Heparin cofactor 2 deficiency

Summary

Heparin cofactor 2 deficiency (MONDO:0012876) is a disease caused by SERPIND1 (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: SERPIND1 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 16

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	heparin cofactor 2 deficiency
Mondo ID	MONDO:0012876
MeSH	C562865
OMIM	612356
DOID	DOID:0111901
SNOMED CT	234468009
UMLS	C0398626
MedGen	96017
GARD	0024895
Is cancer (heuristic)	no

Also known as: heparin cofactor 2 deficiency · thrombophilia 10 due to heparin cofactor II deficiency

Data availability: 16 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › hematologic disorder › blood coagulation disease › thrombophilia › inherited thrombophilia › heparin cofactor 2 deficiency

Related subtypes (11): factor 5 excess with spontaneous thrombosis, thrombophilia due to thrombin defect, thrombophilia due to activated protein C resistance, thrombophilia, X-linked, due to factor 9 defect, thrombophilia, familial, due to decreased release of tissue plasminogen activator, hereditary thrombophilia due to congenital histidine-rich (poly-L) glycoprotein deficiency, hereditary antithrombin deficiency, thrombomodulin-related bleeding disorder, hereditary thrombophilia due to congenital protein S deficiency, hereditary thrombophilia due to congenital protein C deficiency, thrombophilia, X-linked, due to factor 8 defect

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

16 retrieved; paginated sample, class counts are floors:

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

ClinVar	Variant (HGVS)	Gene	Classification	Review
14953	NM_000185.4(SERPIND1):c.321dup (p.Val108fs)	PI4KA	Pathogenic	no assertion criteria provided
14954	NM_000185.4(SERPIND1):c.1429_1430del (p.Phe477fs)	PI4KA	Pathogenic	no assertion criteria provided
14955	NM_000185.4(SERPIND1):c.1385C>T (p.Pro462Leu)	PI4KA	Pathogenic	no assertion criteria provided
3892395	NM_001391906.1(EIF4G3):c.4801_4825dup (p.Lys1609fs)	EIF4G3	Likely pathogenic	criteria provided, single submitter
788340	NM_000185.4(SERPIND1):c.231C>A (p.Asp77Glu)	PI4KA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1676740	NM_000185.4(SERPIND1):c.161T>G (p.Leu54Arg)	PI4KA	Uncertain significance	criteria provided, single submitter
1676783	NM_000185.4(SERPIND1):c.700C>T (p.Leu234Phe)	PI4KA	Uncertain significance	criteria provided, single submitter
1684359	NM_000185.4(SERPIND1):c.488G>C (p.Gly163Ala)	PI4KA	Uncertain significance	no assertion criteria provided
3381926	NM_000185.4(SERPIND1):c.557_558del (p.Phe186fs)	PI4KA	Uncertain significance	criteria provided, single submitter
3778884	NM_000185.4(SERPIND1):c.940C>T (p.Arg314Trp)	PI4KA	Uncertain significance	criteria provided, single submitter
3892392	NM_000185.4(SERPIND1):c.1175T>C (p.Val392Ala)	PI4KA	Uncertain significance	criteria provided, single submitter
3892393	NM_000185.4(SERPIND1):c.1303G>A (p.Asp435Asn)	PI4KA	Uncertain significance	criteria provided, multiple submitters, no conflicts
930228	NM_000185.4(SERPIND1):c.220dup (p.Glu74fs)	PI4KA	Uncertain significance	criteria provided, single submitter
3892394	NM_000185.4(SERPIND1):c.941G>C (p.Arg314Pro)	SERPIND1	Uncertain significance	criteria provided, single submitter
14952	NM_000185.4(SERPIND1):c.623G>A (p.Arg208His)	PI4KA	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
3049069	NM_000185.4(SERPIND1):c.830C>T (p.Ala277Val)	PI4KA	Likely benign	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 3 · 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
SERPIND1	Definitive	Autosomal dominant	heparin cofactor 2 deficiency	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PI4KA	Orphanet:436252	Combined immunodeficiency-multiple intestinal atresia
PI4KA	Orphanet:631079	Autosomal recessive spastic paraplegia type 84
PI4KA	Orphanet:98889	Bilateral perisylvian polymicrogyria

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SERPIND1	HGNC:4838	ENSG00000099937	P05546	Heparin cofactor 2	gencc,clinvar
EIF4G3	HGNC:3298	ENSG00000075151	O43432	Eukaryotic translation initiation factor 4 gamma 3	clinvar
PI4KA	HGNC:8983	ENSG00000241973	P42356	Phosphatidylinositol 4-kinase alpha	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SERPIND1	Heparin cofactor 2	Thrombin inhibitor activated by the glycosaminoglycans, heparin or dermatan sulfate.
EIF4G3	Eukaryotic translation initiation factor 4 gamma 3	Component of the protein complex eIF4F, which is involved in the recognition of the mRNA cap, ATP-dependent unwinding of 5’-terminal secondary structure and recruitment of mRNA to the ribosome.
PI4KA	Phosphatidylinositol 4-kinase alpha	Acts on phosphatidylinositol (PtdIns) in the first committed step in the production of the second messenger inositol-1,4,5,-trisphosphate.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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
Kinase	1	9.2×	0.209
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SERPIND1	Other/Unknown	no		Serpin_fam, Serpin_CS, Serpin_dom
EIF4G3	Other/Unknown	no		W2_domain, MIF4G-like_typ-3, Initiation_fac_eIF4g_MI
PI4KA	Kinase	yes		PI3/4_kinase_cat_dom, PI3K_accessory_dom, Kinase-like_dom_sf

Expression context

Cohort genes with no expression data: 0.

2 cohort genes 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
liver	1
paraflocculus	1
right lobe of liver	1
choroid plexus epithelium	1
male germ cell	1
sperm	1
Brodmann (1909) area 9	1
right frontal lobe	1
superior frontal gyrus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SERPIND1	129	tissue_specific	yes	liver, right lobe of liver, paraflocculus
EIF4G3	295	ubiquitous	marker	sperm, male germ cell, choroid plexus epithelium
PI4KA	143	ubiquitous	marker	superior frontal gyrus, right frontal lobe, Brodmann (1909) area 9

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
EIF4G3	2,665
PI4KA	1,755
SERPIND1	1,151

Intra-cohort edges

A	B	Sources
PI4KA	SERPIND1	string_interaction

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SERPIND1	P05546	9
PI4KA	P42356	4
EIF4G3	O43432	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Synthesis of PIPs at the ER membrane	1	761.3×	0.011	PI4KA
Fibrin formation	1	292.8×	0.011	SERPIND1
Synthesis of PIPs at the Golgi membrane	1	211.5×	0.011	PI4KA
Amplification and propagation of coagulation cascade	1	211.5×	0.011	SERPIND1
Dengue Virus Genome Translation and Replication	1	105.7×	0.017	EIF4G3
Regulation of clotting cascade	1	77.7×	0.019	SERPIND1
ISG15 antiviral mechanism	1	50.1×	0.026	EIF4G3
Post-translational protein phosphorylation	1	33.4×	0.033	SERPIND1
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	28.8×	0.034	SERPIND1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
reorganization of cellular membranes to establish viral sites of replication	1	5617.3×	0.002	PI4KA
host-mediated perturbation of viral process	1	624.1×	0.010	PI4KA
phosphatidylinositol-mediated signaling	1	234.1×	0.014	PI4KA
phosphatidylinositol phosphate biosynthetic process	1	160.5×	0.014	PI4KA
regulation of translational initiation	1	156.0×	0.014	EIF4G3
phosphatidylinositol biosynthetic process	1	122.1×	0.014	PI4KA
translational initiation	1	119.5×	0.014	EIF4G3
positive regulation of translation	1	75.9×	0.020	EIF4G3
blood coagulation	1	57.9×	0.023	SERPIND1
spermatid development	1	48.4×	0.024	EIF4G3
chemotaxis	1	45.3×	0.024	SERPIND1
signal transduction	1	5.3×	0.176	PI4KA

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 2

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
PI4KA	ADENOSINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PI4KA	1	4
SERPIND1	0	0
EIF4G3	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ADENOSINE	4	PI4KA

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
PI4KA	86	Binding:83, Functional:2, ADMET:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

1 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.

Compound	Max phase	Cohort target (bioactivity)
ADENOSINE	4	PI4KA

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PI4KA
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	2	SERPIND1, EIF4G3

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SERPIND1	0	—
EIF4G3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.