000000e-09
GCST90020027_438	Waist-hip index	2.000000e-12
GCST90020028_746	Hip circumference adjusted for BMI	4.000000e-16
GCST90020028_748	Hip circumference adjusted for BMI	6.000000e-10
GCST90020028_749	Hip circumference adjusted for BMI	2.000000e-11
GCST90020028_750	Hip circumference adjusted for BMI	1.000000e-18
GCST90020028_751	Hip circumference adjusted for BMI	8.000000e-09

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0005763	pulse pressure measurement
EFO:0009270	heel bone mineral density
EFO:0004341	body fat distribution
EFO:0004531	urate measurement
EFO:0004980	appendicular lean mass
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008039	BMI-adjusted hip circumference

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D018270	Carcinoma, Ductal, Breast	C04.557.470.200.025.232.500; C04.557.470.615.132.500; C04.588.180.390; C17.800.090.500.390
D006432	Hemochromatosis	C16.320.565.618.337; C18.452.565.500.480; C18.452.648.618.337
D010855	Pierre Robin Syndrome	C05.500.460.606; C05.660.207.540.460.606; C07.320.440.606; C07.650.500.460.606; C16.131.621.207.540.460.606; C16.131.850.500.460.606

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, affects cotreatment, increases expression, affects expression	6
bisphenol A	decreases methylation, increases expression	3
sodium arsenite	decreases expression	3
Nickel	decreases expression	3
Particulate Matter	decreases expression, decreases reaction, increases abundance, affects cotreatment	3
Air Pollutants	decreases expression, increases abundance	2
Cisplatin	affects cotreatment, increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tetrachlorodibenzodioxin	affects expression, decreases expression	2
daidzein	increases expression, affects cotreatment	1
triphenyl phosphate	affects expression	1
trichostatin A	decreases expression	1
daidzin	affects cotreatment, increases expression	1
aflatoxin B2	decreases methylation	1
cupric chloride	decreases expression	1
genistin	affects cotreatment, increases expression	1
glycitein	affects cotreatment, increases expression	1
CGP 52608	affects binding, increases reaction	1
entinostat	increases expression	1
glycitin	affects cotreatment, increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
ICG 001	increases expression	1
bisphenol B	increases expression	1
abrine	decreases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	decreases expression, decreases reaction	1
dorsomorphin	affects cotreatment, increases expression	1
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	increases expression, increases response to substance	1
bisphenol S	increases expression	1
jinfukang	affects cotreatment, increases expression	1
bisphenol AF	increases expression	1

Clinical trials (associated diseases)

52 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
NCT03414970	PHASE3	ACTIVE_NOT_RECRUITING	Hypofractionated Radiation Therapy After Mastectomy in Preventing Recurrence in Patients With Stage IIa-IIIa Breast Cancer
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
NCT00461344	PHASE2	TERMINATED	Docetaxel + Doxorubicin as Neoadjuvant Chemotherapy in Patients With Breast Cancer
NCT07499999	PHASE2	NOT_YET_RECRUITING	Randomized Double-Blind Phase II Trial of Baby Exemestane Versus Baby Tamoxifen in Post-Menopausal Women at High Risk for Breast Cancer
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
NCT00637364	PHASE1/PHASE2	SUSPENDED	High Intensity Focused Ultrasound Tumor Treatment for Pancreatic Cancer Pain
NCT02779855	PHASE1/PHASE2	COMPLETED	Talimogene Laherparepvec in Combination With Neoadjuvant Chemotherapy in Triple Negative Breast Cancer