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…

Primary Disease Associations & Inheritance

Combined oxidative phosphorylation deficiency 21MIM #615918

Clinical highlights

Gene–disease validity (ClinGen)

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.84

LOEUF

LOF

Mechanism· G2P

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

Background carrier burden — how many people carry a rare variant somewhere in TARS2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 89

755 rare PASS variants

Rare truncating (LoF)

1 in 1,400

133 rare PASS variants

Rare synonymous (reference)

1 in 200

383 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for TARS2. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 120	1 in 1,300
South Asian	~43k	1 in 99	1 in 2,000
Remaining (unassigned)	~30k	1 in 89	1 in 1,200
European (Finnish)	~27k	1 in 170	1 in 3,000
Admixed American	~22k	1 in 72	1 in 3,700
African / African American	~21k	1 in 71	1 in 2,000
East Asian	~20k	1 in 110	1 in 2,000
Ashkenazi Jewish	~13k	1 in 270	1 in 740
Middle Eastern	~2,884	1 in 96	≈ 1 in 2,900

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 18 coding exons well covered in gnomAD exomes and genomes.? see exons ↓