HRG

Summary

HRG (histidine rich glycoprotein, HGNC:5181) is a protein-coding gene on chromosome 3q27.3, encoding Histidine-rich glycoprotein (P04196). Plasma glycoprotein that binds a number of ligands such as heme, heparin, heparan sulfate, thrombospondin, plasminogen, and divalent metal ions.

This histidine-rich glycoprotein contains two cystatin-like domains and is located in plasma and platelets. The physiological function has not been determined but it is known that the protein binds heme, dyes and divalent metal ions. The encoded protein also has a peptide that displays antimicrobial activity against C. albicans, E. coli, S. aureus, P. aeruginosa, and E. faecalis. It can inhibit rosette formation and interacts with heparin, thrombospondin and plasminogen. Two of the protein’s effects, the inhibition of fibrinolysis and the reduction of inhibition of coagulation, indicate a potential prothrombotic effect. Mutations in this gene lead to thrombophilia due to abnormal histidine-rich glycoprotein levels.

Source: NCBI Gene 3273 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hereditary thrombophilia due to congenital histidine-rich (poly-L) glycoprotein deficiency (Strong, GenCC)
• GWAS associations: 9
• Clinical variants (ClinVar): 161 total — 2 pathogenic
• MANE Select transcript: NM_000412

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5181
Approved symbol	HRG
Name	histidine rich glycoprotein
Location	3q27.3
Locus type	gene with protein product
Status	Approved
Aliases	HRGP, HPRG
Ensembl gene	ENSG00000113905
Ensembl biotype	protein_coding
OMIM	142640
Entrez	3273

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 15 protein_coding, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000232003, ENST00000468154, ENST00000495413, ENST00000887857, ENST00000887858, ENST00000887859, ENST00000887860, ENST00000887861, ENST00000887862, ENST00000887863, ENST00000887864, ENST00000887865, ENST00000887866, ENST00000887867, ENST00000887868, ENST00000887869, ENST00000887870

RefSeq mRNA: 1 — MANE Select: NM_000412 NM_000412

CCDS: CCDS3280

Canonical transcript exons

ENST00000232003 — 7 exons

Exon	Start	End
ENSE00000781542	186675089	186675190
ENSE00000781543	186672787	186672867
ENSE00001151568	186669938	186670028
ENSE00001177748	186668935	186669051
ENSE00001177754	186666014	186666214
ENSE00001833446	186677047	186678234
ENSE00003586662	186671623	186671789

Expression profiles

Bgee: expression breadth ubiquitous, 125 present calls, max score 99.58.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 5.6984 / max 3396.1566, expressed in 17 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
40286	5.6984	17

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
liver	UBERON:0002107	99.58	gold quality
right lobe of liver	UBERON:0001114	99.54	gold quality
nephron tubule	UBERON:0001231	92.94	gold quality
renal medulla	UBERON:0000362	89.27	gold quality
kidney epithelium	UBERON:0004819	89.07	gold quality
renal glomerulus	UBERON:0000074	85.37	gold quality
metanephric glomerulus	UBERON:0004736	85.30	gold quality
adult mammalian kidney	UBERON:0000082	82.75	gold quality
kidney	UBERON:0002113	81.60	gold quality
oocyte	CL:0000023	80.18	gold quality
secondary oocyte	CL:0000655	80.12	gold quality
diaphragm	UBERON:0001103	78.70	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	77.44	gold quality
cortex of kidney	UBERON:0001225	75.65	gold quality
metanephros	UBERON:0000081	75.31	gold quality
CA1 field of hippocampus	UBERON:0003881	71.76	gold quality
metanephros cortex	UBERON:0010533	70.44	gold quality
adult organism	UBERON:0007023	67.88	gold quality
hair follicle	UBERON:0002073	67.61	gold quality
frontal pole	UBERON:0002795	66.91	gold quality
paraflocculus	UBERON:0005351	66.62	gold quality
middle frontal gyrus	UBERON:0002702	66.58	gold quality
left ventricle myocardium	UBERON:0006566	66.28	gold quality
type B pancreatic cell	CL:0000169	65.75	gold quality
cardiac muscle of right atrium	UBERON:0003379	65.66	gold quality
quadriceps femoris	UBERON:0001377	65.40	gold quality
vastus lateralis	UBERON:0001379	65.38	gold quality
myocardium	UBERON:0002349	65.00	gold quality
tibialis anterior	UBERON:0001385	64.70	silver quality
vena cava	UBERON:0004087	64.61	silver quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-GEOD-130473	yes	3167.69
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

23 targeting HRG, 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-1250-3P	99.96	70.04	4038
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-576-5P	99.84	70.46	2582
HSA-MIR-6515-3P	99.82	68.19	1933
HSA-MIR-3059-5P	99.70	69.93	2491
HSA-MIR-12123	99.52	71.79	2990
HSA-MIR-513C-5P	99.50	68.42	1730
HSA-MIR-514B-5P	99.50	68.19	1766
HSA-MIR-542-3P	99.34	67.58	1270
HSA-MIR-664A-3P	99.22	71.08	2696
HSA-MIR-877-3P	99.09	68.10	1637
HSA-MIR-606	98.72	67.34	960
HSA-MIR-16-1-3P	98.70	69.23	1538
HSA-MIR-6818-3P	98.56	68.23	1307
HSA-MIR-6881-3P	98.04	68.24	1777
HSA-MIR-7111-3P	97.80	66.75	1467
HSA-MIR-517-5P	97.13	68.43	781
HSA-MIR-1236-5P	96.62	66.38	856
HSA-MIR-3651	95.62	64.67	287
HSA-MIR-5684	93.17	64.85	454

Literature-anchored findings (GeneRIF, showing 40)

• By acting as a bridge between DNA on apoptotic cells and Fc gamma RI on monocyte-derived macrophages, HRG is a key physiological mediator of apoptotic cell clearance by macrophages. (PMID:12391183)
• Data indicate that histidine-rich glycoprotein, in combination with the zinc ion, modulates the smooth muscle cell growth response in pathophysiological states. (PMID:12764609)
• Histidine-rich glycoprotein binds to cell-surface heparan sulfate via its N-terminal domain following Zn2+ chelation (PMID:15138272)
• HRG acts as a soluble adaptor molecule that binds to cells at sites of tissue injury, tumor growth, and angiogenesis (PMID:15220341)
• HPRG binds to endothelial cell surface tropomyosin which at least partially mediates the antiangiogenic effects of HPRG (PMID:15269838)
• HRG has the unique property of selectively recognizing necrotic cells and may play an important physiological role in vivo by facilitating the uptake and clearance of necrotic, but not apoptotic, cells by phagocytes (PMID:16107330)
• the anti-angiogenic His/Pro-rich fragment of histidine-rich glycoprotein binds to endothelial cell heparan sulfate in a Zn2+-dependent manner (PMID:16436387)
• the histidine-rich and heparin-binding domain of HRGP mediates the antibacterial activity of the protein (PMID:17229145)
• The protein encoded by this gene has a peptide that displays antimicrobial activity against C. albicans, E. coli, S. aureus, P. aeruginosa, and E. faecalis. (PMID:18797515)
• identified the alpha-subunit of ATP synthase as one of the HRG-binding proteins on the surface of T-cells by HRG-derived glycopeptide affinity chromatography and by a peptide mass finger printing method (PMID:19285951)
• HRG may assist in the maintenance of normal immune function by mediating the clearance of necrotic material, inhibiting the formation of insoluble immune complexes and enhancing their ability to activate complement, resulting in faster clearance. (PMID:19674792)
• Proteolytic cleavage of HRG by plasmin may provide a feedback mechanism to regulate the effects of HRG on the plasminogen/plasmin system and other functions of HRG. (PMID:19712047)
• HRG has the unique property of complexing with IgG and facilitating a proinflammatory innate immune response to promote the clearance of necrotic cells (PMID:20071662)
• Single Nucleotide Polymorphisms in HRG is associated with activated partial thromboplastin time. (PMID:20303064)
• HRG can aid the phagocytosis of necrotic cells via a heparan sulfate-dependent pathway, and this process can be regulated by the presence of certain HRG ligands, such as heparin. (PMID:20573803)
• Host-produced HRG inhibits tumor growth and metastasis by skewing tumor-associated macrophages (TAM) polarization away from the M2- to a tumor-inhibiting M1-like phenotype. Skewing of TAM polarization by HRG relies substantially on downregulation of PlGF. (PMID:21215706)
• by binding to factor XIIa, HRG modulates the intrinsic pathway of coagulation, particularly in the vicinity of a thrombus where platelet release of HRG and Zn(2)(+) will promote this interaction (PMID:21304106)
• the genetic polymorphism (rs9898 C/T) in the HRG gene of a woman affects her chances of becoming pregnant after IVF (PMID:21665544)
• the HRG-fibrin interaction may provide a novel link between coagulation, innate immunity, and inflammation (PMID:21757718)
• The combination of lowered HRG and uterine artery Doppler may predict preterm preeclampsia in early pregnancy. (PMID:22895448)
• HRG does not exhibit the broad interactive properties that have been reported previously, suggesting that copurification of HRG-binding partners or other impurities are responsible for some of the reported functional properties. (PMID:23576524)
• Association between the histidine-rich glycoprotein (HRG) C633T single nucleotide polymorphism (SNP) and recurrent miscarriage was investigated. An association between homozygous carriers and recurrent miscarriage was detected. (PMID:23672470)
• histidine-rich glycoprotein tissue RNA and serum protein might have a role in breast cancer (PMID:24567057)
• genetic association study in Swedish population: Data suggest SNP in HRG (rs2228243, A1042G) is associated with recurrent miscarriage in population studied; women heterozygous for HRG A1042G SNP are protected from recurrent miscarriage. [PILOT STUDY] (PMID:25064236)
• mononuclear phagocytes have specific binding sites for HRG and that these cells are essential for uptake of HRG from blood and distribution of HRG in tissues. Thus, inflammatory cells mediate the effect of HRG on tumor growth and metastatic spread. (PMID:25243896)
• Plasma free fatty acid levels influence Zn(2+) -dependent histidine-rich glycoprotein-heparin interactions via an allosteric switch on serum albumin. (PMID:25353308)
• Results show that HRG is a novel transcriptional target gene of FXR in human hepatoma cells, human upcyteVR primary hepatocytes and 3D human liver microtissues in vitro and in mouse liver in vivo. (PMID:25363753)
• HRG binds to alpha2 integrin through low-affinity interactions in a heparin sulfate-independent manner, thereby blocking endothelial cells adhesion to collagen I. (PMID:26051322)
• HRG could inhibit hepatocellular carcinoma cell proliferation via the FGF-Erk1/2 signaling pathway by reducing Erk1/2 phosphorylation. (PMID:26336134)
• HRG attenuates DNA- and RNA-mediated FXII activation, and FXI activation by FXIIa or by thrombin, suggesting that HRG down regulates the capacity of DNA and RNA to activate the intrinsic coagulation pathway. (PMID:26354857)
• once infertility is established the HRG C633T SNP seems to be important for male infertility and pregnancy rate following IVF (PMID:27210772)
• These data highlight the complex divalent metal-dependent regulatory mechanisms that govern HRG function. (PMID:27930811)
• C633T SNP had no significant effect on sperm DNA integrity (PMID:28356499)
• A novel heterozygous single base pair substitution in exon 2 of HRG gene identified in a familial early-onset deep venous thrombosis case. (PMID:29108964)
• presence of HRG mRNA did not depend on the cancer type, on the preoperative treatment or its absence, as well as on the tumor progression stage and the presence of metastases (PMID:29536307)
• The HRG C633T genotype seems to be associated with gestational hypertensive disorders (PMID:29540166)
• Histidine-rich glycoprotein ameliorates endothelial barrier dysfunction through regulation of NF-kappaB and MAPK signal pathway. (PMID:31093964)
• Levels of caspase-3 and histidine-rich glycoprotein in the embryo secretome as biomarkers of good-quality day-2 embryos and high-quality blastocysts (PMID:31856190)
• Ultrastructural Localization of Histidine-rich Glycoprotein in Skeletal Muscle Fibers: Colocalization With AMP Deaminase. (PMID:31880188)
• HRG switches TNFR1-mediated cell survival to apoptosis in Hepatocellular Carcinoma. (PMID:32929358)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	fetub	ENSDARG00000053973
danio_rerio	si:ch211-284e20.8	ENSDARG00000070918
mus_musculus	Hrg	ENSMUSG00000022877
rattus_norvegicus	Hrgl1	ENSRNOG00000001809
rattus_norvegicus	Hrgl1	ENSRNOG00000070559

Paralogs (3): FETUB (ENSG00000090512), KNG1 (ENSG00000113889), AHSG (ENSG00000145192)

Protein

Protein identifiers

Histidine-rich glycoprotein — P04196 (reviewed: P04196)

Alternative names: Histidine-proline-rich glycoprotein

All UniProt accessions (1): P04196

UniProt curated annotations — full annotation on UniProt →

Function. Plasma glycoprotein that binds a number of ligands such as heme, heparin, heparan sulfate, thrombospondin, plasminogen, and divalent metal ions. Binds heparin and heparin/glycosaminoglycans in a zinc-dependent manner. Binds heparan sulfate on the surface of liver, lung, kidney and heart endothelial cells. Binds to N-sulfated polysaccharide chains on the surface of liver endothelial cells. Inhibits rosette formation. Acts as an adapter protein and is implicated in regulating many processes such as immune complex and pathogen clearance, cell chemotaxis, cell adhesion, angiogenesis, coagulation and fibrinolysis. Mediates clearance of necrotic cells through enhancing the phagocytosis of necrotic cells in a heparan sulfate-dependent pathway. This process can be regulated by the presence of certain HRG ligands such as heparin and zinc ions. Binds to IgG subclasses of immunoglobins containing kappa and lambda light chains with different affinities regulating their clearance and inhibiting the formation of insoluble immune complexes. Tethers plasminogen to the cell surface. Binds T-cells and alters the cell morphology. Modulates angiogenesis by blocking the CD6-mediated antiangiongenic effect of thrombospondins, THBS1 and THBS2. Acts as a regulator of the vascular endothelial growth factor (VEGF) signaling pathway; inhibits endothelial cell motility by reducing VEGF-induced complex formation between PXN/paxillin and ILK/integrin-linked protein kinase and by promoting inhibition of VEGF-induced tyrosine phosphorylation of focal adhesion kinases and alpha-actinins in endothelial cells. Also plays a role in the regulation of tumor angiogenesis and tumor immune surveillance. Normalizes tumor vessels and promotes antitumor immunity by polarizing tumor-associated macrophages, leading to decreased tumor growth and metastasis.

Subunit / interactions. Interacts (via the HRR domain) with TPM1; the interaction appears to contribute to the antiangiogenic properties of the HRR domain. Interacts with THBS2; the interaction blocks the antiangiogenic effect of THBS2 with CD36. Interacts with THBS1 (via the TSP type I repeats); the interaction blocks the antiangiogenic effect of THBS1 with CD3. Interacts with PLG (via its Kringle domains); the interaction tethers PLG to the cell surface and enhances its activation. Interacts with HPSE; the interaction is enhanced at acidic pH, partially inhibits binding of HPSE to cell surface receptors and modulates its enzymatic activity. Interacts (via the HRR domain) with TMP1; the interaction partially mediates the antiangiogenic properties of HRG. Interacts with kappa and lambda light chains of IgG molecules. Interacts with ATP5F1A; the interaction occurs on the surface of T-cells and alters their cell morphology in concert with CONA. Binds IgG molecules containing kappa and lambda light chains and inhibits the formation of insoluble immunoglobulin complexes. Interacts with F12; the interaction, which is enhanced in the presence of zinc ions and inhibited by heparin-binding to HRG, inhibits factor XII autoactivation and contact-initiated coagulation.

Subcellular location. Secreted.

Tissue specificity. Expressed in macrophages and in malignant cells. Expressed by the liver and secreted in plasma (at protein level).

Post-translational modifications. Proteolytic cleavage produces several HRG fragments which are mostly disulfide-linked and, therefore, not released. Cleavage by plasmin is inhibited in the presence of heparin, zinc ions or in an acidic environment. Cleavage reduces binding of HRG to heparan sulfate, but enhances the ability of HRG to bind and tether plasminogen to the cell surface. On platelet activation, releases a 33 kDa antiangiogenic peptide which encompasses the HRR. Also cleaved in the C-terminal by plasmin. N-glycosylated.

Disease relevance. Thrombophilia due to histidine-rich glycoprotein deficiency (THPH11) [MIM:613116] A hemostatic disorder characterized by a tendency to thrombosis. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The His/Pro-rich (HRR) region contains approximately 12 tandem internal repeats of the 5-residue G[H/P][H/P]PH consensus sequence. HRR binds heparan sulfate and possesses antiangiogenic, antibacterial and antifungal properties through binding Candida cells, and preferentially lysing the ergosterol-containing liposomes at low pH. The tandem repeats also bind divalent metal ions and heme. The cystatin domains can also bind heparan sulfate. Binding is enhanced in the presence of zinc ions.

RefSeq proteins (1): NP_000403* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000010	Cystatin_dom	Domain
IPR046350	Cystatin_sf	Homologous_superfamily
IPR050735	Kininogen_Fetuin_HRG	Family

Pfam: PF00031

UniProt features (32 total): sequence variant 10, compositionally biased region 5, disulfide bond 5, glycosylation site 4, region of interest 3, domain 2, signal peptide 1, chain 1, site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P04196-F1	64.90	0.29

Functional residue map

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

Catalytic / active sites (1): 439–440 (cleavage; by plasmin)

Disulfide bonds (5): 24–504, 78–89, 105–126, 203–417, 218–241

Glycosylation sites (4): 63, 125, 344, 345

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-114608	Platelet degranulation
R-HSA-75205	Dissolution of Fibrin Clot
R-HSA-9855719	Regulation of FXIIa and plasma kallikrein activity

MSigDB gene sets: 291 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_ANTIMICROBIAL_HUMORAL_RESPONSE, GOBP_VASCULAR_ENDOTHELIAL_GROWTH_FACTOR_SIGNALING_PATHWAY, GOBP_REGULATION_OF_WOUND_HEALING, GOBP_CELL_CHEMOTAXIS, GOBP_REGULATION_OF_PHOSPHORYLATION, GOBP_REGULATION_OF_COAGULATION, GNF2_GSTM1, GOCC_SECRETORY_GRANULE, REACTOME_PLATELET_ACTIVATION_SIGNALING_AND_AGGREGATION, GOBP_NEGATIVE_REGULATION_OF_BLOOD_VESSEL_ENDOTHELIAL_CELL_MIGRATION, GOBP_PLATELET_ACTIVATION, GOBP_NEGATIVE_REGULATION_OF_CELL_GROWTH, GNF2_HPN

GO Biological Process (29): angiogenesis (GO:0001525), positive regulation of immune response to tumor cell (GO:0002839), chemotaxis (GO:0006935), negative regulation of cell adhesion (GO:0007162), negative regulation of cell population proliferation (GO:0008285), regulation of gene expression (GO:0010468), regulation of platelet activation (GO:0010543), negative regulation of lamellipodium assembly (GO:0010593), negative regulation of angiogenesis (GO:0016525), platelet activation (GO:0030168), regulation of blood coagulation (GO:0030193), negative regulation of cell growth (GO:0030308), regulation of actin cytoskeleton organization (GO:0032956), negative regulation of cell adhesion mediated by integrin (GO:0033629), fibrinolysis (GO:0042730), positive regulation of apoptotic process (GO:0043065), regulation of protein-containing complex assembly (GO:0043254), negative regulation of blood vessel endothelial cell migration (GO:0043537), regulation of peptidyl-tyrosine phosphorylation (GO:0050730), defense response to fungus (GO:0050832), obsolete cytolysis by host of symbiont cells (GO:0051838), positive regulation of focal adhesion assembly (GO:0051894), negative regulation of fibrinolysis (GO:0051918), antimicrobial humoral immune response mediated by antimicrobial peptide (GO:0061844), negative regulation of vascular endothelial growth factor signaling pathway (GO:1900747), positive regulation of blood vessel remodeling (GO:2000504), negative regulation of endothelial cell chemotaxis (GO:2001027), blood coagulation (GO:0007596), hemostasis (GO:0007599)

GO Molecular Function (10): serine-type endopeptidase inhibitor activity (GO:0004867), cysteine-type endopeptidase inhibitor activity (GO:0004869), signaling receptor binding (GO:0005102), heparin binding (GO:0008201), zinc ion binding (GO:0008270), immunoglobulin binding (GO:0019865), heme binding (GO:0020037), heparan sulfate proteoglycan binding (GO:0043395), metal ion binding (GO:0046872), protein binding (GO:0005515)

GO Cellular Component (7): extracellular region (GO:0005576), plasma membrane (GO:0005886), cell surface (GO:0009986), extracellular matrix (GO:0031012), platelet alpha granule lumen (GO:0031093), extracellular exosome (GO:0070062), blood microparticle (GO:0072562)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Response to elevated platelet cytosolic Ca2+	1
Hemostasis	1
FXIIa activates plasma kallikrein-kinin system	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
negative regulation of cellular process	3
cellular anatomical structure	3
blood coagulation	2
endopeptidase inhibitor activity	2
blood vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
immune response to tumor cell	1
positive regulation of response to tumor cell	1
regulation of immune response to tumor cell	1
positive regulation of immune response	1
response to chemical	1
taxis	1
cell adhesion	1
regulation of cell adhesion	1
cell population proliferation	1
regulation of cell population proliferation	1
gene expression	1
regulation of macromolecule biosynthetic process	1
platelet activation	1
regulation of cell activation	1
regulation of lamellipodium assembly	1
lamellipodium assembly	1
negative regulation of plasma membrane bounded cell projection assembly	1
negative regulation of lamellipodium organization	1
angiogenesis	1
regulation of angiogenesis	1
negative regulation of blood vessel morphogenesis	1
cell activation	1
regulation of response to external stimulus	1
regulation of coagulation	1
regulation of wound healing	1
regulation of hemostasis	1
regulation of cell growth	1
cell growth	1
negative regulation of growth	1
actin cytoskeleton organization	1
regulation of actin filament-based process	1
regulation of cytoskeleton organization	1
negative regulation of cell adhesion	1
cell adhesion mediated by integrin	1

Protein interactions and networks

STRING

1708 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HRG	PLG	P00747	998
HRG	AHSG	P02765	863
HRG	KNG1	P01042	845
HRG	SERPIND1	P05546	826
HRG	FGG	P02679	815
HRG	C3	P01024	794
HRG	FGA	P02671	789
HRG	THBS1	P07996	786
HRG	FGB	P02675	779
HRG	SERPINC1	P01008	764
HRG	F2	P00734	756
HRG	APOA1	P02647	755
HRG	APOB	P04114	733
HRG	A2M	P01023	716
HRG	HABP2	Q14520	707

IntAct

46 interactions, top by confidence:

A	B	Type	Score
RCCD1	SPAG9	psi-mi:“MI:0914”(association)	0.640
	HRG	psi-mi:“MI:0407”(direct interaction)	0.600
HRG		psi-mi:“MI:0407”(direct interaction)	0.600
PLSCR1	HRG	psi-mi:“MI:0915”(physical association)	0.590
HRG	PLSCR1	psi-mi:“MI:0403”(colocalization)	0.590
HRG	PLSCR1	psi-mi:“MI:0914”(association)	0.590
RGS20	HRG	psi-mi:“MI:0915”(physical association)	0.560
CYSRT1	HRG	psi-mi:“MI:0915”(physical association)	0.560
HRG	RCHY1	psi-mi:“MI:0915”(physical association)	0.540
RCHY1	HRG	psi-mi:“MI:0915”(physical association)	0.540
HRG	RCHY1	psi-mi:“MI:0403”(colocalization)	0.540
ING4	KAT7	psi-mi:“MI:0914”(association)	0.530
	CD5L	psi-mi:“MI:0915”(physical association)	0.400
	LECT2	psi-mi:“MI:0915”(physical association)	0.400
SDC1	ILVBL	psi-mi:“MI:0915”(physical association)	0.400
RABAC1	HRG	psi-mi:“MI:0915”(physical association)	0.370
HRG	FN1	psi-mi:“MI:0915”(physical association)	0.370
TNFRSF1A	HRG	psi-mi:“MI:0915”(physical association)	0.370
HRG	CHRD	psi-mi:“MI:0915”(physical association)	0.370
SPRY1	HRG	psi-mi:“MI:0915”(physical association)	0.370
HRG		psi-mi:“MI:0915”(physical association)	0.370
HRG	GAMMAHV.ORF4	psi-mi:“MI:0915”(physical association)	0.370
GAMMAHV.ORF31	HRG	psi-mi:“MI:0915”(physical association)	0.370
STING1	ZSWIM8	psi-mi:“MI:0914”(association)	0.350
UTY	KMT2D	psi-mi:“MI:0914”(association)	0.350
S	IGLL5	psi-mi:“MI:0914”(association)	0.350
CACNA1C	SNRPGP15	psi-mi:“MI:0914”(association)	0.350
GNG8	POTEF	psi-mi:“MI:0914”(association)	0.350

BioGRID (60): HRG (Affinity Capture-MS), HRG (Affinity Capture-MS), HRG (Affinity Capture-MS), HRG (Affinity Capture-MS), HRG (Synthetic Lethality), RGS20 (Two-hybrid), CYSRT1 (Two-hybrid), HRG (Affinity Capture-MS), HRG (Affinity Capture-MS), HRG (Affinity Capture-MS), HRG (Affinity Capture-MS), HRG (Affinity Capture-MS), HRG (Affinity Capture-MS), HRG (Affinity Capture-MS), KAT6A (Affinity Capture-MS)

ESM2 similar proteins: A0A1S3PBB7, O08677, O70159, O88393, P01042, P01044, P01045, P01048, P02765, P04196, P08932, P08934, P12763, P24090, P26342, P29695, P29699, P29700, P29701, P49913, P80191, P97515, Q03167, Q1KLX0, Q1KLX1, Q1KLX2, Q1KLX3, Q1KLX6, Q1KLX7, Q1KLX8, Q1KLY0, Q1KLY2, Q1KLY3, Q1KLY4, Q1KLY7, Q1KLY8, Q28640, Q58D62, Q5KQS1, Q5KQS2

Diamond homologs: P04196, P33433, Q28640, Q58D62, Q99PS8, Q9ESB3, Q9UGM5, P29700, Q9QX79, Q9QXC1, P08934, P29701

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	96
Likely benign	30
Benign	16

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
14914	NM_000412.5(HRG):c.308G>A (p.Gly103Glu)	Pathogenic
374832	C223R	Pathogenic

SpliceAI

988 predictions. Top by Δscore:

Variant	Effect	Δscore
3:186666210:GAGTG:G	donor_gain	1.0000
3:186666212:GTG:G	donor_gain	1.0000
3:186666238:C:G	donor_gain	1.0000
3:186669052:G:GG	donor_gain	1.0000
3:186671621:A:AG	acceptor_gain	1.0000
3:186671622:G:GG	acceptor_gain	1.0000
3:186671785:GAGTG:G	donor_gain	1.0000
3:186671787:GTG:G	donor_gain	1.0000
3:186675084:TGTA:T	acceptor_loss	1.0000
3:186675086:TAGG:T	acceptor_loss	1.0000
3:186675087:A:AC	acceptor_loss	1.0000
3:186675087:A:AG	acceptor_gain	1.0000
3:186675088:G:GG	acceptor_gain	1.0000
3:186675088:GGTCT:G	acceptor_gain	1.0000
3:186675186:CTCAG:C	donor_loss	1.0000
3:186675187:TCAGG:T	donor_loss	1.0000
3:186675188:CAG:C	donor_loss	1.0000
3:186675189:AGG:A	donor_loss	1.0000
3:186675190:GGT:G	donor_loss	1.0000
3:186675191:G:A	donor_loss	1.0000
3:186675192:T:G	donor_loss	1.0000
3:186666220:G:GT	donor_gain	0.9900
3:186669048:AATA:A	donor_gain	0.9900
3:186669049:ATA:A	donor_gain	0.9900
3:186669050:TA:T	donor_gain	0.9900
3:186671619:CCA:C	acceptor_loss	0.9900
3:186671620:CA:C	acceptor_loss	0.9900
3:186671621:A:AC	acceptor_loss	0.9900
3:186671622:G:GT	acceptor_loss	0.9900
3:186671622:GT:G	acceptor_gain	0.9900

AlphaMissense

3503 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:186669950:T:A	C105S	0.991
3:186669951:G:C	C105S	0.991
3:186669950:T:C	C105R	0.982
3:186672820:T:C	F198L	0.980
3:186672822:C:A	F198L	0.980
3:186672822:C:G	F198L	0.980
3:186670013:T:A	C126S	0.978
3:186670014:G:C	C126S	0.978
3:186675101:T:A	C218S	0.977
3:186675102:G:C	C218S	0.977
3:186670007:T:C	F124L	0.972
3:186670009:T:A	F124L	0.972
3:186670009:T:G	F124L	0.972
3:186675170:T:A	C241S	0.972
3:186675171:G:C	C241S	0.972
3:186675102:G:A	C218Y	0.970
3:186669952:T:G	C105W	0.968
3:186670013:T:C	C126R	0.968
3:186669951:G:A	C105Y	0.967
3:186666174:T:G	F48C	0.966
3:186670015:C:G	C126W	0.966
3:186672821:T:C	F198S	0.966
3:186675103:C:G	C218W	0.966
3:186666148:T:A	N39K	0.964
3:186666148:T:G	N39K	0.964
3:186675101:T:C	C218R	0.962
3:186666174:T:C	F48S	0.960
3:186669962:G:C	A109P	0.959
3:186672821:T:G	F198C	0.957
3:186675170:T:C	C241R	0.957

dbSNP variants (sampled 300 via entrez): RS1000064250 (3:186676400 A>G), RS1000168242 (3:186669894 G>A), RS1000400441 (3:186670023 G>T), RS1000488286 (3:186666756 T>C), RS1001510262 (3:186672671 C>A,G,T), RS1001665040 (3:186666353 A>G), RS1001771953 (3:186672296 C>T), RS1002011335 (3:186666677 G>A), RS1002897572 (3:186666343 G>A), RS1003178788 (3:186671236 A>G,T), RS1003236479 (3:186665400 G>C,T), RS1003287881 (3:186667521 G>C), RS1003442841 (3:186671034 C>T), RS1003604586 (3:186676587 T>C), RS1003746036 (3:186665206 G>A)

Disease associations

OMIM: gene MIM:142640 | disease phenotypes: MIM:613116

GenCC curated gene-disease

Disease	Classification	Inheritance
hereditary thrombophilia due to congenital histidine-rich (poly-L) glycoprotein deficiency	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
hereditary thrombophilia due to congenital histidine-rich (poly-L) glycoprotein deficiency	Moderate	AD

Mondo (2): hereditary thrombophilia due to congenital histidine-rich (poly-L) glycoprotein deficiency (MONDO:0013143), thrombocytopenia (MONDO:0002049)

Orphanet (1): Hereditary thrombophilia due to congenital histidine-rich (poly-L) glycoprotein deficiency (Orphanet:217467)

HPO phenotypes

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

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST000631_3	Activated partial thromboplastin time	1.000000e-11
GCST001574_5	Activated partial thromboplastin time	1.000000e-111
GCST008478_61	Neurological blood protein biomarker levels	8.000000e-11
GCST010002_446	Refractive error	1.000000e-08
GCST010796_2394	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-08
GCST010796_2395	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-08
GCST010796_2396	Electrocardiogram morphology (amplitude at temporal datapoints)	4.000000e-08
GCST010796_2397	Electrocardiogram morphology (amplitude at temporal datapoints)	5.000000e-08
GCST010796_2398	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004327	electrocardiography

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D013921	Thrombocytopenia	C15.378.140.855; C15.378.243.937
C567737	Thrombophilia Due To Elevated Histidine-Rich Glycoprotein (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Copper	increases activity, affects binding, increases expression	3
sodium arsenite	decreases expression, increases expression	2
Benzo(a)pyrene	decreases expression, increases methylation	2
Cadmium	decreases reaction, increases abundance, increases palmitoylation, affects binding	2
Zinc	decreases reaction, increases activity, affects binding	2
Cyclosporine	decreases expression	2
Aflatoxin B1	affects expression, decreases expression	2
Cadmium Chloride	increases abundance, increases palmitoylation, increases expression, decreases reaction	2
lasiocarpine	decreases expression	1
methyleugenol	decreases expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
bisphenol A	decreases methylation	1
chlortoluron	decreases expression	1
2-bromopalmitate	decreases reaction, increases abundance, increases palmitoylation	1
CGP 52608	affects binding, increases reaction	1
perfluoro-n-nonanoic acid	decreases expression	1
NSC 689534	affects binding, increases expression	1
Irinotecan	increases expression	1
Olanzapine	affects phosphorylation	1
Resveratrol	decreases reaction, increases expression	1
Arsenic Trioxide	increases expression	1
Troglitazone	decreases expression	1
Acetaminophen	decreases expression	1
Arsenic	affects expression	1
Endosulfan	affects cotreatment, decreases expression	1
Estradiol	decreases expression	1
Ethinyl Estradiol	decreases expression	1
Heparin	decreases reaction, increases activity	1
Lead	affects binding	1
Lipopolysaccharides	increases expression, decreases reaction	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00039858	PHASE4	COMPLETED	Evaluation of Argatroban Injection in Pediatric Patients Requiring Anticoagulant Alternatives to Heparin
NCT00239733	PHASE4	TERMINATED	Anti-D for Treating Thrombocytopenia in Adults Infected With Hepatitis C Virus With or Without HIV Co-Infection
NCT00907478	PHASE4	COMPLETED	Study on Bone Marrow Morphology in Adults Receiving Romiplostim for Treatment of Thrombocytopenia Associated With Immune Thrombocytopenia Purpura (ITP)
NCT01727401	PHASE4	TERMINATED	Thromboprophylaxis of Venous Thromboembolism in Acutely-ill Medical Inpatients With Thrombocytopenia
NCT02032134	PHASE4	TERMINATED	Protocol for the Infusion of Buffy Coat-derived Cryopreserved Platelets in Patients With Severe Thrombocytopenia
NCT02267993	PHASE4	COMPLETED	Efficacy and Safety of rhTPO for the Treatment of Thrombocytopenia After Chemotherapy in AML Patients
NCT03633019	PHASE4	UNKNOWN	High-dose Use of rhTPO in CIT Patients
NCT03688191	PHASE4	UNKNOWN	Study of Sirolimus in CTD-TP in China
NCT04906083	PHASE4	UNKNOWN	Avatrombopag in Patients With End-stage Liver Disease and Thrombocytopenia
NCT05217719	PHASE4	UNKNOWN	Effects of Recombinant Human Thrombopoietin on Platelet Levels in ICU Patients
NCT05255003	PHASE4	RECRUITING	STrategies for Anticoagulation in Patients With thRombocytopenia and Cancer-associated Thrombosis
NCT05382013	PHASE4	UNKNOWN	Efficacy and Safety of Avatrombopag for Treating TCP in HBV-ACLF Patients Receiving ALSS Treatment
NCT05944458	PHASE4	COMPLETED	Efficacy of Intravenous N-Acetylcysteine in Preventing Linezolid-Induced Thrombocytopenia in Critically Ill Patients
NCT06562738	PHASE4	RECRUITING	Clinical Study on Efficacy and Safety of Hetrombopag in the Preoperative Patients of Thrombocytopenia
NCT00037791	PHASE3	COMPLETED	Safety and Efficacy of (PN-152,243)/PN-196,444 in the Prevention of Thrombocytopenia
NCT00039910	PHASE3	COMPLETED	Safety and Efficacy of (PN-152,243)/PN-196,444 in the Prevention of Thrombocytopenia
NCT00073580	PHASE3	COMPLETED	Angiomax in Patients With HIT/HITTS Type II Undergoing Off-Pump Coronary Artery Bypass Grafting (CABG) (CHOOSE)
NCT00102323	PHASE3	COMPLETED	AMG 531 Treatment of Thrombocytopenic Subjects With Immune (Idiopathic) Thrombocytopenic Purpura (ITP) Refractory to Splenectomy
NCT00102336	PHASE3	COMPLETED	AMG 531 Treatment of Thrombocytopenic Subjects With Immune (Idiopathic) Thrombocytopenic Purpura (ITP) Prior to Splenectomy
NCT00116688	PHASE3	COMPLETED	Open Label Extension Study of Romiplostim (AMG 531) in Thrombocytopenic Patients With Immune (Idiopathic) Thrombocytopenic Purpura (ITP)
NCT00128713	PHASE3	COMPLETED	Optimal Platelet Dose Strategy for Management of Thrombocytopenia
NCT00151866	PHASE3	COMPLETED	Efficacy of Transfusions With Platelets Stored in Platelet Additive Solution II Versus Plasma
NCT00261924	PHASE3	COMPLETED	Efficacy and Safety Study of Platelets Treated for Pathogen Inactivation and Stored for Up to Seven Days
NCT00415532	PHASE3	COMPLETED	Romiplostim (AMG 531) Versus Medical Standard of Care for Immune (Idiopathic) Thrombocytopenic Purpura
NCT00420914	PHASE3	TERMINATED	Strategies for Transfusion of Platelets (SToP)
NCT00501345	PHASE3	TERMINATED	Aspirin in Patients With Myocardial Infarction and Thrombocytopenia
NCT00508820	PHASE3	COMPLETED	An Open Label Study of Romiplostim in Adult Thrombocytopenic Subjects With ITP
NCT00678587	PHASE3	TERMINATED	Eltrombopag To Reduce The Need For Platelet Transfusion In Subjects With Chronic Liver Disease And Thrombocytopenia Undergoing Elective Invasive Procedures
NCT01438840	PHASE3	COMPLETED	Efficacy and Safety of Oral E5501 Plus Standard of Care for the Treatment of Thrombocytopenia in Adults With Chronic Immune Thrombocytopenia (Amendment 02)
NCT01444417	PHASE3	COMPLETED	Safety and Efficacy Study of Romiplostim to Treat Immune Thrombocytopenia (ITP) in Pediatric Patients
NCT01805648	PHASE3	UNKNOWN	Efficacy and Safety Study of Maintenance Treatment With rhTPO in Thrombocytopenic Subjects With ITP
NCT02244658	PHASE3	UNKNOWN	Recombinant Human Thrombopoietin (rhTPO) in Management of Chemotherapy-induced Thrombocytopenia in Acute Myelocytic Leukemia
NCT02389621	PHASE3	COMPLETED	Safety and Efficacy Study of Lusutrombopag for Thrombocytopenia in Patients With Chronic Liver Disease Undergoing Elective Invasive Procedures
NCT02444728	PHASE3	TERMINATED	Cyclophosphamide and Hydroxychloroquine for Thrombocytopenia in SLE
NCT02487563	PHASE3	COMPLETED	Prospective Study of Patients With Thrombocytopenia Following HSCT
NCT02578901	PHASE3	COMPLETED	American Trial Using Tranexamic Acid in Thrombocytopenia
NCT03326843	PHASE3	TERMINATED	Avatrombopag for the Treatment of Thrombocytopenia in Adults Scheduled for a Surgical Procedure
NCT03515096	PHASE3	COMPLETED	Eltrombopag vs. rhTPO to Increase Platelet Level After HSCT
NCT05563064	PHASE3	UNKNOWN	Effect of Herbal Formulation on Thrombocytes Count
NCT07442513	PHASE3	RECRUITING	Comparison of Etamsylate Versus Placebo to Prevent Bleeding in HSCT