TFR2

Summary

TFR2 (transferrin receptor 2, HGNC:11762) is a protein-coding gene on chromosome 7q22.1, encoding Transferrin receptor protein 2 (Q9UP52). Mediates cellular uptake of transferrin-bound iron in a non-iron dependent manner.

This gene encodes a single-pass type II membrane protein, which is a member of the transferrin receptor-like family. This protein mediates cellular uptake of transferrin-bound iron, and may be involved in iron metabolism, hepatocyte function and erythrocyte differentiation. Mutations in this gene have been associated with hereditary hemochromatosis type III. Alternatively spliced transcript variants encoding different isoforms have been described for this gene.

Source: NCBI Gene 7036 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hemochromatosis type 3 (Definitive, ClinGen)
• GWAS associations: 67
• Clinical variants (ClinVar): 1,078 total — 50 pathogenic, 79 likely-pathogenic
• Phenotypes (HPO): 17
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_003227

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11762
Approved symbol	TFR2
Name	transferrin receptor 2
Location	7q22.1
Locus type	gene with protein product
Status	Approved
Aliases	HFE3, TFRC2
Ensembl gene	ENSG00000106327
Ensembl biotype	protein_coding
OMIM	604720
Entrez	7036

Gene structure

Transcript identifiers

Ensembl transcripts: 84 — 74 protein_coding, 9 retained_intron, 1 nonsense_mediated_decay

ENST00000223051, ENST00000431692, ENST00000461176, ENST00000462090, ENST00000462107, ENST00000465294, ENST00000473374, ENST00000473571, ENST00000473963, ENST00000474947, ENST00000475011, ENST00000476304, ENST00000490084, ENST00000855220, ENST00000855221, ENST00000855222, ENST00000855223, ENST00000855224, ENST00000855225, ENST00000855226, ENST00000855227, ENST00000855228, ENST00000855229, ENST00000855230, ENST00000855231, ENST00000855232, ENST00000855233, ENST00000855234, ENST00000855235, ENST00000855236, ENST00000855237, ENST00000855238, ENST00000855239, ENST00000855240, ENST00000855241, ENST00000855242, ENST00000855243, ENST00000855244, ENST00000855245, ENST00000855246, ENST00000855247, ENST00000855248, ENST00000855249, ENST00000855250, ENST00000855251, ENST00000855252, ENST00000855253, ENST00000855254, ENST00000855255, ENST00000855256, ENST00000855257, ENST00000855258, ENST00000855259, ENST00000855260, ENST00000855261, ENST00000855262, ENST00000855263, ENST00000855264, ENST00000855265, ENST00000855266, ENST00000855267, ENST00000855268, ENST00000855269, ENST00000855270, ENST00000855271, ENST00000855272, ENST00000855273, ENST00000855274, ENST00000855275, ENST00000855276, ENST00000855277, ENST00000855278, ENST00000855279, ENST00000855280, ENST00000855281, ENST00000855282, ENST00000855283, ENST00000855284, ENST00000855285, ENST00000855286, ENST00000958152, ENST00000958153, ENST00000958154, ENST00000958155

RefSeq mRNA: 2 — MANE Select: NM_003227 NM_001206855, NM_003227

CCDS: CCDS34707

Canonical transcript exons

ENST00000223051 — 18 exons

Exon	Start	End
ENSE00003458627	100627907	100627974
ENSE00003478065	100628073	100628136
ENSE00003498296	100620420	100621126
ENSE00003512497	100631806	100631945
ENSE00003519605	100632082	100632198
ENSE00003547052	100627744	100627820
ENSE00003556199	100626763	100626903
ENSE00003582980	100629253	100629372
ENSE00003594951	100628224	100628306
ENSE00003599604	100627264	100627491
ENSE00003618988	100640976	100641228
ENSE00003622412	100633001	100633123
ENSE00003629598	100633416	100633556
ENSE00003629901	100630889	100631052
ENSE00003641036	100633229	100633340
ENSE00003658981	100640686	100640872
ENSE00003659332	100627577	100627661
ENSE00003841370	100641477	100641552

Expression profiles

Bgee: expression breadth ubiquitous, 188 present calls, max score 99.41.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 3.0295 / max 240.9100, expressed in 114 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
85235	1.0509	91
85228	1.0049	90
85226	0.4491	82
85225	0.1257	42
85231	0.1177	10
85227	0.1085	54
85234	0.0798	37
85230	0.0417	13
85232	0.0413	9
85229	0.0100	7

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	99.41	gold quality
liver	UBERON:0002107	99.13	gold quality
vena cava	UBERON:0004087	91.94	silver quality
buccal mucosa cell	CL:0002336	89.97	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	89.24	gold quality
trabecular bone tissue	UBERON:0002483	88.67	gold quality
cervix squamous epithelium	UBERON:0006922	87.66	gold quality
nipple	UBERON:0002030	87.19	silver quality
pylorus	UBERON:0001166	86.57	silver quality
tongue squamous epithelium	UBERON:0006919	85.96	gold quality
pericardium	UBERON:0002407	85.94	silver quality
superior surface of tongue	UBERON:0007371	85.68	silver quality
pons	UBERON:0000988	85.65	silver quality
lateral nuclear group of thalamus	UBERON:0002736	85.61	gold quality
lateral globus pallidus	UBERON:0002476	85.55	gold quality
male germ cell	CL:0000015	85.37	gold quality
sperm	CL:0000019	85.36	gold quality
saphenous vein	UBERON:0007318	85.22	silver quality
bone marrow	UBERON:0002371	84.79	gold quality
type B pancreatic cell	CL:0000169	83.76	gold quality
olfactory bulb	UBERON:0002264	83.57	gold quality
right hemisphere of cerebellum	UBERON:0014890	82.69	gold quality
synovial joint	UBERON:0002217	82.50	silver quality
cerebellar vermis	UBERON:0004720	82.25	gold quality
penis	UBERON:0000989	82.17	silver quality
cerebellar hemisphere	UBERON:0002245	82.00	gold quality
cerebellar cortex	UBERON:0002129	81.84	gold quality
upper arm skin	UBERON:0004263	81.74	gold quality
cerebellum	UBERON:0002037	81.72	gold quality
right frontal lobe	UBERON:0002810	81.65	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-MTAB-9067	yes	267.37
E-HCAD-4	yes	136.63
E-HCAD-6	yes	64.02
E-CURD-112	yes	50.31
E-ANND-3	yes	9.56
E-MTAB-9801	yes	4.13
E-HCAD-10	no	2.22

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
HAMP	Activation

miRNA regulators (miRDB)

26 targeting TFR2, 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-3617-3P	99.98	67.86	918
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-6132	99.60	65.83	1554
HSA-MIR-6836-5P	99.60	65.62	1538
HSA-MIR-3911	99.38	66.95	1087
HSA-MIR-185-5P	99.35	68.60	2497
HSA-MIR-4644	99.35	69.12	2514
HSA-MIR-6843-3P	99.26	66.42	915
HSA-MIR-5690	99.25	67.58	1012
HSA-MIR-7974	99.24	65.48	1137
HSA-MIR-6737-3P	98.95	68.56	1577
HSA-MIR-7157-3P	98.95	68.70	1582
HSA-MIR-4725-5P	98.67	65.42	628
HSA-MIR-504-5P	98.67	65.40	631
HSA-MIR-299-5P	98.56	71.14	1140
HSA-MIR-6881-5P	98.16	67.38	665
HSA-MIR-197-3P	98.09	69.23	1004
HSA-MIR-144-5P	97.66	69.90	531
HSA-MIR-3187-3P	97.38	65.80	904
HSA-MIR-4732-3P	97.15	65.45	881
HSA-MIR-3059-3P	96.71	67.08	606
HSA-MIR-6747-5P	96.17	64.99	743
HSA-MIR-576-3P	96.14	65.63	773
HSA-MIR-4301	95.00	65.22	554

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• identification of a novel TfR2 mutation in a cohort of non-C282Y iron overload patients of mixed ethnic backgrounds (PMID:12130528)
• Mice were created that are homozygous for a mutation that is orthologous to the Y250X mutation identified in some patients with hereditary hemochromatosis type 3. The mutant mice showed profound abnormalities in parameters of iron homeostasis. (PMID:12134060)
• TFR2 maps to chromosome 7. It is an alternately spliced protein and lacks the entire transmembrane and cytoplasmic domains. (PMID:12139409)
• production of anti-TFR2 monoclonal antibodies, their characterization, and their use to study TFR2 tissue distribution and up-regulation in response to TF-bound iron (PMID:12393650)
• TfR2 protein levels are approximately 20-fold lower than TfR in erythroid/myeloid cells. TfR & TfR2 have similar cellular localizations in K562 cells & coimmunoprecipitate to only a limited extent. Under nonreducing conditions, they can form heterodimers. (PMID:12406888)
• Expression of HFE and TfR2 proteins in human platelets may indicate that the mutations in the corresponding genes could influence platelet count, size and/or activation. suggests that HFE may serve a different function in platelets. (PMID:12656741)
• unlike TfR1, which recycles apo-Tf back to the cell surface after the release of iron, TfR2 promotes the intracellular deposition of ligand. (PMID:15317665)
• TfR2 acts as a sensor of iron status such that receptor levels reflect transferrin saturation. (PMID:15319276)
• Has a role monitoring iron levels by sensing changes in the concentration of diferric transferrin. (PMID:15319290)
• Urinary hepcidin is low or undetectable in 8 of 10 hemochromatosis cases irrespective of previous phlebotomy treatments, confirming the proposed role of TFR2 as a regulator of hepcidin production. (PMID:15486069)
• TfR2 plays a role in the pathogenesis of hemochromatosis in Japan. (PMID:15749661)
• HFE and TFR2 interact in cells; this interaction is not abrogated by disease-associated mutations of HFE and TFR2; and that TFR2 competes with TFR1 for binding to HFE (PMID:16893896)
• hemojuvelin and TfR2 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)
• Mutational analysis of TfR2 shows that the mutation G679A, which blocks TfR2 binding to diferric transferrin Fe(2)Tf, increases the rate of receptor turnover and prevents stabilization by Fe(2)Tf. (PMID:17182845)
• although holo-Tf binding to the ectodomain is necessary, the cytoplasmic domain of TfR2 is largely responsible for its stabilization by holo-Tf. (PMID:17202145)
• the TfR2/HFE and TfR1/HFE interactions are distinct. (PMID:17956864)
• Transferrin receptor 2 mediates transferrin-bound iron uptake by receptor-mediated endocytosis. (PMID:18083267)
• that TFR2-related HH may occur at a young age and is characterized by high TS levels (PMID:18245657)
• co-expression of HFE in cells expressing TfR2 led to increased affinity for diferric transferrin, increased transferrin-dependent iron uptake, and relative resistance to iron chelation (PMID:18353247)
• analysis of early-onset haemochromatosis caused by a novel combination of TFR2 mutations [case report] (PMID:18450729)
• TfR2 expression can be modulated through stimuli similar to those known to act on TfR1 and these findings may have important implications for our understanding of the role of TfR2 in the regulation of iron homeostasis. (PMID:19019709)
• we have discovered a novel mitochondrial iron transport system that goes awry in Parkinson’s disease, and which may provide a new target for therapeutic intervention. (PMID:19250966)
• Because the HFE alpha3 domain interacts with receptor 2 (TfR2), these results supported the finding that TfR2/HFE complex is required for transcriptional regulation of hepcidin by holo-transferrin. (PMID:19254567)
• Relative expression level of TFR2 mRNA in prednisone good responders was significantly higher than that in prednisone poor responders in children with acute leukemia. (PMID:19292036)
• In colon cancer cell lines, TfR2 is localized in membrane lipid rafts, induces ERK1/ERK2 phosphorylation, and is preferentially expressed during S-M phases of the cell cycle. (PMID:19729324)
• None of the individuals in this cohort of Brazilian patients with the classical phenotype of HH had any of the aforementioned non-C282Y mutations in the HFE gene or any mutations in the TfR2 and SCL40A1 genes. (PMID:19759876)
• 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)
• findings show that HFE is present in substoichiometric concentrations with respect to both TfR1 and TfR2 in liver tissue; finding supports a model, in which availability of HFE is limiting for formation of complexes with TfR1 or TfR2 (PMID:19819738)
• This shows for the first time that transferrin receptor(TFR)-mediated transferrin-bound iron uptake is mediated primarily via TFR1 but not TFR2 and that a high-capacity TFR-independent pathway exists in hepatoma cells. (PMID:19828835)
• Data suggested that Al(2)Tf cannot form specific ionic interresidual interactions, such as those formed by Fe(2)Tf, to bind to TfR, resulting in impossible complex formation between Al(2)Tf and TfR. (PMID:19859668)
• Hepcidin mRNA expression in vitro is highly sensitive to the presence of serum factors and PI3 kinase inhibition and parallels TfR2 expression (PMID:19924283)
• The association constant for the binding of diferric transferrin (Tf) to TfR2alpha is 5.6x10(6) M(-)(1), which is about 50 times lower than that for the binding of Tf to TfR1, with correspondingly reduced rates of iron uptake. (PMID:20096706)
• Data show that ULBP1, TFR2 and IFITM1 were associated with increased susceptibility to Vgamma9Vdelta2 T-cell cytotoxicity. (PMID:20220060)
• transferrin receptor 2 and HFE are involved in holotransferrin-dependent signaling for the regulation of furin which involved Erk phosphorylation. Furin in turn may control hepcidin expression. (PMID:20634490)
• rs4820268 variant of TFR2 gene is involved in the regulation of serum iron levels. (PMID:21208937)
• TfR2 mRNA expression in hyperplastic anemia patients increases and closely correlates with hyperplasia status of bone marrow and anemia level in peripheral blood. (PMID:21518504)
• Data sugggest that TfR-lytic peptide might provide a potent and selective anticancer therapy for patients. (PMID:21849092)
• TF, TFR2 and TMPRSS6 polymorphisms are significantly associated with decreased iron status, but only variants in TMPRSS6 are genetic risk factors for iron deficiency and iron-deficiency anemia. (PMID:22323359)
• The hemochromatosis proteins HFE, TfR2, and HJV form a membrane-associated protein complex for hepcidin regulation. (PMID:22728873)
• Mutations in the TFR2 gene is associated with hemochromatosis. (PMID:22890139)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	tfr2	ENSDARG00000103727
mus_musculus	Tfr2	ENSMUSG00000029716
rattus_norvegicus	Tfr2	ENSRNOG00000001407

Paralogs (5): TFRC (ENSG00000072274), NAALAD2 (ENSG00000077616), FOLH1 (ENSG00000086205), NAALADL1 (ENSG00000168060), NAALADL2 (ENSG00000177694)

Protein

Protein identifiers

Transferrin receptor protein 2 — Q9UP52 (reviewed: Q9UP52)

All UniProt accessions (3): Q9UP52, E7ET36, H7C544

UniProt curated annotations — full annotation on UniProt →

Function. Mediates cellular uptake of transferrin-bound iron in a non-iron dependent manner. May be involved in iron metabolism, hepatocyte function and erythrocyte differentiation.

Subunit / interactions. Homodimer.

Subcellular location. Cell membrane Cytoplasm.

Tissue specificity. Predominantly expressed in liver. While the alpha form is also expressed in spleen, lung, muscle, prostate and peripheral blood mononuclear cells, the beta form is expressed in all tissues tested, albeit weakly.

Disease relevance. Hemochromatosis 3 (HFE3) [MIM:604250] A disorder of iron metabolism characterized by iron overload. Excess iron is deposited in a variety of organs leading to their failure, and resulting in serious illnesses including cirrhosis, hepatomas, diabetes, cardiomyopathy, arthritis, and hypogonadotropic hypogonadism. Severe effects of the disease usually do not appear until after decades of progressive iron loading. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. The variant Lys-172 found in hereditary hemochromatosis type III affects the putative initiation codon of the beta isoform thus preventing its translation.

Similarity. Belongs to the peptidase M28 family. M28B subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9UP52-1	Alpha	yes
Q9UP52-2	Beta
Q9UP52-3	Gamma

RefSeq proteins (2): NP_001193784, NP_003218* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003137	PA_domain	Domain
IPR007484	Peptidase_M28	Domain
IPR036757	TFR-like_dimer_dom_sf	Homologous_superfamily
IPR037324	TfR1/2_PA	Domain
IPR039373	Peptidase_M28B	Family
IPR046450	PA_dom_sf	Homologous_superfamily

Pfam: PF02225, PF04389

UniProt features (23 total): sequence variant 7, glycosylation site 4, topological domain 2, disulfide bond 2, splice variant 2, chain 1, transmembrane region 1, sequence conflict 1, region of interest 1, short sequence motif 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UP52-F1	83.98	0.70

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 (2): 108, 111

Glycosylation sites (4): 754, 240, 339, 540

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-917977	Transferrin endocytosis and recycling
R-HSA-382551	Transport of small molecules
R-HSA-917937	Iron uptake and transport

MSigDB gene sets: 231 (showing top): GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_DN, GOBP_POSITIVE_REGULATION_OF_PROTEIN_MATURATION, GOBP_POSITIVE_REGULATION_OF_ENDOCYTOSIS, GOBP_TRANSITION_METAL_ION_TRANSPORT, GOBP_INTRACELLULAR_IRON_ION_HOMEOSTASIS, GOBP_REGULATION_OF_HORMONE_LEVELS, GOCC_CELL_SURFACE, GOBP_HORMONE_TRANSPORT, GOBP_VESICLE_MEDIATED_TRANSPORT, GGGTGGRR_PAX4_03, GOBP_IRON_ION_TRANSPORT, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_CELL_CELL_SIGNALING, GOBP_REGULATION_OF_VESICLE_MEDIATED_TRANSPORT, GOBP_RESPONSE_TO_METAL_ION

GO Biological Process (12): iron ion transport (GO:0006826), intracellular iron ion homeostasis (GO:0006879), receptor-mediated endocytosis (GO:0006898), response to iron ion (GO:0010039), transferrin transport (GO:0033572), positive regulation of endocytosis (GO:0045807), positive regulation of transcription by RNA polymerase II (GO:0045944), multicellular organismal-level iron ion homeostasis (GO:0060586), cellular response to iron ion (GO:0071281), positive regulation of peptide hormone secretion (GO:0090277), endocytic iron import into cell (GO:0140298), positive regulation of protein maturation (GO:1903319)

GO Molecular Function (3): transferrin receptor activity (GO:0004998), co-receptor binding (GO:0039706), protein binding (GO:0005515)

GO Cellular Component (6): plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), cytoplasmic vesicle (GO:0031410), HFE-transferrin receptor complex (GO:1990712), cytoplasm (GO:0005737), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Iron uptake and transport	1
Transport of small molecules	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
inorganic ion homeostasis	2
endocytosis	2
cellular anatomical structure	2
transition metal ion transport	1
intracellular monoatomic cation homeostasis	1
response to metal ion	1
iron ion transport	1
protein transport	1
regulation of endocytosis	1
positive regulation of transport	1
positive regulation of cellular component organization	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
monoatomic cation homeostasis	1
multicellular organismal-level chemical homeostasis	1
response to iron ion	1
cellular response to metal ion	1
positive regulation of peptide secretion	1
peptide hormone secretion	1
positive regulation of hormone secretion	1
regulation of peptide hormone secretion	1
receptor-mediated endocytosis	1
iron import into cell	1
positive regulation of gene expression	1
positive regulation of protein metabolic process	1
protein maturation	1
regulation of protein maturation	1
cargo receptor activity	1
protein binding	1
binding	1
membrane	1
cell periphery	1
plasma membrane	1
cell surface	1
side of membrane	1
cytoplasm	1
intracellular vesicle	1
plasma membrane signaling receptor complex	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1036 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TFR2	HJV	Q6ZVN8	999
TFR2	HFE	Q30201	999
TFR2	SLC40A1	Q9NP59	959
TFR2	EPOR	P19235	945
TFR2	HAMP	P81172	941
TFR2	TMPRSS6	Q8IU80	909
TFR2	BMP6	P22004	887
TFR2	SLC11A2	P49281	839
TFR2	CYBRD1	Q53TN4	807
TFR2	IREB2	P48200	780
TFR2	HEPH	Q9BQS7	718
TFR2	NEO1	Q92859	685
TFR2	CP	P00450	683
TFR2	TFRC	P02786	656
TFR2	STEAP3	Q658P3	644

IntAct

14 interactions, top by confidence:

A	B	Type	Score
OLFM4	TFR2	psi-mi:“MI:0915”(physical association)	0.560
SEC22A	TFR2	psi-mi:“MI:0915”(physical association)	0.560
SOCS3	TFR2	psi-mi:“MI:0915”(physical association)	0.370
CFTR	TFR2	psi-mi:“MI:0915”(physical association)	0.370
TFR2	TAF5L	psi-mi:“MI:0914”(association)	0.350
LRRFIP1	CCNB1	psi-mi:“MI:0914”(association)	0.350
BRD4	SUMO1	psi-mi:“MI:0914”(association)	0.350
TBC1D2B	CEP120	psi-mi:“MI:0914”(association)	0.350
TFR2	TRIM55	psi-mi:“MI:0915”(physical association)	0.000
OLFM4	TFR2	psi-mi:“MI:0915”(physical association)	0.000
SEC22A	TFR2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (27): CD81 (Two-hybrid), TFR2 (Affinity Capture-Western), CD81 (Affinity Capture-Western), TFR2 (Affinity Capture-MS), EXT1 (Affinity Capture-MS), MAD2L2 (Affinity Capture-MS), TFR2 (Affinity Capture-MS), PDF (Affinity Capture-MS), TFR2 (Two-hybrid), SEC22A (Two-hybrid), TFR2 (Affinity Capture-MS), TAF5L (Affinity Capture-MS), GLG1 (Affinity Capture-MS), GALNT12 (Affinity Capture-MS), TFR2 (Affinity Capture-MS)

ESM2 similar proteins: A8T644, A8T650, A8T655, A8T658, A8T662, A8T666, A8T672, A8T682, A8T688, A8T6A1, A8T6A6, B2GUY2, O43292, O95479, P10852, P17852, P26006, P56201, P57716, Q0V8G3, Q0V8L2, Q13219, Q16549, Q502B3, Q5STE3, Q5XIA1, Q61139, Q62849, Q6NZ07, Q86UX2, Q8CFX1, Q8CGU6, Q8CIY2, Q8HZK2, Q8HZK3, Q8NBP7, Q8R4K8, Q8VCM8, Q92542, Q99JP7

Diamond homologs: A0A1D6L709, B2GUY2, D4B1R0, O35409, O43023, O54697, O77564, P70627, P91406, Q04609, Q5RDH6, Q5WN23, Q7M758, Q7Y228, Q852M4, Q9CZR2, Q9HBA9, Q9JKX3, Q9M1S8, Q9UP52, Q9UQQ1, Q9Y3Q0, P02786, P47161, Q07891, Q2V905, Q62351, Q8HZV3, Q90997, Q99376, Q9GLD3, Q9MYZ3, B2W3C7, C4JHZ6, E3RJ99, E4URG0, E5A6Z0, P80561, P81715, Q02PA2

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

1078 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	50
Likely pathogenic	79
Uncertain significance	214
Likely benign	617
Benign	22

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1074157	NM_003227.4(TFR2):c.1638_1639del (p.Leu546_Tyr547insTer)	Pathogenic
1323686	NM_003227.4(TFR2):c.1768-1G>A	Pathogenic
1355498	NM_003227.4(TFR2):c.318del (p.Ser107fs)	Pathogenic
1370639	NM_003227.4(TFR2):c.63del (p.Val22fs)	Pathogenic
1403018	NM_003227.4(TFR2):c.745del (p.His249fs)	Pathogenic
1425195	NM_003227.4(TFR2):c.484del (p.Leu162fs)	Pathogenic
1436409	NM_003227.4(TFR2):c.1938C>A (p.Tyr646Ter)	Pathogenic
1452584	NM_003227.4(TFR2):c.960T>G (p.Tyr320Ter)	Pathogenic
1979493	NM_003227.4(TFR2):c.18dup (p.Leu7fs)	Pathogenic
2002212	NM_003227.4(TFR2):c.529C>T (p.Gln177Ter)	Pathogenic
2009645	NM_003227.4(TFR2):c.252C>A (p.Tyr84Ter)	Pathogenic
2086408	NM_003227.4(TFR2):c.1179del (p.Pro395fs)	Pathogenic
2106932	NM_003227.4(TFR2):c.2281dup (p.Ala761fs)	Pathogenic
2117477	NM_003227.4(TFR2):c.990del (p.Tyr331fs)	Pathogenic
2128816	NM_003227.4(TFR2):c.192del (p.Arg65fs)	Pathogenic
21362	NM_003227.4(TFR2):c.1186C>T (p.Arg396Ter)	Pathogenic
2151820	NM_003227.4(TFR2):c.1286dup (p.Gly430fs)	Pathogenic
2704006	NM_003227.4(TFR2):c.689_690del (p.Asp230fs)	Pathogenic
2735061	NM_003227.4(TFR2):c.1841dup (p.Leu615fs)	Pathogenic
2746810	NM_003227.4(TFR2):c.867del (p.Phe290fs)	Pathogenic
2749051	NM_003227.4(TFR2):c.753_756del (p.Arg252fs)	Pathogenic
2760944	NM_003227.4(TFR2):c.829dup (p.Val277fs)	Pathogenic
2777575	NM_003227.4(TFR2):c.1362_1363insT (p.Arg455fs)	Pathogenic
2799824	NM_003227.4(TFR2):c.1812T>G (p.Tyr604Ter)	Pathogenic
2814974	NM_003227.4(TFR2):c.1467_1468delinsAT (p.Trp489_Leu490delinsTer)	Pathogenic
2838210	NM_003227.4(TFR2):c.750del (p.His249_Tyr250insTer)	Pathogenic
2842084	NM_003227.4(TFR2):c.17del (p.Gly6fs)	Pathogenic
2853994	NM_003227.4(TFR2):c.183_211del (p.Leu62fs)	Pathogenic
3007571	NM_003227.4(TFR2):c.73del (p.Arg25fs)	Pathogenic
3013755	NM_003227.4(TFR2):c.1132dup (p.Gln378fs)	Pathogenic

SpliceAI

2578 predictions. Top by Δscore:

Variant	Effect	Δscore
7:100621127:C:CA	acceptor_loss	1.0000
7:100621128:T:A	acceptor_loss	1.0000
7:100627230:C:CA	donor_gain	1.0000
7:100627742:ACAC:A	donor_gain	1.0000
7:100627743:CA:C	donor_gain	1.0000
7:100627743:CACC:C	donor_gain	1.0000
7:100627743:CACCT:C	donor_gain	1.0000
7:100627822:T:A	acceptor_loss	1.0000
7:100628221:CA:C	donor_loss	1.0000
7:100628223:C:CT	donor_loss	1.0000
7:100628223:CCT:C	donor_gain	1.0000
7:100628225:T:TA	donor_gain	1.0000
7:100628251:T:TA	donor_gain	1.0000
7:100628261:C:CT	donor_gain	1.0000
7:100628262:C:CT	donor_gain	1.0000
7:100628302:GAAGC:G	acceptor_gain	1.0000
7:100628303:AAGC:A	acceptor_gain	1.0000
7:100628304:AGC:A	acceptor_gain	1.0000
7:100628305:GC:G	acceptor_gain	1.0000
7:100628306:CC:C	acceptor_gain	1.0000
7:100628307:C:CA	acceptor_loss	1.0000
7:100628307:C:CC	acceptor_gain	1.0000
7:100628314:C:CT	acceptor_gain	1.0000
7:100630885:ATAC:A	donor_loss	1.0000
7:100630886:TACCT:T	donor_loss	1.0000
7:100630887:A:AC	donor_gain	1.0000
7:100630887:ACCTG:A	donor_loss	1.0000
7:100630888:C:CA	donor_loss	1.0000
7:100630888:C:CC	donor_gain	1.0000
7:100630888:CCTGG:C	donor_gain	1.0000

AlphaMissense

5184 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:100626849:C:G	A684P	0.998
7:100626882:A:G	W673R	0.998
7:100626882:A:T	W673R	0.998
7:100628272:G:C	S475R	0.998
7:100628272:G:T	S475R	0.998
7:100628274:T:G	S475R	0.998
7:100620903:G:T	A787D	0.997
7:100620904:C:G	A787P	0.997
7:100620936:A:G	L776P	0.997
7:100626846:C:G	A685P	0.997
7:100626870:C:G	A677P	0.997
7:100626880:C:A	W673C	0.997
7:100626880:C:G	W673C	0.997
7:100628232:A:G	W489R	0.997
7:100628232:A:T	W489R	0.997
7:100620878:C:A	W795C	0.996
7:100620878:C:G	W795C	0.996
7:100620915:A:G	L783P	0.996
7:100620922:A:G	W781R	0.996
7:100620922:A:T	W781R	0.996
7:100620933:G:T	A777D	0.996
7:100626836:A:G	L688P	0.996
7:100626851:C:G	R683P	0.996
7:100626869:G:T	A677E	0.996
7:100627946:G:C	S522R	0.996
7:100627946:G:T	S522R	0.996
7:100627948:T:G	S522R	0.996
7:100626863:C:T	G679E	0.995
7:100626866:C:G	R678P	0.995
7:100627455:C:G	D602H	0.995

dbSNP variants (sampled 300 via entrez): RS1000331731 (7:100642061 C>T), RS1000669050 (7:100629819 C>T), RS1000849458 (7:100630005 A>G), RS1001278564 (7:100628494 G>A), RS1001367156 (7:100637035 G>A), RS1001464007 (7:100629818 T>C), RS1001713595 (7:100636703 C>T), RS1002317847 (7:100638194 G>A,T), RS1002776970 (7:100638504 C>A), RS1002838491 (7:100638666 G>C), RS1002859413 (7:100633476 C>T), RS1002908623 (7:100631442 C>A,G,T), RS1002966135 (7:100627090 C>T), RS1003079177 (7:100620440 A>G), RS1003147831 (7:100642816 A>C)

Disease associations

OMIM: gene MIM:604720 | disease phenotypes: MIM:235200, MIM:604250

GenCC curated gene-disease

Disease	Classification	Inheritance
hemochromatosis type 3	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
hemochromatosis type 3	Definitive	AR

Mondo (3): hereditary hemochromatosis (MONDO:0006507), hemochromatosis type 3 (MONDO:0011417), hemochromatosis type 1 (MONDO:0021001)

Orphanet (3): TFR2-related hemochromatosis (Orphanet:225123), Symptomatic form of HFE-related hemochromatosis (Orphanet:465508), NON RARE IN EUROPE: Hemochromatosis type 1 (Orphanet:139498)

HPO phenotypes

17 total (17 of 17 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000044	Hypogonadotropic hypogonadism
HP:0000141	Amenorrhea
HP:0000802	Impotence
HP:0000953	Hyperpigmentation of the skin
HP:0000979	Purpura
HP:0001369	Arthritis
HP:0001394	Cirrhosis
HP:0001638	Cardiomyopathy
HP:0001875	Decreased total neutrophil count
HP:0001888	Decreased total lymphocyte count
HP:0001903	Anemia
HP:0002910	Elevated circulating hepatic transaminase concentration
HP:0003281	Increased circulating ferritin concentration
HP:0003452	Increased circulating iron concentration
HP:0012378	Fatigue
HP:0012463	Elevated transferrin saturation

GWAS associations

67 associations (top):

Study	Trait	p-value
GCST000498_1	Hematological parameters	5.000000e-10
GCST000502_2	Hematocrit	4.000000e-10
GCST000503_13	Mean corpuscular volume	3.000000e-11
GCST000935_1	Iron status biomarkers	7.000000e-08
GCST001765_21	Red blood cell traits	2.000000e-20
GCST002679_3	Iron status biomarkers (iron levels)	1.000000e-18
GCST002680_4	Iron status biomarkers (transferrin saturation)	6.000000e-12
GCST004003_12	Hematocrit	1.000000e-08
GCST004004_18	Mean corpuscular volume	1.000000e-07
GCST004004_56	Mean corpuscular volume	1.000000e-08
GCST004005_12	Hemoglobin levels	1.000000e-08
GCST004005_3	Hemoglobin levels	3.000000e-12
GCST004006_22	Mean corpuscular hemoglobin	1.000000e-13
GCST004008_1	Red blood cell count	3.000000e-16
GCST004332_1	Red blood cell count	1.000000e-08
GCST004601_100	Red blood cell count	4.000000e-90
GCST004602_58	Mean corpuscular volume	9.000000e-85
GCST004603_41	Platelet count	2.000000e-13
GCST004604_122	Hematocrit	8.000000e-12
GCST004605_35	Mean corpuscular hemoglobin concentration	5.000000e-42
GCST004607_156	Plateletcrit	2.000000e-10
GCST004612_36	High light scatter reticulocyte percentage of red cells	2.000000e-12
GCST004615_48	Hemoglobin concentration	2.000000e-16
GCST004619_115	Reticulocyte fraction of red cells	9.000000e-16
GCST004621_115	Red cell distribution width	2.000000e-13
GCST004621_116	Red cell distribution width	7.000000e-10
GCST004621_117	Red cell distribution width	9.000000e-37
GCST004628_93	Immature fraction of reticulocytes	2.000000e-09
GCST004630_262	Mean corpuscular hemoglobin	3.000000e-116
GCST005992_12	Mean corpuscular hemoglobin concentration	9.000000e-15

EFO canonical traits (15, from GWAS)

EFO ID	Trait name
EFO:0004305	erythrocyte count
EFO:0004348	hematocrit
EFO:0004461	iron biomarker measurement
EFO:0006333	transferrin saturation measurement
EFO:0004509	hemoglobin measurement
EFO:0004527	mean corpuscular hemoglobin
EFO:0004309	platelet count
EFO:0004528	mean corpuscular hemoglobin concentration
EFO:0007985	platelet crit
EFO:0007986	reticulocyte count
EFO:0009188	Red cell distribution width
EFO:0004615	apolipoprotein B measurement
EFO:0004842	eosinophil count
EFO:0004587	lymphocyte count
EFO:0010701	mean reticulocyte volume

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D006432	Hemochromatosis	C16.320.565.618.337; C18.452.565.500.480; C18.452.648.618.337
C537248	Hemochromatosis, type 3 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3988361 (PROTEIN FAMILY)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, decreases expression	4
dorsomorphin	increases expression, decreases expression, affects cotreatment	2
(+)-JQ1 compound	decreases expression	2
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	2
Methapyrilene	decreases expression, increases methylation	2
GSK-J4	decreases expression	1
sotorasib	affects cotreatment, decreases expression	1
ferric ammonium citrate	decreases expression	1
benzo(e)pyrene	increases methylation	1
potassium chromate(VI)	increases expression	1
periodate-oxidized adenosine	affects expression	1
nickel sulfate	increases expression	1
benazol P	affects expression	1
9-chloro-2-(2-furyl)-(1,2,4)triazolo(1,5-c)quinazolin-5-imine	decreases expression	1
phenethyl isothiocyanate	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
chromium hexavalent ion	increases expression	1
kenpaullone	decreases expression	1
SU 9516	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	decreases expression	1
bisphenol S	decreases expression	1
trametinib	affects cotreatment, decreases expression	1
NVP-BKM120	affects cotreatment, decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Arsenic	increases methylation	1
Vehicle Emissions	decreases methylation	1
Deferoxamine	decreases expression	1
Iron	affects binding, affects response to substance	1
N-Nitrosopyrrolidine	decreases expression	1

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