VKORC1

Chr 16ARAD

vitamin K epoxide reductase complex subunit 1

Also known as: EDTP308, MST134, MST576, VKCFD2, VKOR

NCBI Gene: 79001 ENSG00000167397 UniProt: Q9BQB6 OMIM: 608547

The protein is the catalytic subunit of vitamin K epoxide reductase complex, which reduces inactive vitamin K 2,3-epoxide to active vitamin K required for gamma-carboxylation of clotting factors and normal blood coagulation. Mutations cause combined deficiency of vitamin K-dependent clotting factors type 2, presenting with bleeding disorders that can manifest in infancy or childhood. The condition follows autosomal recessive inheritance.

GeneReviews OMIM ResearchSummary from RefSeq, UniProt

This gene encodes the catalytic subunit of the vitamin K epoxide reductase complex, which is responsible for the reduction of inactive vitamin K 2,3-epoxide to active vitamin K in the endoplasmic reticulum membrane. Vitamin K is a required co-factor for carboxylation of glutamic acid residues by vitamin K-dependent gamma-carboxylase in blood-clotting enzymes. Allelic variation in this gene is associated with vitamin k-dependent clotting factors combined deficiency of 2, and increased resistance or sensitivity to warfarin, an inhibitor of vitamin K epoxide reductase. Pseudogenes of this gene are located on chromosomes 1 and X. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2015]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismAR/ADLOEUF 1.022 OMIM phenotypes

Clinical Summary— VKORC1

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Gene-Disease Validity (ClinGen)

vitamin K-dependent clotting factors, combined deficiency of, type 2 · ARModerate

Moderate evidence — consider for supplementary testing

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.32) despite low pLI — interpret in context.

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ClinVar Variants

5 unique Pathogenic / Likely Pathogenic· 23 VUS of 44 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — VKORC1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.02LOEUF

pLI 0.162

Z-score 1.55

OE 0.32 (0.13–1.02)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.31Z-score

OE missense 0.91 (0.76–1.09)

85 obs / 93.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.32 (0.13–1.02)

0≤0.351.4

Missense OE?0.91 (0.76–1.09)

0≤0.61.4

Synonymous OE?0.90

0≤1.21.6

LoF obs/exp: 2 / 6.2Missense obs/exp: 85 / 93.3Syn Z: 0.54

This gene — mechanism propensity

0.76top 25%

GOF

0.6541th %ile

LOF

0.2092th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median · 1 literature citation

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNAn inactive mutant (VKORC1(C132A/C135A)) was dominant negative in heterodimers with wild type VKORC1, resulting in decreased KO reduction in cells and carboxylation in vitro.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References

1.PMID 23918929 ↗

ClinVar Variant Classifications

44 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic3

Likely Pathogenic2

VUS23

Likely Benign6

Benign6

Conflicting1

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	3	0	0	3
Likely Pathogenic	0	2	0	0	2
VUS	0	12	6	5	23
Likely Benign	0	2	3	1	6
Benign	0	3	2	1	6
Conflicting	—				1
Total	0	22	11	7	41

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

14 pathogenic / likely-pathogenic (of 21) ClinVar copy-number / structural variants overlap VKORC1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →