vitamin K-dependent clotting factors, combined deficiency of, type 1

Summary

vitamin K-dependent clotting factors, combined deficiency of, type 1 (MONDO:0010187) is a disease caused by GGCX (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: GGCX (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 196

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	vitamin K-dependent clotting factors, combined deficiency of, type 1
Mondo ID	MONDO:0010187
MeSH	C564741
OMIM	277450
DOID	DOID:0112173
SNOMED CT	724356003
UMLS	C1848534
MedGen	376381
GARD	0018195
Is cancer (heuristic)	no

Also known as: congenital vitamin K-dependent coagulation factors combined deficiency caused by mutation in GGCX · GGCX congenital vitamin K-dependent coagulation factors combined deficiency · hereditary combined deficiency of factors II, VII, IX and X · vitamin K-dependent clotting factors, combined deficiency of, 1 · vitamin K-dependent clotting factors, combined deficiency of, type 1 · VKCFD1

Data availability: 196 ClinVar variants · 6 GenCC gene-disease records.

Disease family

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 › vitamin K-dependent clotting factors, combined deficiency of, type 1

Related subtypes (4): congenital factor VII deficiency, congenital factor X deficiency, 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

196 retrieved; paginated sample, class counts are floors:

114 uncertain significance, 29 benign, 21 conflicting classifications of pathogenicity, 14 likely benign, 6 pathogenic, 6 likely pathogenic, 4 benign/likely benign, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
16194	NM_000821.7(GGCX):c.1181T>G (p.Leu394Arg)	GGCX	Pathogenic	no assertion criteria provided
16195	NM_000821.7(GGCX):c.1502G>C (p.Trp501Ser)	GGCX	Pathogenic	no assertion criteria provided
16197	NM_000821.7(GGCX):c.1454G>C (p.Arg485Pro)	GGCX	Pathogenic	criteria provided, single submitter
16198	NM_000821.7(GGCX):c.215-1G>T	GGCX	Pathogenic	no assertion criteria provided
16206	NM_000821.7(GGCX):c.763G>A (p.Val255Met)	GGCX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3023945	NM_000821.7(GGCX):c.938_939del (p.Pro313fs)	GGCX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3899386	NM_000821.7(GGCX):c.1837C>T (p.Gln613Ter)	GGCX	Pathogenic	criteria provided, single submitter
992374	NM_000821.7(GGCX):c.1987C>T (p.Gln663Ter)	GGCX	Pathogenic	criteria provided, single submitter
1679656	NM_000821.7(GGCX):c.973dup (p.Arg325fs)	GGCX	Likely pathogenic	criteria provided, single submitter
3335889	NM_000821.7(GGCX):c.1426C>G (p.Arg476Gly)	GGCX	Likely pathogenic	no assertion criteria provided
3392475	NM_000821.7(GGCX):c.1282C>T (p.Pro428Ser)	GGCX	Likely pathogenic	criteria provided, single submitter
3779694	NM_000821.7(GGCX):c.610C>T (p.Arg204Cys)	GGCX	Likely pathogenic	criteria provided, multiple submitters, no conflicts
4073621	NM_000821.7(GGCX):c.1450C>T (p.Pro484Ser)	GGCX	Likely pathogenic	criteria provided, single submitter
992373	NM_000821.7(GGCX):c.773G>A (p.Gly258Asp)	GGCX	Likely pathogenic	no assertion criteria provided
337254	NM_000821.7(GGCX):c.*107T>G	GGCX	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
337257	NM_000821.7(GGCX):c.2133T>G (p.Pro711=)	GGCX	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
337260	NM_000821.7(GGCX):c.1906C>A (p.Pro636Thr)	GGCX	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
337267	NM_000821.7(GGCX):c.1107C>T (p.Leu369=)	GGCX	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
337269	NM_000821.7(GGCX):c.849G>C (p.Val283=)	GGCX	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
337270	NM_000821.7(GGCX):c.789C>T (p.Asp263=)	GGCX	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
337273	NM_000821.7(GGCX):c.529A>G (p.Asn177Asp)	GGCX	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
337274	NM_000821.7(GGCX):c.507T>C (p.Phe169=)	GGCX	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
337276	NM_000821.7(GGCX):c.198C>T (p.Val66=)	GGCX	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
337278	NM_000821.7(GGCX):c.159C>A (p.Thr53=)	GGCX	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
337281	NM_000821.7(GGCX):c.24G>A (p.Ala8=)	GGCX	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
895040	NM_000821.7(GGCX):c.1743G>A (p.Leu581=)	GGCX	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
895041	NM_000821.7(GGCX):c.1485C>T (p.Pro495=)	GGCX	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
895044	NM_000821.7(GGCX):c.1439+15C>T	GGCX	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
895109	NM_000821.7(GGCX):c.540-8C>T	GGCX	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
896486	NM_000821.7(GGCX):c.1155+12C>A	GGCX	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 14 · Orphanet: 5 · 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
GGCX	Definitive	Autosomal recessive	vitamin K-dependent clotting factors, combined deficiency of, type 1	10
VKORC1	Strong	Autosomal recessive	vitamin K-dependent clotting factors, combined deficiency of, type 2	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GGCX	Orphanet:436274	Pseudoxanthoma elasticum-like skin manifestations with retinitis pigmentosa
GGCX	Orphanet:91135	Body skin hyperlaxity due to vitamin K-dependent coagulation factor deficiency
GGCX	Orphanet:98434	Hereditary combined deficiency of vitamin K-dependent clotting factors
VKORC1	Orphanet:98434	Hereditary combined deficiency of vitamin K-dependent clotting factors
MAT2A	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection

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
GGCX	HGNC:4247	ENSG00000115486	P38435	Vitamin K-dependent gamma-carboxylase	gencc,clinvar
VKORC1	HGNC:23663	ENSG00000167397	Q9BQB6	Vitamin K epoxide reductase complex subunit 1	gencc
MAT2A	HGNC:6904	ENSG00000168906	P31153	S-adenosylmethionine synthase isoform type-2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GGCX	Vitamin K-dependent gamma-carboxylase	Mediates the vitamin K-dependent carboxylation of glutamate residues to calcium-binding gamma-carboxyglutamate (Gla) residues with the concomitant epoxidation of vitamin K hydroquinone to vitamin K epoxide.
VKORC1	Vitamin K epoxide reductase complex subunit 1	Involved in vitamin K metabolism.
MAT2A	S-adenosylmethionine synthase isoform type-2	Catalyzes the formation of S-adenosylmethionine from methionine and ATP.

Protein-family classification

Druggable: 3 · 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)	3	12.0×	6e-04

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GGCX	Enzyme (other)	yes	4.1.1.90	VKG_COase, HTTM-like, RmlC_Cupin_sf
VKORC1	Enzyme (other)	yes	1.17.4.4	VKOR, VKOR_sf, VKORC1/VKORC1L1
MAT2A	Enzyme (other)	yes	2.5.1.6	S-AdoMet_synthetase, S-AdoMet_synt_N, S-AdoMet_synt_central

Expression context

Cohort genes with no expression data: 0.

3 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
buccal mucosa cell	1
liver	1
tendon of biceps brachii	1
right lobe of liver	1
stromal cell of endometrium	1
thoracic aorta	1
body of pancreas	1
left lobe of thyroid gland	1
right lobe of thyroid gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GGCX	283	ubiquitous	marker	buccal mucosa cell, tendon of biceps brachii, liver
VKORC1	134	ubiquitous	marker	stromal cell of endometrium, right lobe of liver, thoracic aorta
MAT2A	295	ubiquitous	marker	body of pancreas, right lobe of thyroid gland, left lobe of thyroid gland

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MAT2A	3,924
GGCX	1,117
VKORC1	1,009

Intra-cohort edges

A	B	Sources
GGCX	VKORC1	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MAT2A	P31153	59
GGCX	P38435	29
VKORC1	Q9BQB6	6

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. 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
Defective gamma-carboxylation of F9	1	1903.3×	0.003	GGCX
Metabolism of vitamin K	1	1268.9×	0.003	VKORC1
Gamma-carboxylation of protein precursors	1	380.7×	0.006	GGCX
Methylation	1	271.9×	0.006	MAT2A
Phase II - Conjugation of compounds	1	92.8×	0.015	MAT2A
Biological oxidations	1	43.3×	0.027	MAT2A
Metabolism	1	3.9×	0.237	MAT2A

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
vitamin K metabolic process	2	1404.3×	1e-05	GGCX, VKORC1
blood coagulation	2	115.8×	0.001	GGCX, VKORC1
peptidyl-glutamic acid carboxylation	1	2808.7×	0.002	VKORC1
negative regulation of bone development	1	2808.7×	0.002	GGCX
S-adenosylmethionine biosynthetic process	1	1404.3×	0.002	MAT2A
negative regulation of testosterone biosynthetic process	1	1404.3×	0.002	GGCX
cellular response to methionine	1	1123.5×	0.003	MAT2A
positive regulation of coagulation	1	936.2×	0.003	VKORC1
negative regulation of neurotransmitter secretion	1	802.5×	0.003	GGCX
protein hexamerization	1	468.1×	0.004	MAT2A
one-carbon metabolic process	1	374.5×	0.005	MAT2A
protein heterooligomerization	1	351.1×	0.005	MAT2A
type B pancreatic cell proliferation	1	295.6×	0.005	GGCX
positive regulation of TORC1 signaling	1	98.5×	0.015	MAT2A
bone development	1	92.1×	0.015	VKORC1
protein modification process	1	81.4×	0.016	GGCX
cellular response to insulin stimulus	1	56.7×	0.021	GGCX
protein maturation	1	54.5×	0.021	GGCX
cellular response to leukemia inhibitory factor	1	53.0×	0.021	MAT2A
xenobiotic metabolic process	1	49.7×	0.021	VKORC1
glucose homeostasis	1	43.5×	0.023	GGCX

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 3 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
GGCX	0	0
MAT2A	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
WARFARIN	4	VKORC1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 3.

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

Symbol	Assays	Type breakdown
MAT2A	64	Binding:64
GGCX	5	Binding:5
VKORC1	3	Binding:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GGCX	4.1.1.90	peptidyl-glutamate 4-carboxylase
VKORC1	1.17.4.4	vitamin-K-epoxide reductase (warfarin-sensitive)
MAT2A	2.5.1.6	methionine adenosyltransferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	2	GGCX, MAT2A
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
GGCX	5	VKORC1
MAT2A	64	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.