TARS2

Chr 1AR

threonyl-tRNA synthetase 2, mitochondrial

Also known as: COXPD21, TARSL1, thrRS

NCBI Gene: 80222ENSG00000143374UniProt: Q9BW92

This gene encodes a member of the class-II aminoacyl-tRNA synthetase family. The encoded protein is a mitochondrial aminoacyl-tRNA synthetase. Alternative splicing results in multiple transcript variants. A related pseudogene has been identified on chromosome 4. [provided by RefSeq, Dec 2012]

Primary Disease Associations & Inheritance

Combined oxidative phosphorylation deficiency 21MIM #615918
AR
348
ClinVar variants
30
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— TARS2
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Gene-Disease Validity (ClinGen)
Leigh syndrome · ARLimited

Limited evidence — not for standalone diagnostic reporting

2 total gene-disease associations curated

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
30 Pathogenic / Likely Pathogenic· 139 VUS of 348 total submissions

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.
0.84LOEUF
pLI 0.000
Z-score 2.39
OE 0.61 (0.44–0.84)
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.
1.77Z-score
OE missense 0.76 (0.69–0.83)
323 obs / 425.8 exp
Tolerant

Mild missense constraint

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.0.61 (0.44–0.84)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.76 (0.69–0.83)
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.0.98
0≤1.21.6
LoF obs/exp: 26 / 42.9Missense obs/exp: 323 / 425.8Syn Z: 0.15

ClinVar Variant Classifications

348 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic12
Likely Pathogenic18
VUS139
Likely Benign119
Benign50
Conflicting10
12
Pathogenic
18
Likely Pathogenic
139
VUS
119
Likely Benign
50
Benign
10
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
12
0
12
Likely Pathogenic
0
11
6
1
18
VUS
5
116
17
1
139
Likely Benign
0
6
56
57
119
Benign
0
2
43
5
50
Conflicting
—10
Total513513464348

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

View in ClinVar →

Protein Context — Lollipop Plot

TARS2 · 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 21

MIM #615918

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Novel TARS2 variant identified in a Chinese patient with mitochondrial encephalomyopathy and a systematic review.
He P et al.·Am J Med Genet A
2023Review
Clinical, neuroradiological, and molecular characterization of mitochondrial threonyl-tRNA-synthetase (TARS2)-related disorder.
Accogli A et al.·Genet Med
2023
TARS2 Variants Cause Combination Oxidative Phosphorylation Deficiency-21: A Case Report and Literature Review.
Gao X et al.·Neuropediatrics
2024Review
Elucidating the molecular mechanisms associated with TARS2-related mitochondrial disease.
Zheng WQ et al.·Hum Mol Genet
2022Functional
VARS2 and TARS2 mutations in patients with mitochondrial encephalomyopathies.
Diodato D et al.·Hum Mutat
2014Cohort
TARS2 c.470 C > G is a chinese-specific founder mutation in three unrelated families with mitochondrial encephalomyopathy.
Zhang S et al.·Orphanet J Rare Dis
2024
Identification of Four Novel Candidate Genes for Non-syndromic Intellectual Disability in Pakistani Families.
Ahmed I et al.·Biochem Genet
2024
Potential prognostic biomarkers of hepatocellular carcinoma based on 4D label-free quantitative proteomics analysis pilot investigation.
Suo L et al.·Int J Biol Markers
2024
A homozygous TARS2 variant is a novel cause of syndromic neonatal diabetes.
Donis R et al.·Diabet Med
2025
Novel compound heterozygous TARS2 variants in a Chinese family with mitochondrial encephalomyopathy: a case report.
Li X et al.·BMC Med Genet
2020Case report
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC

No open access results found

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