TF

Summary

TF (transferrin, HGNC:11740) is a protein-coding gene on chromosome 3q22.1, encoding Serotransferrin (P02787). Transferrins are iron binding transport proteins which can bind two Fe(3+) ions in association with the binding of an anion, usually bicarbonate.

This gene encodes a glycoprotein with an approximate molecular weight of 76.5 kDa. It is thought to have been created as a result of an ancient gene duplication event that led to generation of homologous C and N-terminal domains each of which binds one ion of ferric iron. The function of this protein is to transport iron from the intestine, reticuloendothelial system, and liver parenchymal cells to all proliferating cells in the body. This protein may also have a physiologic role as granulocyte/pollen-binding protein (GPBP) involved in the removal of certain organic matter and allergens from serum.

Source: NCBI Gene 7018 — RefSeq curated summary.

At a glance

• Gene–disease (curated): atransferrinemia (Strong, GenCC)
• GWAS associations: 56
• Clinical variants (ClinVar): 505 total — 5 pathogenic, 12 likely-pathogenic
• Phenotypes (HPO): 11
• Druggable target: yes
• MANE Select transcript: NM_001063

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11740
Approved symbol	TF
Name	transferrin
Location	3q22.1
Locus type	gene with protein product
Status	Approved
Aliases	PRO1557, PRO2086
Ensembl gene	ENSG00000091513
Ensembl biotype	protein_coding
OMIM	190000
Entrez	7018

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 8 protein_coding, 6 retained_intron, 4 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000402696, ENST00000414694, ENST00000460531, ENST00000461695, ENST00000462495, ENST00000466911, ENST00000467842, ENST00000474287, ENST00000475382, ENST00000482271, ENST00000485977, ENST00000493011, ENST00000494430, ENST00000498622, ENST00000877245, ENST00000877246, ENST00000877247, ENST00000877248, ENST00000877249

RefSeq mRNA: 3 — MANE Select: NM_001063 NM_001063, NM_001354703, NM_001354704

CCDS: CCDS3080

Canonical transcript exons

ENST00000402696 — 17 exons

Exon	Start	End
ENSE00000583033	133764182	133764275
ENSE00000778404	133764875	133764907
ENSE00000885874	133755363	133755495
ENSE00000885878	133759175	133759329
ENSE00001078172	133770508	133770572
ENSE00001271462	133768029	133768164
ENSE00001271473	133766278	133766433
ENSE00001371851	133756282	133756337
ENSE00002418587	133756831	133757009
ENSE00003475254	133754495	133754671
ENSE00003491953	133748412	133748584
ENSE00003511531	133757769	133757946
ENSE00003536159	133753595	133753703
ENSE00003575359	133777049	133777238
ENSE00003617207	133746393	133746483
ENSE00003685626	133775433	133775617
ENSE00003811732	133778586	133796641

Expression profiles

Bgee: expression breadth ubiquitous, 249 present calls, max score 99.99.

FANTOM5 (CAGE): breadth broad, TPM avg 79.7798 / max 12806.9701, expressed in 282 samples.

FANTOM5 promoters (14 alternative TSS)

Promoter ID	TPM avg	Samples expressed
38670	77.1253	270
38668	2.2130	1041
38683	0.5233	76
38690	0.3817	55
38671	0.3111	64
38686	0.2973	73
38689	0.2590	27
38688	0.1992	14
38685	0.1754	48
38691	0.1350	39

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
inferior vagus X ganglion	UBERON:0005363	99.99	gold quality
medulla oblongata	UBERON:0001896	99.96	gold quality
corpus callosum	UBERON:0002336	99.96	gold quality
superior vestibular nucleus	UBERON:0007227	99.96	gold quality
endothelial cell	CL:0000115	99.95	gold quality
pons	UBERON:0000988	99.95	gold quality
middle frontal gyrus	UBERON:0002702	99.94	gold quality
inferior olivary complex	UBERON:0002127	99.93	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	99.93	gold quality
cranial nerve II	UBERON:0000941	99.92	gold quality
ventral tegmental area	UBERON:0002691	99.92	gold quality
right lobe of liver	UBERON:0001114	99.91	gold quality
subthalamic nucleus	UBERON:0001906	99.91	gold quality
substantia nigra pars reticulata	UBERON:0001966	99.88	gold quality
liver	UBERON:0002107	99.88	gold quality
dorsal plus ventral thalamus	UBERON:0001897	99.87	gold quality
globus pallidus	UBERON:0001875	99.86	gold quality
lateral globus pallidus	UBERON:0002476	99.86	gold quality
medial globus pallidus	UBERON:0002477	99.85	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	99.85	gold quality
spinal cord	UBERON:0002240	99.83	gold quality
substantia nigra pars compacta	UBERON:0001965	99.80	gold quality
midbrain	UBERON:0001891	99.73	gold quality
substantia nigra	UBERON:0002038	99.71	gold quality
lateral nuclear group of thalamus	UBERON:0002736	99.69	gold quality
putamen	UBERON:0001874	99.41	gold quality
Ammon’s horn	UBERON:0001954	99.36	gold quality
amygdala	UBERON:0001876	99.26	gold quality
hypothalamus	UBERON:0001898	99.26	gold quality
caudate nucleus	UBERON:0001873	99.13	gold quality

Single-cell (SCXA)

Detected in 14 experiment(s), a significant marker in 11.

Experiment	Marker?	Max mean expression
E-GEOD-137537	yes	29508.79
E-GEOD-98556	yes	22926.60
E-MTAB-7316	yes	9690.36
E-GEOD-84465	yes	5869.42
E-HCAD-9	yes	3487.83
E-HCAD-25	yes	2873.40
E-HCAD-35	yes	1901.26
E-GEOD-180759	yes	1695.41
E-HCAD-4	yes	20.87
E-CURD-112	yes	10.23
E-MTAB-9388	yes	7.58
E-MTAB-6142	no	17.43
E-MTAB-5061	no	3.55
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

25 targeting TF, 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-5700	99.64	69.88	2280
HSA-MIR-6832-3P	99.52	70.44	1726
HSA-MIR-653-5P	99.46	67.35	1300
HSA-MIR-1912-3P	99.32	67.40	936
HSA-MIR-4685-5P	99.25	65.99	1563
HSA-MIR-6837-5P	99.25	65.47	1632
HSA-MIR-196A-3P	99.19	67.34	1204
HSA-MIR-3160-3P	99.07	64.78	955
HSA-MIR-1295B-5P	99.03	67.50	810
HSA-MIR-6770-5P	98.97	66.76	1853
HSA-MIR-153-3P	98.96	72.51	1644
HSA-MIR-412-3P	98.86	66.89	712
HSA-MIR-6754-3P	98.84	66.60	889
HSA-MIR-501-5P	98.77	68.88	1328
HSA-MIR-500A-5P	98.76	69.13	1241
HSA-MIR-1910-3P	98.44	67.51	1695
HSA-MIR-3130-5P	98.14	66.00	711
HSA-MIR-6511A-5P	98.13	67.47	1770
HSA-MIR-4423-3P	97.98	69.66	912
HSA-MIR-4678	97.59	68.31	902
HSA-MIR-4482-5P	97.53	65.68	598
HSA-MIR-4640-5P	97.42	66.33	1543
HSA-MIR-4726-5P	97.24	65.67	1299
HSA-MIR-635	96.00	65.54	687

Literature-anchored findings (GeneRIF, showing 40)

• mutational analysis of the transferrin receptor reveals overlapping HFE and transferrin binding sites (PMID:11800564)
• Solute carrier 11a1 (Slc11a1; formerly Nramp1) regulates metabolism and release of iron acquired by phagocytic, but not transferrin-receptor-mediated, iron uptake (PMID:11903051)
• Proband serum contains two transferrin forms: one of 80 kD analogous to the normal one, and a smaller one of 50 kD, which may arise from a specific degradation or be the gene product of a modified allele. (PMID:11920219)
• These results suggest that wild-type HFE negatively modulates the endocytic uptake of transferrin. This inhibitory effect is attenuated in cells expressing C282Y-mutant HFE. (PMID:11940510)
• A series of mutations in the carbonate-binding threonine and arginine residues of the N-terminal and C-terminal lobes of full-length transferrin (and in the N-lobe by itself) substantially alters the synergistic anion-binding functions of transferrin. (PMID:12044175)
• Mutation 375glu-lys is predicted to cause a conformational change in the coiled region of the carboxyl-terminal iron-binding lobe. (PMID:12111369)
• differential effect of a his tag at the N- and C-termini: functional studies with recombinant human serum transferrin (PMID:12135367)
• high-capacity multivalent metal-inducible mechanism for Fe acquisition from transferrin and lactoferrin (PMID:12165535)
• Serum levels of soluble intercellular adhesion molecule-1 (sICAM-1), ceruloplasmin (Cp), and transferrin (Tf) in rheumatoid arthritis. Serum Tf levels were significantly diminished and serum levels of sICAM-1 and Cp were significantly increased. (PMID:12175089)
• Binding patterns of vanadium ions with different valence states to human transferrin (PMID:12207902)
• a protein identical to or highly homologous with serum TF was purified from follicular fluid; follicular fluid transferrin significantly increased sperm motility (PMID:12223217)
• The roles of the two basic residues in the “dilysine trigger” regions of transferrins have been clarified and their different behaviors compared to those of the lactoferrins. (PMID:12450380)
• The position of arginine 124 controls the rate of iron release from the N-lobe of the human protein. (PMID:12458193)
• E2 induces Tf gene expression through a nonconsensus distal ERE (PMID:12459033)
• a complex of Yb3+-transferrin is recognized by human transferrin receptor, a possible pathway for Yb3+ accumulation in cells (PMID:12473103)
• review of role in bacterial infections, iron homeostasis, and free radical generation; and implications for theraputic use. (PMID:12617162)
• analyses and comparison of the oligosaccharides present on the different isoforms of purified transferrin isolated from control and patients with severe alcohol abuse (PMID:12626412)
• These findings demonstrate that papillary thyroid carcinoma cells synthesize unique post-translationally modified thyroglobulin and transferrin variants in situ. (PMID:12819023)
• In the urban population, the loci TF (AvaI in exon5) and ACE (I/D polymorphism of the Alu repeat in intron16) were studied in 130 and 141 subjects.The polymorphic loci of the urban and rural populations did not differ in the allele frequencies (PMID:12884526)
• Transferrin and other target genes identified may play a functional role in the downstream pathway of GADD153. (PMID:12939601)
• The analysis involved the data on nine polymorphic codominant loci: HP, GC, TF, PI, PGM1, GLO1, C3, ACP1, and ESD. The loci were selected by significance of differences in genotype frequencies between tuberculosis patients and healthy controls (PMID:12942785)
• Transferrin C1 homozygosity carriers had an increased risk of Alzheimer’s in subjects > or =75 years of age, showing that homozygosity for the Transferrin C1 allele was associated with an approximately three-fold increased risk. (PMID:12951205)
• examination of iron release to pyrophosphate from the isolated recombinant C-lobe and from that lobe in the intact protein, each free and bound to receptor (PMID:14567694)
• identification of C-lobe as binding site to receptor (PMID:14580189)
• holo-transferrin blocked apoptosis of N.1 cells that was induced by Myc-activation or by treatment with TNFalpha, FasL, and TRAIL (PMID:14614458)
• Recycling, degradation and sensitivity to the synergistic anion of transferrin in the receptor-independent route of iron uptake by human hepatoma (HuH-7) cells (PMID:14643898)
• dynamics simulation of the open form of human serum transferrin apoprotein shows that it is flexible enough to sample conformations that are consistent with iron binding (PMID:14645044)
• analysis of the structure of TfR-Tf complex explains differences in the iron-release properties of free and receptor bound Tf (PMID:14980223)
• apotransferrin can influence oligodendroglia gene expression and differentiation through multiple mechanisms depending on the maturation of the cell. (PMID:15042587)
• The combination of the C2 allele of transferrin and the C282Y allele of the haemochromatosis gene increase susceptibility for developing Alzheimer’s disease. (PMID:15060098)
• Urinary levels are increaed in normoalbuminuric type 2 diabetic patients. (PMID:15111541)
• In TfC1 homozygotes a shift was found toward higher sialylation, but in TfC1C2 heterozygotes the 5- and 6-sialylated bands were less concentrated (PMID:15214509)
• isolation of transferrin from plasma by ion exchange column chromatography produced a broad pink protein band that subsequently separated on a gel filtration column into three proteins containing many metals. (PMID:15214510)
• degraded by arg-gingipain and lys-gingiapin of Porphyromonas gingivalis, providing sources of iron and peptides which may contribute to tissue destruction by catalyzing the formation of toxic hydroxyradicals (PMID:15271890)
• Transfserrin receptor 2 mRNA levels do not change in cells exposed to diferric transferrin (diferric transferrin) (PMID:15319290)
• Tyr188 is a critical residue not only for iron binding but also for chelator binding and iron release in transferrin (PMID:15327995)
• mutational analysis of patients with atransferrinemia (PMID:15466165)
• fucosylation at the reducing-terminal GlcNAc (Fucalpha1-6GlcNAc) specifically occurred at Asn630, as demonstrated by treatment of the glycopeptides with alpha1-3/4-L-fucosidase (PMID:15536627)
• EGF-like domains of factor Xa and factor IXa are important for the activation of the factor VII–tissue factor complex (PMID:15634274)
• This co-culture system represents a potentially powerful tool to study neuron-glia interactions that occur during myelinogenesis and the role of Transferrin in this process. (PMID:15892129)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
danio_rerio	sxph	ENSDARG00000013240
mus_musculus	Trf	ENSMUSG00000032554

Paralogs (3): LTF (ENSG00000012223), SRPRB (ENSG00000144867), MELTF (ENSG00000163975)

Protein

Protein identifiers

Serotransferrin — P02787 (reviewed: P02787)

Alternative names: Beta-1 metal-binding globulin, Siderophilin

All UniProt accessions (7): P02787, C9JB55, C9JVG0, F8WC57, F8WCI6, F8WEK9, H7C5E8

UniProt curated annotations — full annotation on UniProt →

Function. Transferrins are iron binding transport proteins which can bind two Fe(3+) ions in association with the binding of an anion, usually bicarbonate. It is responsible for the transport of iron from sites of absorption and heme degradation to those of storage and utilization. Serum transferrin may also have a further role in stimulating cell proliferation. (Microbial infection) Serves as an iron source for Neisseria species, which capture the protein and extract its iron for their own use. (Microbial infection) Serves as an iron source for parasite T.brucei (strain 427), which capture TF via its own transferrin receptor ESAG6:ESAG7 and extract its iron for its own use.

Subunit / interactions. Monomer. Part of a complex composed of SLC40A1/ferroportin, TF/transferrin and HEPH/hephaestin that transfers iron from cells to transferrin. Interacts with TFRC. (Microbial infection) Binds to Neisseria transferrin-binding protein A (tbpA or tbp1). Forms a large complex with TbpA and TbpB. (Microbial infection) Binds to Neisseria transferrin-binding protein B (tbpb or tbp2).

Subcellular location. Secreted.

Tissue specificity. Expressed by the liver and secreted in plasma.

Disease relevance. Atransferrinemia (ATRAF) [MIM:209300] A rare autosomal recessive disorder characterized by abnormal synthesis of transferrin leading to iron overload and microcytic hypochromic anemia. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Has a bilobed structure, each lobe binds a single Fe(3+) ion. Does not always bind 2 Fe(3+) ions. (Microbial infection) Binds to Neisseria transferrin-binding proteins A and B via its C-terminal lobe only. The L3 helix finger of TbpA inserts into the C-terminal lobe of TF, altering its conformation and probably disturbing the coordination of iron 2. Electron microscopy suggests that in the TbpA-TbpB-TF complex, TF is captured directly above the loop domain of TbpA in a chamber of about 1000 Angstroms(3) formed by the 3 proteins, where interactions between the proteins serve to abstract iron 2 from TF. Binding to TbpB does not alter the conformation of the C-terminal lobe.

Similarity. Belongs to the transferrin family.

RefSeq proteins (3): NP_001054, NP_001341632, NP_001341633 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001156	Transferrin-like_dom	Domain
IPR016357	Transferrin	Family
IPR018195	Transferrin_Fe_BS	Binding_site
IPR030685	Serotransferrin_mammal	Family

Pfam: PF00405

UniProt features (161 total): strand 42, helix 37, disulfide bond 19, binding site 16, sequence variant 16, turn 10, sequence conflict 10, glycosylation site 4, modified residue 3, domain 2, signal peptide 1, chain 1

Structure

Experimental structures (PDB)

66 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
1RYO	X-RAY DIFFRACTION	1.2
1A8E	X-RAY DIFFRACTION	1.6
3SKP	X-RAY DIFFRACTION	1.7
1A8F	X-RAY DIFFRACTION	1.8
1D3K	X-RAY DIFFRACTION	1.8
1FQE	X-RAY DIFFRACTION	1.8
3FGS	X-RAY DIFFRACTION	1.8
1JQF	X-RAY DIFFRACTION	1.85
1OQG	X-RAY DIFFRACTION	1.9
1D4N	X-RAY DIFFRACTION	2
1N84	X-RAY DIFFRACTION	2.05
1FQF	X-RAY DIFFRACTION	2.1
1N7X	X-RAY DIFFRACTION	2.1
3V83	X-RAY DIFFRACTION	2.1
1BP5	X-RAY DIFFRACTION	2.2
1N7W	X-RAY DIFFRACTION	2.2
28MR	X-RAY DIFFRACTION	2.26
28MS	X-RAY DIFFRACTION	2.37
1DTG	X-RAY DIFFRACTION	2.4
1OQH	X-RAY DIFFRACTION	2.4
4H0W	X-RAY DIFFRACTION	2.4
9THQ	X-RAY DIFFRACTION	2.44
4X1B	X-RAY DIFFRACTION	2.45
1B3E	X-RAY DIFFRACTION	2.5
5WTD	X-RAY DIFFRACTION	2.5
6JAS	X-RAY DIFFRACTION	2.5
9THO	X-RAY DIFFRACTION	2.55
2O84	X-RAY DIFFRACTION	2.6
3V8X	X-RAY DIFFRACTION	2.6
6CTC	X-RAY DIFFRACTION	2.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P02787-F1	93.39	0.86

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 (16): 207; 268; 411; 445; 471; 475; 477; 478; 536; 604; 82; 114 …

Post-translational modifications (3): 42, 389, 685

Disulfide bonds (19): 28–67, 38–58, 137–213, 156–350, 177–193, 180–198, 190–196, 246–260, 358–615, 364–396, 374–387, 421–693, 437–656, 469–542, 493–684, 503–517, 514–525, 582–596, 634–639

Glycosylation sites (4): 51, 432, 491, 630

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-114608	Platelet degranulation
R-HSA-381426	Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)
R-HSA-8856825	Cargo recognition for clathrin-mediated endocytosis
R-HSA-8856828	Clathrin-mediated endocytosis
R-HSA-8957275	Post-translational protein phosphorylation
R-HSA-917937	Iron uptake and transport
R-HSA-917977	Transferrin endocytosis and recycling

MSigDB gene sets: 319 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_PROTEASOMAL_UBIQUITIN_DEPENDENT_PROTEIN_CATABOLIC_PROCESS, GOBP_ANTIMICROBIAL_HUMORAL_RESPONSE, GOBP_POSITIVE_REGULATION_OF_ENDOCYTOSIS, HARRIS_HYPOXIA, GOCC_SECRETORY_GRANULE, GOBP_TRANSITION_METAL_ION_TRANSPORT, REACTOME_PLATELET_ACTIVATION_SIGNALING_AND_AGGREGATION, ASTON_MAJOR_DEPRESSIVE_DISORDER_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_INTRACELLULAR_IRON_ION_HOMEOSTASIS, GOBP_POSITIVE_REGULATION_OF_PROTEIN_CATABOLIC_PROCESS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOCC_CELL_SURFACE, TGACCTY_ERR1_Q2

GO Biological Process (13): iron ion transport (GO:0006826), intracellular iron ion homeostasis (GO:0006879), cell surface receptor signaling pathway (GO:0007166), antibacterial humoral response (GO:0019731), osteoclast differentiation (GO:0030316), regulation of protein stability (GO:0031647), positive regulation of proteasomal ubiquitin-dependent protein catabolic process (GO:0032436), positive regulation of receptor-mediated endocytosis (GO:0048260), multicellular organismal-level iron ion homeostasis (GO:0060586), cellular response to iron ion (GO:0071281), monoatomic ion transport (GO:0006811), response to bacterium (GO:0009617), iron ion export across plasma membrane (GO:1903988)

GO Molecular Function (9): ferrous iron binding (GO:0008198), ferric iron binding (GO:0008199), enzyme binding (GO:0019899), iron chaperone activity (GO:0034986), transmembrane transporter binding (GO:0044325), transferrin receptor binding (GO:1990459), iron ion binding (GO:0005506), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (24): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), early endosome (GO:0005769), late endosome (GO:0005770), endoplasmic reticulum lumen (GO:0005788), plasma membrane (GO:0005886), clathrin-coated pit (GO:0005905), basal plasma membrane (GO:0009925), cell surface (GO:0009986), endosome membrane (GO:0010008), apical plasma membrane (GO:0016324), endocytic vesicle (GO:0030139), clathrin-coated endocytic vesicle membrane (GO:0030669), cytoplasmic vesicle (GO:0031410), vesicle (GO:0031982), secretory granule lumen (GO:0034774), basal part of cell (GO:0045178), perinuclear region of cytoplasm (GO:0048471), recycling endosome (GO:0055037), extracellular exosome (GO:0070062), blood microparticle (GO:0072562), HFE-transferrin receptor complex (GO:1990712), endosome (GO:0005768), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
Response to elevated platelet cytosolic Ca2+	1
Metabolism of proteins	1
Clathrin-mediated endocytosis	1
Membrane Trafficking	1
Post-translational protein modification	1
Transport of small molecules	1
Iron uptake and transport	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
endosome	4
iron ion binding	3
inorganic ion homeostasis	2
protein binding	2
membrane	2
plasma membrane region	2
cytoplasm	2
transition metal ion transport	1
intracellular monoatomic cation homeostasis	1
signal transduction	1
antimicrobial humoral response	1
defense response to bacterium	1
myeloid leukocyte differentiation	1
regulation of biological quality	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
receptor-mediated endocytosis	1
positive regulation of endocytosis	1
regulation of receptor-mediated endocytosis	1
monoatomic cation homeostasis	1
multicellular organismal-level chemical homeostasis	1
response to iron ion	1
cellular response to metal ion	1
transport	1
response to other organism	1
iron ion transmembrane transport	1
export across plasma membrane	1
metallochaperone activity	1
signaling receptor binding	1
transition metal ion binding	1
binding	1
cation binding	1
endoplasmic reticulum	1
intracellular organelle lumen	1
cell periphery	1
endomembrane system	1
basal part of cell	1

Protein interactions and networks

STRING

1772 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TF	ALB	P02768	854
TF	TFRC	P02786	799
TF	A2M	P01023	794
TF	HPX	P02790	788
TF	SERPINA1	P01009	787
TF	TTR	P02766	766
TF	APOA1	P02647	755
TF	CP	P00450	755
TF	GC	P02774	741
TF	AHSG	P02765	731
TF	HP	P00737	711
TF	APOA2	P02652	671
TF	KNG1	P01042	657
TF	HRG	P04196	649
TF	A1BG	P04217	642

IntAct

225 interactions, top by confidence:

A	B	Type	Score
TFRC	TF	psi-mi:“MI:0407”(direct interaction)	0.850
MAPK6	HERC2	psi-mi:“MI:0914”(association)	0.840
	TFRC	psi-mi:“MI:0914”(association)	0.780
	TFRC	psi-mi:“MI:0915”(physical association)	0.780
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
RETREG3	PLSCR1	psi-mi:“MI:0914”(association)	0.640
tbp1	TF	psi-mi:“MI:0407”(direct interaction)	0.630
tbp1	TF	psi-mi:“MI:0915”(physical association)	0.630
tbpB	TF	psi-mi:“MI:0407”(direct interaction)	0.620

BioGRID (220): TF (Affinity Capture-MS), TF (Affinity Capture-MS), TF (Affinity Capture-MS), TF (Affinity Capture-MS), TF (Affinity Capture-MS), TF (Affinity Capture-MS), TF (Affinity Capture-MS), TF (Affinity Capture-MS), TF (Affinity Capture-MS), TF (Affinity Capture-MS), TF (Affinity Capture-MS), TF (Affinity Capture-MS), TF (Affinity Capture-MS), TF (Affinity Capture-MS), TF (Affinity Capture-MS)

ESM2 similar proteins: A2A863, A5A6I6, A5Z1X6, B0FYY4, E7E2N8, K9IMD0, O77698, O77811, O93429, O97490, P02787, P02788, P02789, P07228, P08071, P08582, P09571, P12346, P12606, P12607, P14632, P19134, P20233, P22297, P24627, P27425, P31226, P53712, P54996, P56410, P79815, P79819, P80426, P80429, Q02942, Q26643, Q27874, Q29443, Q29477, Q29492

Diamond homologs: A5A6I6, K9IMD0, O77698, O77811, O93429, O97490, P02787, P02788, P02789, P08071, P08582, P09571, P12346, P14632, P19134, P20233, P24627, P27425, P31226, P56410, P79815, P79819, P80426, P80429, Q02942, Q0VIL3, Q29443, Q29477, Q29545, Q501K5, Q6PGT3, Q92079, Q921I1, Q9DBD0, Q9IBF7, Q9R0R1, Q9TUM0, Q9VTZ5, P22297, Q26643

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
TFCP2	“up-regulates quantity by expression”	TF	“transcriptional regulation”

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	12
Uncertain significance	102
Likely benign	327
Benign	24

Top pathogenic / likely-pathogenic (17)

Variant ID	HGVS	Classification
12614	NM_001063.4(TF):c.830G>A (p.Gly277Asp)	Pathogenic
12618	NM_001063.4(TF):c.1936A>G (p.Lys646Glu)	Pathogenic
12619	NM_001063.4(TF):c.562_564delinsAA (p.Gln188fs)	Pathogenic
12620	NM_001063.4(TF):c.1429G>C (p.Ala477Pro)	Pathogenic
12621	NM_001063.4(TF):c.229G>A (p.Asp77Asn)	Pathogenic
1699991	NM_001063.4(TF):c.1444C>T (p.Pro482Ser)	Likely pathogenic
218294	NM_001063.4(TF):c.1825C>T (p.Arg609Trp)	Likely pathogenic
3588594	NM_001063.4(TF):c.147del (p.Pro50fs)	Likely pathogenic
3588595	NM_001063.4(TF):c.216+2T>C	Likely pathogenic
3588596	NM_001063.4(TF):c.325+1G>A	Likely pathogenic
3588597	NM_001063.4(TF):c.394C>T (p.Arg132Ter)	Likely pathogenic
3588598	NM_001063.4(TF):c.440G>A (p.Trp147Ter)	Likely pathogenic
3588599	NM_001063.4(TF):c.817C>T (p.Arg273Ter)	Likely pathogenic
3588600	NM_001063.4(TF):c.1007_1008del (p.Gly335_Tyr336insTer)	Likely pathogenic
3588601	NM_001063.4(TF):c.1088G>A (p.Trp363Ter)	Likely pathogenic
3588602	NM_001063.4(TF):c.1872+1G>C	Likely pathogenic
4278393	NM_001063.4(TF):c.923dup (p.His308fs)	Likely pathogenic

SpliceAI

2866 predictions. Top by Δscore:

Variant	Effect	Δscore
3:133753589:TTTCA:T	acceptor_loss	1.0000
3:133753591:TCA:T	acceptor_loss	1.0000
3:133753592:CA:C	acceptor_loss	1.0000
3:133753699:AGAGG:A	donor_gain	1.0000
3:133753700:GAGG:G	donor_gain	1.0000
3:133753700:GAGGG:G	donor_gain	1.0000
3:133753701:AGG:A	donor_gain	1.0000
3:133753702:GG:G	donor_gain	1.0000
3:133753702:GGG:G	donor_gain	1.0000
3:133753703:GG:G	donor_gain	1.0000
3:133753704:G:GC	donor_loss	1.0000
3:133753704:G:GG	donor_gain	1.0000
3:133753705:T:A	donor_loss	1.0000
3:133754595:C:T	donor_gain	1.0000
3:133755353:T:TA	acceptor_gain	1.0000
3:133756826:CCCA:C	acceptor_loss	1.0000
3:133756829:A:AC	acceptor_loss	1.0000
3:133756829:A:AG	acceptor_gain	1.0000
3:133756830:G:GT	acceptor_gain	1.0000
3:133756830:GA:G	acceptor_gain	1.0000
3:133756830:GAGA:G	acceptor_gain	1.0000
3:133756830:GAGAA:G	acceptor_gain	1.0000
3:133756974:G:GT	donor_gain	1.0000
3:133757010:G:GA	donor_loss	1.0000
3:133757011:T:G	donor_loss	1.0000
3:133757767:A:AG	acceptor_gain	1.0000
3:133757768:G:GG	acceptor_gain	1.0000
3:133757946:TGTG:T	donor_loss	1.0000
3:133757947:G:GG	donor_gain	1.0000
3:133757948:TGA:T	donor_loss	1.0000

AlphaMissense

4603 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:133759213:T:A	W363R	0.999
3:133759213:T:C	W363R	0.999
3:133759215:G:C	W363C	0.999
3:133759215:G:T	W363C	0.999
3:133759246:T:A	C374S	0.999
3:133759247:G:C	C374S	0.999
3:133759257:G:C	W377C	0.999
3:133759257:G:T	W377C	0.999
3:133766354:C:G	C469W	0.999
3:133766384:G:C	W479C	0.999
3:133766384:G:T	W479C	0.999
3:133775452:G:C	W569C	0.999
3:133775452:G:T	W569C	0.999
3:133759255:T:A	W377R	0.998
3:133759255:T:C	W377R	0.998
3:133766352:T:A	C469S	0.998
3:133766352:T:C	C469R	0.998
3:133766353:G:A	C469Y	0.998
3:133766353:G:C	C469S	0.998
3:133766382:T:A	W479R	0.998
3:133766382:T:C	W479R	0.998
3:133768049:T:A	C503S	0.998
3:133768050:G:C	C503S	0.998
3:133770509:T:A	C542S	0.998
3:133770510:G:C	C542S	0.998
3:133770537:T:G	F551C	0.998
3:133775531:T:A	C596S	0.998
3:133775532:G:C	C596S	0.998
3:133777125:T:C	F650S	0.998
3:133777125:T:G	F650C	0.998

dbSNP variants (sampled 300 via entrez): RS1000020981 (3:133694000 G>A,C), RS1000053739 (3:133696845 A>G), RS1000057607 (3:133665553 G>C), RS1000085376 (3:133765435 G>A), RS1000089105 (3:133726053 GT>G), RS1000097910 (3:133768736 A>G,T), RS1000105133 (3:133748180 A>C,G,T), RS1000134933 (3:133705289 A>G), RS1000135737 (3:133736834 G>A,C), RS1000227919 (3:133784916 T>A), RS1000260914 (3:133771845 A>G), RS1000276633 (3:133699192 G>A), RS1000301326 (3:133729960 G>A), RS1000321689 (3:133742928 G>A), RS1000330118 (3:133671805 A>T)

Disease associations

OMIM: gene MIM:190000 | disease phenotypes: MIM:209300

GenCC curated gene-disease

Disease	Classification	Inheritance
atransferrinemia	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
atransferrinemia	Moderate	AR

Mondo (3): atransferrinemia (MONDO:0008846), iron deficiency anemia (MONDO:0001356), prostate cancer (MONDO:0008315)

Orphanet (2): Congenital atransferrinemia (Orphanet:1195), Familial prostate cancer (Orphanet:1331)

HPO phenotypes

11 total (11 of 11 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000821	Hypothyroidism
HP:0001369	Arthritis
HP:0001392	Abnormality of the liver
HP:0001626	Abnormality of the cardiovascular system
HP:0001635	Congestive heart failure
HP:0001732	Abnormality of the pancreas
HP:0001903	Anemia
HP:0001931	Hypochromic anemia
HP:0002719	Recurrent infections
HP:0012239	Atransferrinemia

GWAS associations

56 associations (top):

Study	Trait	p-value
GCST000301_16	Iron status biomarkers	2.000000e-06
GCST000301_24	Iron status biomarkers	3.000000e-15
GCST000301_5	Iron status biomarkers	5.000000e-06
GCST000302_2	Iron status biomarkers	1.000000e-09
GCST000935_2	Iron status biomarkers	3.000000e-47
GCST001021_4	Iron status biomarkers	5.000000e-10
GCST001021_9	Iron status biomarkers	8.000000e-06
GCST001103_1	Alcohol consumption (transferrin glycosylation)	5.000000e-43
GCST001103_2	Alcohol consumption (transferrin glycosylation)	1.000000e-09
GCST001103_4	Alcohol consumption (transferrin glycosylation)	1.000000e-35
GCST001174_1	Hepcidin levels	2.000000e-16
GCST002609_2	Iron status biomarkers	2.000000e-47
GCST002609_3	Iron status biomarkers	5.000000e-20
GCST002660_1	Hereditary hemochromatosis-related traits (HFE mutation homozygotes)	2.000000e-20
GCST002660_2	Hereditary hemochromatosis-related traits (HFE mutation homozygotes)	9.000000e-11
GCST002678_2	Iron status biomarkers (transferrin levels)	0.000000e+00
GCST002678_9	Iron status biomarkers (transferrin levels)	3.000000e-49
GCST002679_1	Iron status biomarkers (iron levels)	7.000000e-20
GCST002680_1	Iron status biomarkers (transferrin saturation)	7.000000e-38
GCST002680_6	Iron status biomarkers (transferrin saturation)	7.000000e-09
GCST004570_14	Iron status biomarkers (iron levels)	3.000000e-06
GCST004571_10	Iron status biomarkers (total iron binding capacity)	9.881313e-324
GCST004571_16	Iron status biomarkers (total iron binding capacity)	4.001932e-322
GCST004572_22	Iron status biomarkers (transferrin saturation)	9.881313e-324
GCST004572_29	Iron status biomarkers (transferrin saturation)	4.001932e-322
GCST004602_132	Mean corpuscular volume	2.000000e-12
GCST004602_133	Mean corpuscular volume	3.000000e-13
GCST004602_134	Mean corpuscular volume	7.000000e-12
GCST004605_65	Mean corpuscular hemoglobin concentration	2.000000e-10
GCST004605_66	Mean corpuscular hemoglobin concentration	6.000000e-09

EFO canonical traits (10, from GWAS)

EFO ID	Trait name
EFO:0004461	iron biomarker measurement
EFO:0006341	transferrin measurement
EFO:0006334	total iron binding capacity
EFO:0004329	alcohol drinking
EFO:0006333	transferrin saturation measurement
EFO:0004528	mean corpuscular hemoglobin concentration
EFO:0009188	Red cell distribution width
EFO:0004527	mean corpuscular hemoglobin
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004305	erythrocyte count

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D018798	Anemia, Iron-Deficiency	C15.378.050.196.300; C18.452.565.400.500
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750
C538259	Congenital atransferrinemia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4865 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Iron	increases uptake, decreases reaction, affects activity, affects cotreatment, affects transport (+3 more)	14
Aluminum	decreases uptake, increases uptake, affects activity, affects cotreatment, decreases secretion (+1 more)	9
Benzo(a)pyrene	decreases reaction, affects expression, increases methylation, affects cotreatment, decreases expression	6
bisphenol A	affects expression, decreases expression, increases expression	5
Copper	affects binding, affects reaction, affects cotreatment	5
Lead	affects binding, affects reaction, affects response to substance	4
Aflatoxin B1	decreases methylation, affects expression, decreases expression	4
deoxynivalenol	affects cotreatment, affects expression, increases expression, decreases expression	3
sodium arsenite	increases expression, increases methylation, decreases expression	3
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases reaction, increases expression, affects cotreatment	3
Acetaminophen	affects expression, decreases expression	3
Cadmium	decreases expression, increases abundance, affects abundance, affects binding	3
Dexamethasone	decreases expression, increases expression, decreases reaction, increases reaction, affects reaction (+1 more)	3
Nickel	decreases expression, affects binding	3
1-Methyl-3-isobutylxanthine	decreases reaction, increases reaction, affects reaction, affects cotreatment, decreases expression (+1 more)	3
Cyclosporine	affects expression, decreases expression	3
zinc chloride	decreases reaction, increases uptake, increases expression	2
perfluorooctanoic acid	decreases expression	2
LDN 193189	affects cotreatment, increases expression	2
Rosiglitazone	increases reaction, affects expression, affects reaction, affects cotreatment, decreases expression (+2 more)	2
Resveratrol	affects secretion, decreases reaction, increases activity	2
Ethanol	decreases reaction, increases expression, affects cotreatment, decreases expression	2
Asbestos	increases expression, affects response to substance	2
Ascorbic Acid	affects binding, affects cotreatment, increases expression, decreases expression	2
Busulfan	decreases reaction, increases expression	2
Gallium	affects binding, increases uptake	2
Hydrocortisone	affects reaction, affects cotreatment, increases expression, decreases expression, decreases reaction (+1 more)	2
Manganese	decreases uptake, affects binding	2
Methapyrilene	affects binding, decreases reaction, decreases expression	2
Quercetin	affects cotreatment, decreases expression, decreases reaction, increases activity	2

ChEMBL screening assays

22 unique, capped per target: 13 binding, 9 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1069453	Binding	Inhibition of [59Fe] uptake from [59Fe]transferrin in human SK-N-MC cells assessed as at 50 uM after 3 hrs relative to untreated control	Conjugates of desferrioxamine B (DFOB) with derivatives of adamantane or with orally available chelators as potential agents for treating iron overload. — J Med Chem
CHEMBL813547	Functional	Ability to remove iron from human iron transport protein transferrin, at a concentration of 0.1 mM, expressed as % iron removal in 30 minutes	Ferric ion sequestering agents. 11. Synthesis and kinetics of iron removal from transferrin of catechoyl derivatives of desferrioxamine B. — J Med Chem

Cellosaurus cell lines

13 cell lines: 8 spontaneously immortalized cell line, 4 transformed cell line, 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_AK30	GM10912	Transformed cell line	Male
CVCL_AK31	GM10913	Transformed cell line	Male
CVCL_AK32	GM10914	Transformed cell line	Female
CVCL_AK33	GM10929	Transformed cell line	Female
CVCL_D8C6	Ubigene A-549 TF KO	Cancer cell line	Male
CVCL_IR03	Super-CHO C1	Spontaneously immortalized cell line	Female
CVCL_IR04	Super-CHO C2	Spontaneously immortalized cell line	Female
CVCL_IR05	Super-CHO C2.8	Spontaneously immortalized cell line	Female
CVCL_IR06	Super-CHO ISS9	Spontaneously immortalized cell line	Female
CVCL_JF87	hTf/CHO-S #29/sf	Spontaneously immortalized cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00199277	PHASE4	UNKNOWN	Iron Therapy in Colo-Rectal Neoplasm and Iron Deficiency Anemia: Intravenous Iron Sucrose Versus Oral Ferrous Sulphate.
NCT00298441	PHASE4	COMPLETED	Efficacy of Intravenous Iron Administration in Hemodialysis Patients
NCT00593619	PHASE4	SUSPENDED	Trial Comparing the Safety of Two Different Intravenous Iron Formulations
NCT00706667	PHASE4	TERMINATED	Intravenous Ferric Carboxymaltose (Ferinject®) With or Without Erythropoietin in Patients Undergoing Orthopaedic Surgery
NCT00802139	PHASE4	COMPLETED	Efficacy and Safety Study of Iron Sucrose and Oral Iron Acetyl-transferrin Hydroglycerin
NCT00830037	PHASE4	TERMINATED	A Clinical Trial of Oral Versus IV Iron in Patients With Chronic Kidney Disease
NCT01100879	PHASE4	TERMINATED	Ferric Carboxymaltose for Treatment of Anaemia of Cancer in Subjects With Multiple Myeloma Receiving Chemotherapy
NCT01148745	PHASE4	COMPLETED	Iron Indices and Intravenous Ferumoxytol: Time to Steady State
NCT01151592	PHASE4	WITHDRAWN	Safety Assessment of Iron Sucrose (Venofer) in Patients With Chronic Kidney Disease Who Cannot Tolerate Ferumoxytol (Feraheme) or Iron Dextran (INFed or Dexferrum)
NCT01221844	PHASE4	COMPLETED	Bovine Lactoferrin to Prevent and Cure Iron Deficiency and Iron Deficiency Anemia in Complicated Pregnancies
NCT01245777	PHASE4	COMPLETED	Restless Legs Syndrome With Iron Deficiency or Anaemia in the 3rd Trimester of Pregnancy
NCT01418898	PHASE4	UNKNOWN	Nutrient Fortified Oat Drink
NCT01864161	PHASE4	COMPLETED	Endovenous Versus Liposomal Iron in CKD
NCT01904864	PHASE4	COMPLETED	Comparison of NovaFerrum® vs Ferrous Sulfate Treatment in Young Children With Nutritional Iron Deficiency Anemia
NCT01925703	PHASE4	COMPLETED	Short-Term Effects & Safety of an Accelerated Intravenous Iron Regimen in Patients With Heart Failure
NCT01942460	PHASE4	COMPLETED	Ferumoxytol for Iron-Deficiency Anemia in Chronic Kidney Disease and Peritoneal Dialysis Patients
NCT01950247	PHASE4	COMPLETED	Evaluate the Utility of Serum Hepcidin Levels to Predict Response to Oral or IV Iron
NCT02487719	PHASE4	UNKNOWN	Different Iron Supplements for Prevention of Anemia in Pregnancy
NCT02590224	PHASE4	COMPLETED	The Effect of Iron Deficiency Anemia During Pregnancy
NCT02774057	PHASE4	UNKNOWN	Trial of Captafer® vs. Oral Iron Sulfate in the Treatment of Iron Deficiency Anemia in Patients With IBD
NCT03112187	PHASE4	COMPLETED	FLIPS: Ferfer Liposomal Iron Performance Study
NCT03236246	PHASE4	COMPLETED	KRX-0502 (Ferric Citrate) in Subjects With NDD-CKD and IDA (The COMPASS Trial)
NCT03524651	PHASE4	COMPLETED	Ferrous Acetyl-Aspartate Casein Formulation Evaluation Over Ferrous Sulfate in Iron Deficiency Anemia
NCT03830034	PHASE4	UNKNOWN	Amino Acid Chelated Iron Versus Ferrous Fumarate in the Treatment of Iron Deficiency Anemia With Pregnancy: Randomized Controlled Trial
NCT04168346	PHASE4	NOT_YET_RECRUITING	Preoperative Intravenous Iron Therapy in Patients With Gastric Cancer
NCT04616092	PHASE4	UNKNOWN	Effect of Preoperative Intravenous Ferric Carboxymaltose for Clipping Surgery
NCT04627181	PHASE4	UNKNOWN	Do Iron And Vitamin B12 Injections Given Together, Improve Hemoglobin In Patients On Hemodialysis?
NCT04913649	PHASE4	RECRUITING	Intravenous Iron to Treat Postoperative Anemia in Older Cardiac Surgery Patients
NCT05007899	PHASE4	COMPLETED	Alternate Day Versus Daily Oral Iron Therapy in Adolescents
NCT05278793	PHASE4	UNKNOWN	The Efficacy of Intermittent Versus Daily Oral Iron Supplementation in Anaemic Pregnant Women.
NCT05358509	PHASE4	COMPLETED	Reducing Anemia in Pregnancy in India: the RAPIDIRON Trial
NCT05456932	PHASE4	UNKNOWN	Predicting Response to Iron Supplementation in Patients With Active Inflammatory Bowel Disease
NCT05681871	PHASE4	COMPLETED	South African Paediatric Surgical Outcomes Study 2
NCT05708170	PHASE4	NOT_YET_RECRUITING	Impact of Intravenous Iron on Musculoskeletal Function in Older Adults
NCT05921968	PHASE4	UNKNOWN	Effect of Lactoferrin Versus Intravenous Iron Sucrose in Treatment of Anemia
NCT05929729	PHASE4	RECRUITING	Iron Deficiency Anemia (IDA) and the Brain
NCT06176430	PHASE4	UNKNOWN	Comparison of Twice Weekly Versus Daily Iron Therapy in Treating Anemia in Children With Cerebral Palsy
NCT06238895	PHASE4	COMPLETED	Optimizing Dosing Strategies in Oral Iron Supplementation
NCT06492512	PHASE4	RECRUITING	Oral Iron Supplementation on Alternate vs. Consecutive Days for Iron Deficiency Anemia in Pregnancy
NCT06550362	PHASE4	NOT_YET_RECRUITING	Daily Iron vs Every-other-day Iron for Pediatric Patients With IDA