congenital vitamin K-dependent coagulation factors deficiency

Summary

congenital vitamin K-dependent coagulation factors deficiency (MONDO:0015722) is a disease (an umbrella term covering 5 Mondo subtypes) with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Umbrella term: 5 Mondo subtypes
• Cohort genes: 1
• ClinVar variants: 1
• Phenotypes (HPO): 31

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		272	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

31 HPO clinical features (Orphanet curated; top 31 by frequency):

HPO ID	Term	Frequency
HP:0000978	Bruising susceptibility	Frequent (30-79%)
HP:0001892	Abnormal bleeding	Frequent (30-79%)
HP:0003645	Prolonged partial thromboplastin time	Frequent (30-79%)
HP:0004855	Reduced protein S activity	Frequent (30-79%)
HP:0005543	Reduced protein C activity	Frequent (30-79%)
HP:0008151	Prolonged prothrombin time	Frequent (30-79%)
HP:0008169	Reduced factor VII activity	Frequent (30-79%)
HP:0008321	Reduced factor X activity	Frequent (30-79%)
HP:0011858	Reduced factor IX activity	Frequent (30-79%)
HP:0040226	Decreased level of heparin co-factor II	Frequent (30-79%)
HP:0002621	Atherosclerosis	Occasional (5-29%)
HP:0004646	Hypoplasia of the nasal bone	Occasional (5-29%)
HP:0005261	Joint hemorrhage	Occasional (5-29%)
HP:0006118	Shortening of all distal phalanges of the fingers	Occasional (5-29%)
HP:0010655	Epiphyseal stippling	Occasional (5-29%)
HP:0011890	Prolonged bleeding following procedure	Occasional (5-29%)
HP:0011891	Post-partum hemorrhage	Occasional (5-29%)
HP:0012541	Cephalohematoma	Occasional (5-29%)
HP:0030137	Prolonged bleeding following circumcision	Occasional (5-29%)
HP:0031364	Ecchymosis	Occasional (5-29%)
HP:0000132	Menorrhagia	Occasional (5-29%)
HP:0000421	Epistaxis	Occasional (5-29%)
HP:0000939	Osteoporosis	Occasional (5-29%)
HP:0000973	Cutis laxa	Occasional (5-29%)
HP:0001102	Angioid streaks of the fundus	Occasional (5-29%)
HP:0002170	Intracranial hemorrhage	Occasional (5-29%)
HP:0001629	Ventricular septal defect	Very rare (<1-4%)
HP:0001631	Atrial septal defect	Very rare (<1-4%)
HP:0002239	Gastrointestinal hemorrhage	Very rare (<1-4%)
HP:0004415	Pulmonary artery stenosis	Very rare (<1-4%)
HP:0011884	Abnormal umbilical stump bleeding	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital vitamin K-dependent coagulation factors deficiency
Mondo ID	MONDO:0015722
OMIM	277450
Orphanet	169826, 98434
DOID	DOID:0112172
ICD-11	54644599
UMLS	C4510617
MedGen	1378036
GARD	0020121
Is cancer (heuristic)	no

Also known as: congenital vitamin K-dependent coagulation factors combined deficiency · vitamin K-dependent clotting factors, combined deficiency of

Data availability: 1 ClinVar variant.

Disease family

An umbrella term covering 5 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › hematologic disorder › blood coagulation disease › coagulation protein disease › congenital vitamin K-dependent coagulation factors deficiency

Related subtypes (27): factor XIII deficiency, factor VII deficiency, factor X deficiency, thrombophilia due to activated protein C resistance, hypoplasminogenemia, congenital high-molecular-weight kininogen deficiency, congenital factor XII deficiency, alpha-2-plasmin inhibitor deficiency, Tatsumi factor deficiency, East Texas bleeding disorder, inherited prekallikrein deficiency, congenital plasminogen activator inhibitor type 1 deficiency, thrombomodulin-related bleeding disorder, hemorrhagic disease due to alpha-1-antitrypsin Pittsburgh mutation, multiple sclerosis-ichthyosis-factor VIII deficiency syndrome, congenital fibrinogen deficiency, combined deficiency of factor V and factor VIII, hemophilia, factor V deficiency, acquired coagulation factor deficiency, von Willebrand disease (hereditary or acquired), factor V short isoforms-related bleeding disorder, factor V amsterdam bleeding disorder, factor V atlanta bleeding disorder, combined deficiency of factor VII and factor X, plasminogen deficiency, type II, dysplasminogenemia

Subtypes (5): congenital factor VII deficiency, congenital factor X deficiency, vitamin K-dependent clotting factors, combined deficiency of, type 1, vitamin K-dependent clotting factors, combined deficiency of, type 2, congenital prothrombin deficiency

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

1 retrieved; paginated sample, class counts are floors:

1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2206	NM_024006.6(VKORC1):c.292C>T (p.Arg98Trp)	VKORC1	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

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

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
VKORC1	Orphanet:98434	Hereditary combined deficiency of vitamin K-dependent clotting factors

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
VKORC1	HGNC:23663	ENSG00000167397	Q9BQB6	Vitamin K epoxide reductase complex subunit 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
VKORC1	Vitamin K epoxide reductase complex subunit 1	Involved in vitamin K metabolism.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
VKORC1	Enzyme (other)	yes	1.17.4.4	VKOR, VKOR_sf, VKORC1/VKORC1L1

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
right lobe of liver	1
stromal cell of endometrium	1
thoracic aorta	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
VKORC1	134	ubiquitous	marker	stromal cell of endometrium, right lobe of liver, thoracic aorta

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
VKORC1	1,009

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
VKORC1	Q9BQB6	6

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
Metabolism of vitamin K	1	3806.7×	3e-04	VKORC1

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
peptidyl-glutamic acid carboxylation	1	8426.0×	7e-04	VKORC1
positive regulation of coagulation	1	2808.7×	9e-04	VKORC1
vitamin K metabolic process	1	2106.5×	9e-04	VKORC1
bone development	1	276.3×	0.005	VKORC1
blood coagulation	1	173.7×	0.007	VKORC1
xenobiotic metabolic process	1	149.1×	0.007	VKORC1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) 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
VKORC1	WARFARIN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
VKORC1	1	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
WARFARIN	4	VKORC1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
VKORC1	3	Binding:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
VKORC1	1.17.4.4	vitamin-K-epoxide reductase (warfarin-sensitive)

Pharmacogenomics

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

Cohort genes with a CPIC/DPWG dosing guideline

Symbol	CPIC guidelines
VKORC1	1

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)
WARFARIN	4	VKORC1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	VKORC1
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.