VARS2

Chr 6AR

valyl-tRNA synthetase 2, mitochondrial

Also known as: COXPD20, VALRS, VARS2L, VARSL

NCBI Gene: 57176ENSG00000137411UniProt: Q5ST30

This gene encodes a mitochondrial aminoacyl-tRNA synthetase, which catalyzes the attachment of valine to tRNA(Val) for mitochondrial translation. Mutations in this gene cause combined oxidative phosphorylation deficiency-20, and are also associated with early-onset mitochondrial encephalopathies. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Aug 2014]

Primary Disease Associations & Inheritance

Combined oxidative phosphorylation deficiency 20MIM #615917
AR
370
ClinVar variants
27
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— VARS2
🧬
Gene-Disease Validity (ClinGen)
mitochondrial disease · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
27 Pathogenic / Likely Pathogenic· 204 VUS of 370 total submissions
Some data sources returned errors (1)

clinvar: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.69LOEUF
pLI 0.000
Z-score 3.73
OE 0.53 (0.41–0.69)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
2.39Z-score
OE missense 0.73 (0.67–0.79)
451 obs / 618.4 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.53 (0.41–0.69)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.73 (0.67–0.79)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.84
0≤1.21.6
LoF obs/exp: 39 / 73.6Missense obs/exp: 451 / 618.4Syn Z: 2.02

ClinVar Variant Classifications

370 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic9
Likely Pathogenic18
VUS204
Likely Benign130
Benign4
Conflicting5
9
Pathogenic
18
Likely Pathogenic
204
VUS
130
Likely Benign
4
Benign
5
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
0
8
0
9
Likely Pathogenic
13
2
3
0
18
VUS
0
188
12
4
204
Likely Benign
0
6
59
65
130
Benign
0
1
1
2
4
Conflicting
—5
Total141978371370

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

View in ClinVar →

Protein Context — Lollipop Plot

VARS2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Combined oxidative phosphorylation deficiency 20

MIM #615917

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
New perspective in diagnostics of mitochondrial disorders: two years' experience with whole-exome sequencing at a national paediatric centre.
Pronicka E et al.·J Transl Med
2016
Clinical, biochemical, and genetic features associated with VARS2-related mitochondrial disease.
Bruni F et al.·Hum Mutat
2018
VARS2 and TARS2 mutations in patients with mitochondrial encephalomyopathies.
Diodato D et al.·Hum Mutat
2014Cohort
A novel compound heterozygous mutation in VARS2 in a newborn with mitochondrial cardiomyopathy: a case report of a Chinese family.
Ma K et al.·BMC Med Genet
2018Case report
Neonatal encephalocardiomyopathy caused by mutations in VARS2.
Baertling F et al.·Metab Brain Dis
2017Case report
Recessive VARS2 mutation underlies a novel syndrome with epilepsy, mental retardation, short stature, growth hormone deficiency, and hypogonadism.
Alsemari A et al.·Hum Genomics
2017
VARS2-linked mitochondrial encephalopathy: two case reports enlarging the clinical phenotype.
Begliuomini C et al.·BMC Med Genet
2019Case report
VARS2 V552V variant as prognostic marker in patients with early breast cancer.
Chae YS et al.·Med Oncol
2011Cohort
Novel Variants in VARS2 Demonstrate the Phenotypic Variability of a Rare Mitochondriopathy That Responds to Valine Supplementation.
Marquez J et al.·J Inherit Metab Dis
2025Case report
A novel VARS2 gene variant in a patient with epileptic encephalopathy.
Ruzman L et al.·Ups J Med Sci
2019Case report
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools