TARS2

Summary

TARS2 (threonyl-tRNA synthetase 2, mitochondrial, HGNC:30740) is a protein-coding gene on chromosome 1q21.2, encoding Threonine–tRNA ligase, mitochondrial (Q9BW92). Catalyzes the attachment of threonine to tRNA(Thr) in a two-step reaction: threonine is first activated by ATP to form Thr-AMP and then transferred to the acceptor end of tRNA(Thr). It is a selective cancer dependency (DepMap: 73.8% of cell lines).

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.

Source: NCBI Gene 80222 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 17
• Clinical variants (ClinVar): 346 total — 2 pathogenic, 15 likely-pathogenic
• Phenotypes (HPO): 16
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 73.8% of screened cell lines
• MANE Select transcript: NM_025150

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30740
Approved symbol	TARS2
Name	threonyl-tRNA synthetase 2, mitochondrial
Location	1q21.2
Locus type	gene with protein product
Status	Approved
Aliases	FLJ12528
Ensembl gene	ENSG00000143374
Ensembl biotype	protein_coding
OMIM	612805
Entrez	80222

Gene structure

Transcript identifiers

Ensembl transcripts: 32 — 22 protein_coding, 5 retained_intron, 3 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

ENST00000369051, ENST00000369053, ENST00000369054, ENST00000369064, ENST00000460794, ENST00000462578, ENST00000463555, ENST00000466989, ENST00000467982, ENST00000479372, ENST00000480070, ENST00000483046, ENST00000606933, ENST00000895420, ENST00000895421, ENST00000895422, ENST00000895423, ENST00000895424, ENST00000895425, ENST00000895426, ENST00000895427, ENST00000895428, ENST00000923165, ENST00000923166, ENST00000923167, ENST00000923168, ENST00000923169, ENST00000923170, ENST00000923171, ENST00000923172, ENST00000923173, ENST00000948114

RefSeq mRNA: 3 — MANE Select: NM_025150 NM_001271895, NM_001271896, NM_025150

CCDS: CCDS60251, CCDS60252, CCDS952

Canonical transcript exons

ENST00000369064 — 18 exons

Exon	Start	End
ENSE00000959658	150490601	150490725
ENSE00001448725	150506916	150507602
ENSE00002228064	150487419	150487516
ENSE00003458298	150496482	150496628
ENSE00003482095	150491394	150491511
ENSE00003604445	150496810	150496908
ENSE00003667634	150491598	150491662
ENSE00003694893	150497530	150497747
ENSE00003695801	150492411	150492489
ENSE00003696240	150505591	150505705
ENSE00003696402	150504906	150504978
ENSE00003696948	150499216	150499293
ENSE00003698259	150498502	150498664
ENSE00003700057	150504335	150504435
ENSE00003700321	150488964	150489087
ENSE00003700676	150498897	150499034
ENSE00003702024	150504632	150504733
ENSE00003723358	150487858	150488054

Expression profiles

Bgee: expression breadth ubiquitous, 254 present calls, max score 91.25.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 24.6934 / max 463.3193, expressed in 1811 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
5106	24.6934	1811

Top tissues by expression

281 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
gastrocnemius	UBERON:0001388	91.25	gold quality
apex of heart	UBERON:0002098	91.18	gold quality
muscle of leg	UBERON:0001383	91.07	gold quality
hindlimb stylopod muscle	UBERON:0004252	90.50	gold quality
cerebellar vermis	UBERON:0004720	90.04	gold quality
triceps brachii	UBERON:0001509	89.60	silver quality
right adrenal gland	UBERON:0001233	89.57	gold quality
muscle organ	UBERON:0001630	89.45	gold quality
heart left ventricle	UBERON:0002084	89.10	gold quality
right hemisphere of cerebellum	UBERON:0014890	89.04	gold quality
cerebellar cortex	UBERON:0002129	88.98	gold quality
cerebellar hemisphere	UBERON:0002245	88.98	gold quality
cardiac ventricle	UBERON:0002082	88.82	gold quality
buccal mucosa cell	CL:0002336	88.80	silver quality
right lobe of liver	UBERON:0001114	88.71	gold quality
right frontal lobe	UBERON:0002810	88.58	gold quality
right adrenal gland cortex	UBERON:0035827	88.52	gold quality
left adrenal gland	UBERON:0001234	88.50	gold quality
left adrenal gland cortex	UBERON:0035825	88.17	gold quality
lower esophagus mucosa	UBERON:0035834	88.13	gold quality
prefrontal cortex	UBERON:0000451	88.01	gold quality
granulocyte	CL:0000094	87.95	gold quality
adrenal cortex	UBERON:0001235	87.91	gold quality
cerebellum	UBERON:0002037	87.91	gold quality
adrenal gland	UBERON:0002369	87.70	gold quality
right atrium auricular region	UBERON:0006631	87.62	gold quality
skin of leg	UBERON:0001511	87.41	gold quality
right ovary	UBERON:0002118	87.29	gold quality
Brodmann (1909) area 9	UBERON:0013540	87.27	gold quality
left ovary	UBERON:0002119	87.15	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.68

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ATF4, QRICH1

miRNA regulators (miRDB)

19 targeting TARS2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-1303	99.65	69.77	1662
HSA-MIR-3136-3P	99.57	66.59	781
HSA-MIR-7155-3P	99.57	66.48	794
HSA-MIR-4667-3P	99.26	65.45	1608
HSA-MIR-4279	99.19	66.70	2437
HSA-MIR-7151-3P	99.04	69.72	2370
HSA-MIR-3149	98.77	67.13	1639
HSA-MIR-619-5P	98.57	64.97	1988
HSA-MIR-10395-3P	98.10	66.70	1726
HSA-MIR-3152-5P	96.98	66.88	819

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 73.8% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 5)

• TARS2 mutations caused fatal mitochondrial encephalomyopathy in two siblings. (PMID:24827421)
• Identification of a TARS2 splicing variant in several human cell lines, which encodes a hmtThrRS derivative lacking a peptide covering a portion of both the editing and the aminoacylation domains. (PMID:26811336)
• Novel compound heterozygous TARS2 variants in a Chinese family with mitochondrial encephalomyopathy: a case report. (PMID:33153448)
• Mitochondrial Threonyl-tRNA Synthetase TARS2 Is Required for Threonine-Sensitive mTORC1 Activation. (PMID:33340489)
• Clinical, neuroradiological, and molecular characterization of mitochondrial threonyl-tRNA-synthetase (TARS2)-related disorder. (PMID:37454282)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
mus_musculus	Tars2	ENSMUSG00000028107
rattus_norvegicus	Tars2	ENSRNOG00000057194
drosophila_melanogaster	ThrRS	FBGN0027081
caenorhabditis_elegans		WBGENE00004189
caenorhabditis_elegans		WBGENE00006617

Paralogs (4): TARS1 (ENSG00000113407), MRPL39 (ENSG00000154719), PARS2 (ENSG00000162396), TARS3 (ENSG00000185418)

Protein

Protein identifiers

Threonine–tRNA ligase, mitochondrial — Q9BW92 (reviewed: Q9BW92)

Alternative names: Threonyl-tRNA synthetase, Threonyl-tRNA synthetase-like 1

All UniProt accessions (4): Q9BW92, Q5T5E9, U3KQ50, U3KQG0

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the attachment of threonine to tRNA(Thr) in a two-step reaction: threonine is first activated by ATP to form Thr-AMP and then transferred to the acceptor end of tRNA(Thr). Also edits incorrectly charged tRNA(Thr) via its editing domain.

Subunit / interactions. Homodimer.

Subcellular location. Mitochondrion matrix.

Disease relevance. Combined oxidative phosphorylation deficiency 21 (COXPD21) [MIM:615918] A mitochondrial disorder characterized by a lethal encephalomyopathy. Shortly after birth, affected individuals manifest axial hypotonia, limb hypertonia, psychomotor delay, and increased serum lactate. Additional features include subsarcolemmal lipofuscin-positive deposits in muscle, cerebral spongiosis, and hepatic steatosis. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the class-II aminoacyl-tRNA synthetase family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9BW92-1	1	yes
Q9BW92-2	2

RefSeq proteins (3): NP_001258824, NP_001258825, NP_079426* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002314	aa-tRNA-synt_IIb	Domain
IPR002320	Thr-tRNA-ligase_IIa	Family
IPR004095	TGS	Domain
IPR004154	Anticodon-bd	Domain
IPR006195	aa-tRNA-synth_II	Domain
IPR012675	Beta-grasp_dom_sf	Homologous_superfamily
IPR012676	TGS-like	Homologous_superfamily
IPR012947	tRNA_SAD	Domain
IPR018163	Thr/Ala-tRNA-synth_IIc_edit	Homologous_superfamily
IPR033728	ThrRS_core	Domain
IPR036621	Anticodon-bd_dom_sf	Homologous_superfamily
IPR045864	aa-tRNA-synth_II/BPL/LPL	Homologous_superfamily
IPR047246	ThrRS_anticodon	Domain

Pfam: PF00587, PF02824, PF03129, PF07973

Catalyzed reactions (Rhea), 1 shown:

• tRNA(Thr) + L-threonine + ATP = L-threonyl-tRNA(Thr) + AMP + diphosphate + H(+) (RHEA:24624)

UniProt features (8 total): sequence conflict 2, transit peptide 1, chain 1, domain 1, modified residue 1, splice variant 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BW92-F1	91.19	0.83

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (1): 52

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-379726	Mitochondrial tRNA aminoacylation
R-HSA-379724	tRNA Aminoacylation
R-HSA-392499	Metabolism of proteins
R-HSA-72766	Translation

MSigDB gene sets: 229 (showing top): GSE45365_NK_CELL_VS_CD8_TCELL_DN, GOBP_AMINO_ACID_ACTIVATION, GOBP_TRNA_METABOLIC_PROCESS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_MITOCHONDRIAL_TRANSLATION, GOBP_TRANSLATION, MARTIN_VIRAL_GPCR_SIGNALING_UP, GOBP_MITOCHONDRIAL_RNA_METABOLIC_PROCESS, KEGG_AMINOACYL_TRNA_BIOSYNTHESIS, KIM_GASTRIC_CANCER_CHEMOSENSITIVITY, GOBP_REGULATION_OF_TRANSLATIONAL_FIDELITY, REACTOME_MITOCHONDRIAL_TRNA_AMINOACYLATION, chr1q21, GOCC_MITOCHONDRIAL_MATRIX

GO Biological Process (6): threonyl-tRNA aminoacylation (GO:0006435), mitochondrial threonyl-tRNA aminoacylation (GO:0070159), translation (GO:0006412), tRNA aminoacylation for protein translation (GO:0006418), tRNA aminoacylation (GO:0043039), aminoacyl-tRNA metabolism involved in translational fidelity (GO:0106074)

GO Molecular Function (8): aminoacyl-tRNA deacylase activity (GO:0002161), threonine-tRNA ligase activity (GO:0004829), ATP binding (GO:0005524), protein homodimerization activity (GO:0042803), nucleotide binding (GO:0000166), aminoacyl-tRNA ligase activity (GO:0004812), protein binding (GO:0005515), ligase activity (GO:0016874)

GO Cellular Component (3): mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
tRNA Aminoacylation	1
Translation	1
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
mitochondrion	2
tRNA metabolic process	2
catalytic activity, acting on a tRNA	2
tRNA aminoacylation for protein translation	1
threonyl-tRNA aminoacylation	1
tRNA aminoacylation for mitochondrial protein translation	1
peptidyltransferase activity	1
translational initiation	1
translational elongation	1
translational termination	1
macromolecule biosynthetic process	1
protein metabolic process	1
protein biosynthetic process	1
translation	1
tRNA aminoacylation	1
amino acid activation	1
regulation of translational fidelity	1
carboxylic ester hydrolase activity	1
aminoacyl-tRNA metabolism involved in translational fidelity	1
deacylase activity	1
aminoacyl-tRNA ligase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
identical protein binding	1
protein dimerization activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
ligase activity, forming carbon-oxygen bonds	1
binding	1
catalytic activity	1
cytoplasm	1
intracellular membrane-bounded organelle	1
intracellular organelle lumen	1
intracellular anatomical structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

2292 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TARS2	LARS2	Q15031	979
TARS2	LARS1	Q9P2J5	971
TARS2	AARS1	P49588	894
TARS2	IARS2	Q9NSE4	882
TARS2	NARS2	Q96I59	880
TARS2	NARS1	O43776	871
TARS2	EPRS1	P07814	852
TARS2	VARS1	P26640	851
TARS2	IARS1	P41252	846
TARS2	PARS2	Q7L3T8	843
TARS2	AARS2	Q5JTZ9	832
TARS2	VARS2	Q5ST30	827
TARS2	HARS1	P12081	826
TARS2	GARS1	P41250	823
TARS2	YARS2	Q9Y2Z4	822

IntAct

138 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
	PMPCB	psi-mi:“MI:0914”(association)	0.640
CETN1	SFI1	psi-mi:“MI:0914”(association)	0.640
RCCD1	SPAG9	psi-mi:“MI:0914”(association)	0.640
TARS2	MAL2	psi-mi:“MI:0915”(physical association)	0.560
TARS2	SFT2D1	psi-mi:“MI:0915”(physical association)	0.560
TARS2	DDIT4L	psi-mi:“MI:0915”(physical association)	0.560
MAL2	TARS2	psi-mi:“MI:0915”(physical association)	0.560
SFT2D1	TARS2	psi-mi:“MI:0915”(physical association)	0.560
DDIT4L	TARS2	psi-mi:“MI:0915”(physical association)	0.560
	TARS2	psi-mi:“MI:0915”(physical association)	0.560
TARS3	TARS2	psi-mi:“MI:0915”(physical association)	0.560
ARL6IP1	TARS2	psi-mi:“MI:0915”(physical association)	0.560
TARS2	ASB6	psi-mi:“MI:0915”(physical association)	0.560
TARS2	SLC17A9	psi-mi:“MI:0915”(physical association)	0.560
PLIN3	TARS2	psi-mi:“MI:0915”(physical association)	0.560
TARS2	TNFRSF10D	psi-mi:“MI:0915”(physical association)	0.560
SYPL1	TARS2	psi-mi:“MI:0915”(physical association)	0.560
TARS2	FKBP7	psi-mi:“MI:0915”(physical association)	0.560
WDR83	SH2B2	psi-mi:“MI:0914”(association)	0.530
UQCRFS1	NDUFAB1	psi-mi:“MI:0914”(association)	0.530
P2RY10	ATM	psi-mi:“MI:0914”(association)	0.530
PIGT	ZNF609	psi-mi:“MI:0914”(association)	0.530
rep	NKRF	psi-mi:“MI:0914”(association)	0.500

BioGRID (178): TARS2 (Affinity Capture-MS), TARS2 (Affinity Capture-MS), TARS2 (Affinity Capture-MS), TARS2 (Affinity Capture-MS), TARS2 (Affinity Capture-MS), TARS2 (Affinity Capture-MS), TARS2 (Affinity Capture-MS), TARS2 (Affinity Capture-RNA), TARS2 (Affinity Capture-MS), TARS2 (Affinity Capture-MS), TARS2 (Affinity Capture-MS), TARS2 (Affinity Capture-MS), TARS2 (Affinity Capture-MS), TARS2 (Affinity Capture-MS), TARS2 (Proximity Label-MS)

ESM2 similar proteins: A0A7N9VSG0, A0JNU3, D3ZBP4, D3ZX08, F1MH07, O43542, O55137, O55171, O88202, O88267, P15575, P16444, P22412, P31429, P41226, P43477, Q08DH8, Q0P5I5, Q14CH7, Q2KHY1, Q2V057, Q32Q92, Q3SZM7, Q3UQ84, Q5E9L5, Q5JTZ9, Q5M876, Q5RCH4, Q66KF6, Q68FW7, Q6P3H4, Q6PAY6, Q86U10, Q8K4F6, Q8K4V2, Q8R123, Q8TDZ2, Q8VCZ9, Q8VDG5, Q8VDP3

Diamond homologs: A0PZN1, A1ARE5, A1U2C3, A1V3R3, A1WU53, A2BQ78, A2C155, A2RTX5, A2S2N6, A3DET1, A3MJT8, A3N8T1, A3NUI4, A3PBX1, A4G619, A4J4Y7, A5EVK6, A5I6L8, A5IJ45, A5N258, A6QNM8, A7FY87, A7GI05, A8F8Q8, A8G3W3, A9A078, A9ABF9, A9BHF0, B0B8F5, B0BA34, B0S169, B1IMV3, B1L0T7, B1L7W6, B2A5P2, B4UAM8, B7XIA1, B8FN26, B8J4E4, B8J823

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
QRICH1	“up-regulates quantity by expression”	TARS2	“transcriptional regulation”
ATF4	“up-regulates quantity by expression”	TARS2	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 147 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Mitochondrial ribosome-associated quality control	7	9.3×	5e-03

GO biological processes:

GO term	Partners	Fold	FDR
mitochondrial translation	7	9.5×	7e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

346 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	15
Uncertain significance	134
Likely benign	106
Benign	50

Top pathogenic / likely-pathogenic (17)

Variant ID	HGVS	Classification
3767312	TARS2, 1-BP DUP, NT988	Pathogenic
3767313	R171K	Pathogenic
1174009	NM_025150.5(TARS2):c.1678G>C (p.Asp560His)	Likely pathogenic
1341959	NM_025150.5(TARS2):c.470C>G (p.Thr157Arg)	Likely pathogenic
1341960	NM_025150.5(TARS2):c.2143G>A (p.Glu715Lys)	Likely pathogenic
143049	NM_025150.5(TARS2):c.845C>T (p.Pro282Leu)	Likely pathogenic
1992417	NM_025150.5(TARS2):c.464C>T (p.Pro155Leu)	Likely pathogenic
1992419	NM_025150.5(TARS2):c.1318G>A (p.Glu440Lys)	Likely pathogenic
1992420	NM_025150.5(TARS2):c.980G>A (p.Arg327Gln)	Likely pathogenic
1992421	NM_025150.5(TARS2):c.1255C>T (p.Arg419Trp)	Likely pathogenic
2663569	NM_025150.5(TARS2):c.191C>G (p.Ser64Ter)	Likely pathogenic
3359231	NM_025150.5(TARS2):c.1900C>T (p.Gln634Ter)	Likely pathogenic
3892600	NM_025150.5(TARS2):c.996T>G (p.Tyr332Ter)	Likely pathogenic
4072010	NM_025150.5(TARS2):c.774G>T (p.Ser258=)	Likely pathogenic
4072011	NM_025150.5(TARS2):c.1099C>T (p.His367Tyr)	Likely pathogenic
432091	NM_025150.5(TARS2):c.1756C>T (p.Arg586Ter)	Likely pathogenic
4845769	NM_025150.5(TARS2):c.1037G>A (p.Arg346His)	Likely pathogenic

SpliceAI

2395 predictions. Top by Δscore:

Variant	Effect	Δscore
1:150488924:A:G	acceptor_gain	1.0000
1:150488941:A:AG	acceptor_gain	1.0000
1:150488942:T:G	acceptor_gain	1.0000
1:150488947:A:AG	acceptor_gain	1.0000
1:150488948:C:G	acceptor_gain	1.0000
1:150488954:A:AG	acceptor_gain	1.0000
1:150488954:ACT:A	acceptor_gain	1.0000
1:150488955:C:G	acceptor_gain	1.0000
1:150488956:T:A	acceptor_gain	1.0000
1:150488959:T:TA	acceptor_gain	1.0000
1:150489083:AAGCA:A	donor_gain	1.0000
1:150489084:AGCA:A	donor_gain	1.0000
1:150489084:AGCAG:A	donor_loss	1.0000
1:150489085:GCA:G	donor_gain	1.0000
1:150489085:GCAG:G	donor_gain	1.0000
1:150489086:CA:C	donor_gain	1.0000
1:150489086:CAGTA:C	donor_loss	1.0000
1:150489087:AGT:A	donor_loss	1.0000
1:150489088:G:A	donor_loss	1.0000
1:150489088:G:GG	donor_gain	1.0000
1:150489089:TA:T	donor_loss	1.0000
1:150489090:AA:A	donor_loss	1.0000
1:150491392:A:AG	acceptor_gain	1.0000
1:150491393:G:GG	acceptor_gain	1.0000
1:150491393:GGACA:G	acceptor_gain	1.0000
1:150491524:G:T	donor_gain	1.0000
1:150498895:A:AG	acceptor_gain	1.0000
1:150498895:AGCT:A	acceptor_gain	1.0000
1:150498896:G:GG	acceptor_gain	1.0000
1:150498896:GCTG:G	acceptor_gain	1.0000

AlphaMissense

4613 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:150497733:C:A	N408K	0.989
1:150497733:C:G	N408K	0.989
1:150497724:G:C	K405N	0.988
1:150497724:G:T	K405N	0.988
1:150504732:T:A	W607R	0.987
1:150504732:T:C	W607R	0.987
1:150490616:A:C	S135R	0.986
1:150490618:C:A	S135R	0.986
1:150490618:C:G	S135R	0.986
1:150498632:G:C	D457H	0.986
1:150497593:T:A	W362R	0.983
1:150497593:T:C	W362R	0.983
1:150496840:A:C	S318R	0.982
1:150496842:C:A	S318R	0.982
1:150496842:C:G	S318R	0.982
1:150499279:T:C	F535L	0.982
1:150499281:C:A	F535L	0.982
1:150499281:C:G	F535L	0.982
1:150497551:T:C	F348L	0.981
1:150497553:C:A	F348L	0.981
1:150497553:C:G	F348L	0.981
1:150498509:T:C	F416L	0.981
1:150498511:C:A	F416L	0.981
1:150498511:C:G	F416L	0.981
1:150504666:C:G	H585D	0.980
1:150497722:A:G	K405E	0.979
1:150497595:G:C	W362C	0.977
1:150497595:G:T	W362C	0.977
1:150499019:G:C	W508C	0.974
1:150499019:G:T	W508C	0.974

dbSNP variants (sampled 300 via entrez): RS1000312846 (1:150494352 C>A,T), RS1000537988 (1:150503226 G>C), RS1000601900 (1:150501274 T>C), RS1000840981 (1:150487721 G>A,T), RS1000983602 (1:150506759 A>G,T), RS1001014739 (1:150506538 A>C,G), RS1001144516 (1:150505358 A>G), RS1001227198 (1:150492015 G>A), RS1001551017 (1:150495310 A>G), RS1001570120 (1:150507426 G>A), RS1001592716 (1:150500401 C>G,T), RS1001897742 (1:150487315 A>G), RS1002158598 (1:150501845 A>C), RS1002295877 (1:150494212 C>A,T), RS1002538920 (1:150506481 C>A,T)

Disease associations

OMIM: gene MIM:612805 | disease phenotypes: MIM:615918

GenCC curated gene-disease

Disease	Classification	Inheritance
combined oxidative phosphorylation defect type 21	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (2)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Leigh syndrome	Limited	AR
mitochondrial disease	Definitive	AR

Mondo (3): combined oxidative phosphorylation defect type 21 (MONDO:0014398), neurodevelopmental disorder (MONDO:0700092), spastic hemiplegia (MONDO:0001168)

Orphanet (1): Combined oxidative phosphorylation defect type 21 (Orphanet:420733)

HPO phenotypes

16 total (16 of 16 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000817	Reduced eye contact
HP:0001250	Seizure
HP:0001263	Global developmental delay
HP:0001397	Hepatic steatosis
HP:0002059	Cerebral atrophy
HP:0002079	Hypoplasia of the corpus callosum
HP:0002151	Increased circulating lactate concentration
HP:0002509	Limb hypertonia
HP:0003348	Hyperalaninemia
HP:0003577	Congenital onset
HP:0003593	Infantile onset
HP:0003811	Neonatal death
HP:0008358	Hyperprolinemia
HP:0008936	Axial hypotonia
HP:0011813	Increased cerebral lipofuscin

GWAS associations

17 associations (top):

Study	Trait	p-value
GCST003837_3	Chronotype	6.000000e-17
GCST003838_3	Morning vs. evening chronotype	5.000000e-07
GCST007565_195	Morning person	6.000000e-30
GCST007576_319	Chronotype	6.000000e-30
GCST010002_366	Refractive error	3.000000e-15
GCST010245_47	LDL cholesterol levels	4.000000e-08
GCST010696_11	Cortical thickness (min-P)	2.000000e-23
GCST010697_17	Cortical surface area (min-P)	9.000000e-09
GCST010698_23	Subcortical volume (min-P)	2.000000e-08
GCST010699_48	Brain morphology (min-P)	3.000000e-08
GCST010700_28	Cortical thickness (MOSTest)	8.000000e-38
GCST010701_113	Cortical surface area (MOSTest)	9.000000e-12
GCST010702_126	Subcortical volume (MOSTest)	4.000000e-09
GCST010703_244	Brain morphology (MOSTest)	9.000000e-12
GCST90002400_520	Plateletcrit	3.000000e-24
GCST90011898_27	Alanine aminotransferase levels	1.000000e-12
GCST90013405_84	Liver enzyme levels (alanine transaminase)	2.000000e-20

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0008328	chronotype measurement
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004346	neuroimaging measurement
EFO:0004840	cortical thickness
EFO:0007985	platelet crit

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3351186 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.23	Kd	5.919	nM	CHEMBL5653589
8.23	ED50	5.919	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 4 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149549: Binding affinity to human TARS2 incubated for 45 mins by Kinobead based pull down assay	kd	0.0059	uM

CTD chemical–gene interactions

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Acetaminophen	affects cotreatment, decreases expression	2
Cadmium Chloride	decreases expression	2
bisphenol A	decreases expression	1
sodium arsenite	decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
gossypol acetic acid	decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
aflatoxin B2	increases methylation	1
epigallocatechin gallate	decreases expression, affects cotreatment	1
di-n-butylphosphoric acid	affects expression	1
Benzo(a)pyrene	affects methylation	1
Carbamazepine	affects expression	1
Coumestrol	affects cotreatment, increases expression	1
Hydrogen Peroxide	affects cotreatment, decreases expression	1
Lipopolysaccharides	affects cotreatment, decreases expression	1
Phenobarbital	affects expression	1
Potassium Dichromate	decreases expression	1
Theophylline	affects cotreatment, decreases expression	1
Thiram	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Cyclosporine	decreases expression	1
Aflatoxin B1	increases methylation	1
Copper Sulfate	decreases expression	1
Lactic Acid	decreases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3383853	Binding	Inhibition of threonyl tRNA synthetase (unknown origin) assessed as depletion of tRNAs at 50 uM by SToPs assay	Borrelidin B: isolation, biological activity, and implications for nitrile biosynthesis. — J Nat Prod

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_E0QJ	Ubigene HeLa TARS2 KO	Cancer cell line	Female

Clinical trials (associated diseases)

202 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism
NCT03229928	Not specified	COMPLETED	Clinical Testing of a Real-Time Behavior Measurement Tool: Measuring Outcomes for CHAnge
NCT03232489	Not specified	UNKNOWN	Study for the Evaluation of the Feasibility of Applying Advanced MRI Scanning in Pediatric Clinical Practice