hereditary thrombophilia due to congenital histidine-rich (poly-L) glycoprotein deficiency

Summary

hereditary thrombophilia due to congenital histidine-rich (poly-L) glycoprotein deficiency (MONDO:0013143) is a disease caused by HRG (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: HRG (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 18

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary thrombophilia due to congenital histidine-rich (poly-L) glycoprotein deficiency
Mondo ID	MONDO:0013143
MeSH	C567737
OMIM	613116
Orphanet	217467
DOID	DOID:0111903
ICD-11	1764310021
UMLS	C2751090
MedGen	416465
GARD	0017125
Is cancer (heuristic)	no

Also known as: hereditary thrombophilia due to congenital HRG deficiency · THPH11 · thrombophilia 11 due to HRG deficiency · thrombophilia due to histidine-rich glycoprotein deficiency

Data availability: 18 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › skeletal system disorder › bone disorder › osteonecrosis › avascular necrosis › secondary avascular necrosis › hereditary thrombophilia due to congenital histidine-rich (poly-L) glycoprotein deficiency

Related subtypes (5): Gaucher disease type I, hereditary antithrombin deficiency, traumatic avascular necrosis, secondary non-traumatic avascular necrosis, osteonecrosis of the jaw

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

18 retrieved; paginated sample, class counts are floors:

11 uncertain significance, 3 benign, 2 pathogenic, 1 pathogenic/likely pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
14914	NM_000412.5(HRG):c.308G>A (p.Gly103Glu)	HRG	Pathogenic	no assertion criteria provided
374832	C223R	HRG	Pathogenic	no assertion criteria provided
440913	NM_000412.5(HRG):c.271C>T (p.Pro91Ser)	LOC126806897	Pathogenic/Likely pathogenic	no assertion criteria provided
809579	NM_000412.5(HRG):c.125G>A (p.Arg42Gln)	HRG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1676737	NM_000412.5(HRG):c.72C>A (p.Cys24Ter)	HRG	Uncertain significance	criteria provided, single submitter
1684325	NM_000412.5(HRG):c.736C>A (p.Pro246Thr)	HRG	Uncertain significance	no assertion criteria provided
1684326	NM_000412.5(HRG):c.946C>T (p.Pro316Ser)	HRG	Uncertain significance	no assertion criteria provided
1684328	NM_000412.5(HRG):c.745C>T (p.His249Tyr)	HRG	Uncertain significance	no assertion criteria provided
2367592	NM_000412.5(HRG):c.62C>T (p.Pro21Leu)	HRG	Uncertain significance	criteria provided, multiple submitters, no conflicts
3064475	NM_000412.5(HRG):c.227C>T (p.Ser76Leu)	HRG	Uncertain significance	criteria provided, multiple submitters, no conflicts
3065603	NM_000412.5(HRG):c.372del (p.Phe124fs)	HRG	Uncertain significance	criteria provided, single submitter
3393119	NM_000412.5(HRG):c.1194_1196del (p.His400del)	HRG	Uncertain significance	criteria provided, single submitter
3891356	NM_000412.5(HRG):c.1015A>G (p.Arg339Gly)	HRG	Uncertain significance	criteria provided, single submitter
3891357	NM_000412.5(HRG):c.796G>A (p.Gly266Ser)	HRG	Uncertain significance	criteria provided, single submitter
4813108	NM_000412.5(HRG):c.694del (p.Glu232fs)	HRG	Uncertain significance	no assertion criteria provided
1285353	NM_000412.5(HRG):c.610C>T (p.Pro204Ser)	HRG	Benign	criteria provided, multiple submitters, no conflicts
1285354	NM_000412.5(HRG):c.1342C>T (p.Arg448Cys)	HRG	Benign	criteria provided, multiple submitters, no conflicts
1285355	NM_000412.5(HRG):c.1478A>T (p.Asn493Ile)	HRG	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
HRG	Strong	Autosomal dominant	hereditary thrombophilia due to congenital histidine-rich (poly-L) glycoprotein deficiency	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HRG	Orphanet:217467	Hereditary thrombophilia due to congenital histidine-rich (poly-L) glycoprotein deficiency

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
HRG	HGNC:5181	ENSG00000113905	P04196	Histidine-rich glycoprotein	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HRG	Histidine-rich glycoprotein	Plasma glycoprotein that binds a number of ligands such as heme, heparin, heparan sulfate, thrombospondin, plasminogen, and divalent metal ions.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HRG	Other/Unknown	no		Cystatin_dom, Cystatin_sf, Kininogen_Fetuin_HRG

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
liver	1
nephron tubule	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HRG	125	tissue_specific	marker	liver, right lobe of liver, nephron tubule

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HRG	1,814

Structural data

PDB: 0 · AlphaFold-only: 1 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
HRG	P04196	64.90

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Regulation of FXIIa and plasma kallikrein activity	1	1142.0×	0.002	HRG
Dissolution of Fibrin Clot	1	815.7×	0.002	HRG
Platelet degranulation	1	87.8×	0.011	HRG

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of immune response to tumor cell	1	8426.0×	0.002	HRG
positive regulation of blood vessel remodeling	1	8426.0×	0.002	HRG
negative regulation of endothelial cell chemotaxis	1	5617.3×	0.002	HRG
negative regulation of lamellipodium assembly	1	3370.4×	0.002	HRG
regulation of peptidyl-tyrosine phosphorylation	1	3370.4×	0.002	HRG
regulation of platelet activation	1	2808.7×	0.002	HRG
obsolete cytolysis by host of symbiont cells	1	2106.5×	0.002	HRG
regulation of blood coagulation	1	1872.4×	0.002	HRG
negative regulation of fibrinolysis	1	1404.3×	0.002	HRG
negative regulation of cell adhesion mediated by integrin	1	1296.3×	0.002	HRG
negative regulation of vascular endothelial growth factor signaling pathway	1	1296.3×	0.002	HRG
fibrinolysis	1	842.6×	0.003	HRG
regulation of protein-containing complex assembly	1	732.7×	0.003	HRG
negative regulation of blood vessel endothelial cell migration	1	732.7×	0.003	HRG
positive regulation of focal adhesion assembly	1	648.1×	0.003	HRG
defense response to fungus	1	443.5×	0.004	HRG
negative regulation of cell adhesion	1	383.0×	0.004	HRG
platelet activation	1	267.5×	0.006	HRG
negative regulation of angiogenesis	1	168.5×	0.008	HRG
antimicrobial humoral immune response mediated by antimicrobial peptide	1	162.0×	0.008	HRG
regulation of actin cytoskeleton organization	1	157.5×	0.008	HRG
negative regulation of cell growth	1	144.0×	0.009	HRG
chemotaxis	1	135.9×	0.009	HRG
regulation of gene expression	1	83.4×	0.013	HRG
angiogenesis	1	62.4×	0.017	HRG
positive regulation of apoptotic process	1	56.7×	0.018	HRG
negative regulation of cell population proliferation	1	42.1×	0.024	HRG

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
HRG	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	HRG

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
HRG	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.