TARS2

Chr 1AR

threonyl-tRNA synthetase 2, mitochondrial

Also known as: COXPD21, TARSL1, thrRS

NCBI Gene: 80222 ENSG00000143374 UniProt: Q9BW92 OMIM: 612805

The encoded protein is a mitochondrial aminoacyl-tRNA synthetase that charges tRNA with threonine for mitochondrial protein synthesis. Biallelic mutations cause combined oxidative phosphorylation deficiency 21, an autosomal recessive disorder affecting mitochondrial respiratory chain function. The pathogenic mechanism involves dominant-negative effects that disrupt mitochondrial translation and oxidative phosphorylation.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.841 OMIM phenotype

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

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

20 unique Pathogenic / Likely Pathogenic· 135 VUS of 351 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.84LOEUF

pLI 0.000

Z-score 2.39

OE 0.61 (0.44–0.84)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.77Z-score

OE missense 0.76 (0.69–0.83)

323 obs / 425.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.61 (0.44–0.84)

0≤0.351.4

Missense OE?0.76 (0.69–0.83)

0≤0.61.4

Synonymous OE?0.98

0≤1.21.6

LoF obs/exp: 26 / 42.9Missense obs/exp: 323 / 425.8Syn Z: 0.15

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveTARS2-related combined oxidative phosphorylation deficiencyLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6936th %ile

GOF

0.5856th %ile

LOF

0.2871th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

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

ClinVar Variant Classifications

351 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic2

Likely Pathogenic18

VUS135

Likely Benign118

Benign50

Conflicting10

Pathogenic

Likely Pathogenic

135

VUS

118

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	2	0	2
Likely Pathogenic	4	12	1	1	18
VUS	7	118	9	1	135
Likely Benign	0	6	55	57	118
Benign	0	2	43	5	50
Conflicting	—				10
Total	11	138	110	64	333

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

View in ClinVar →

12 pathogenic / likely-pathogenic (of 19) ClinVar copy-number / structural variants overlap TARS2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →