TARS1

Summary

TARS1 (threonyl-tRNA synthetase 1, HGNC:11572) is a protein-coding gene on chromosome 5p13.3, encoding Threonine–tRNA ligase 1, cytoplasmic (P26639). 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 common-essential gene (DepMap: required in 99.9% of cancer cell lines).

Aminoacyl-tRNA synthetases catalyze the aminoacylation of tRNA by their cognate amino acid. Because of their central role in linking amino acids with nucleotide triplets contained in tRNAs, aminoacyl-tRNA synthetases are thought to be among the first proteins that appeared in evolution. Threonyl-tRNA synthetase belongs to the class-II aminoacyl-tRNA synthetase family

Source: NCBI Gene 6897 — RefSeq curated summary.

At a glance

• Gene–disease (curated): trichothiodystrophy 7, nonphotosensitive (Moderate, GenCC) — +1 more curated relationship
• GWAS associations: 11
• Clinical variants (ClinVar): 160 total — 3 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 94
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 99.9% of screened cell lines (common-essential)
• MANE Select transcript: NM_152295

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11572
Approved symbol	TARS1
Name	threonyl-tRNA synthetase 1
Location	5p13.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000113407
Ensembl biotype	protein_coding
OMIM	187790
Entrez	6897

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 14 protein_coding, 5 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined, 2 retained_intron

ENST00000265112, ENST00000455217, ENST00000502508, ENST00000502553, ENST00000503422, ENST00000504698, ENST00000505012, ENST00000506040, ENST00000507716, ENST00000508361, ENST00000509410, ENST00000509731, ENST00000513066, ENST00000514259, ENST00000626210, ENST00000627006, ENST00000915152, ENST00000915153, ENST00000915154, ENST00000915155, ENST00000915156, ENST00000949499, ENST00000949500

RefSeq mRNA: 3 — MANE Select: NM_152295 NM_001258437, NM_001258438, NM_152295

CCDS: CCDS3899, CCDS58943

Canonical transcript exons

ENST00000265112 — 19 exons

Exon	Start	End
ENSE00001887096	33467560	33468086
ENSE00002076123	33440965	33441143
ENSE00003476255	33455587	33455704
ENSE00003483052	33456002	33456066
ENSE00003496126	33462099	33462203
ENSE00003505515	33448541	33448731
ENSE00003522516	33453289	33453412
ENSE00003535018	33461158	33461295
ENSE00003539932	33463753	33463825
ENSE00003551690	33461667	33461744
ENSE00003556432	33466871	33466985
ENSE00003574475	33459695	33459861
ENSE00003578469	33456149	33456227
ENSE00003586021	33458566	33458664
ENSE00003641092	33460902	33461064
ENSE00003645841	33461906	33462006
ENSE00003652809	33454945	33455066
ENSE00003684496	33445324	33445404
ENSE00003687163	33457257	33457403

Expression profiles

Bgee: expression breadth ubiquitous, 296 present calls, max score 98.36.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 112.0697 / max 3456.9281, expressed in 1826 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
56045	84.2808	1824
56046	21.0711	1783
56047	2.7808	1087
203516	2.1647	1111
203517	0.7725	462
56044	0.5065	283
56050	0.4934	262

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sural nerve	UBERON:0015488	98.36	gold quality
adrenal tissue	UBERON:0018303	98.09	gold quality
tongue squamous epithelium	UBERON:0006919	97.93	gold quality
islet of Langerhans	UBERON:0000006	96.78	gold quality
mucosa of transverse colon	UBERON:0004991	96.54	gold quality
gingiva	UBERON:0001828	96.52	gold quality
gingival epithelium	UBERON:0001949	96.48	gold quality
ventricular zone	UBERON:0003053	96.46	gold quality
buccal mucosa cell	CL:0002336	96.28	gold quality
colonic epithelium	UBERON:0000397	96.22	gold quality
oral cavity	UBERON:0000167	95.96	gold quality
cartilage tissue	UBERON:0002418	95.82	gold quality
right lobe of liver	UBERON:0001114	95.76	gold quality
lower esophagus mucosa	UBERON:0035834	95.74	gold quality
body of pancreas	UBERON:0001150	95.70	gold quality
rectum	UBERON:0001052	95.55	gold quality
muscle layer of sigmoid colon	UBERON:0035805	95.48	gold quality
calcaneal tendon	UBERON:0003701	95.40	gold quality
adenohypophysis	UBERON:0002196	95.38	gold quality
stromal cell of endometrium	CL:0002255	95.33	gold quality
pancreas	UBERON:0001264	95.26	gold quality
sigmoid colon	UBERON:0001159	95.05	gold quality
esophagus mucosa	UBERON:0002469	94.98	gold quality
gluteal muscle	UBERON:0002000	94.97	gold quality
corpus epididymis	UBERON:0004359	94.81	gold quality
tonsil	UBERON:0002372	94.67	gold quality
tongue	UBERON:0001723	94.66	gold quality
colon	UBERON:0001155	94.60	gold quality
mouth mucosa	UBERON:0003729	94.57	gold quality
large intestine	UBERON:0000059	94.56	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.03
E-CURD-112	yes	5.27

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

15 targeting TARS1, 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-105-5P	99.54	69.24	2060
HSA-MIR-7853-5P	99.54	69.30	2055
HSA-MIR-532-3P	99.34	65.76	1195
HSA-MIR-130A-5P	99.33	70.26	2623
HSA-MIR-892C-5P	99.16	70.56	2116
HSA-MIR-4326	98.97	67.63	962
HSA-MIR-4691-5P	98.41	66.77	1343
HSA-MIR-8057	97.64	66.54	897
HSA-MIR-4712-5P	97.24	67.79	775
HSA-MIR-770-5P	97.24	68.10	758
HSA-MIR-505-5P	97.01	65.54	778
HSA-MIR-101-5P	96.84	65.66	649
HSA-MIR-4764-3P	96.81	67.94	580
HSA-MIR-4330	95.44	66.39	993
HSA-MIR-1298-3P	94.05	64.84	620

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 99.9% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 8)

• Our series mainly underscores that interstitial lung disease is frequent in anti-PL7(tars antibody)patients, leading to high morbidity. (PMID:23375620)
• A previously undiscovered function for TARS as an angiogenic, pro-migratory extracellular signaling molecule. (PMID:23425968)
• Results show that TARS expression is increased in epithelial ovarian cancer. (PMID:25163878)
• Threonyl-tRNA synthetase regulates MUC1 biosynthesis and is associated with pancreatic cancer cell migration. (PMID:29328069)
• This work highlights the functional significance of aminoacyl-tRNA synthetases in the emergence and control of higher order organisms. (PMID:30902983)
• Bi-allelic TARS Mutations Are Associated with Brittle Hair Phenotype. (PMID:31374204)
• Contribution of upregulated aminoacyl-tRNA biosynthesis to metabolic dysregulation in gastric cancer. (PMID:34159625)
• A model organism pipeline provides insight into the clinical heterogeneity of TARS1 loss-of-function variants. (PMID:38956874)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	tars1	ENSDARG00000013250
mus_musculus	Tars1	ENSMUSG00000022241
rattus_norvegicus	Tars1	ENSRNOG00000019023

Paralogs (4): TARS2 (ENSG00000143374), MRPL39 (ENSG00000154719), PARS2 (ENSG00000162396), TARS3 (ENSG00000185418)

Protein

Protein identifiers

Threonine–tRNA ligase 1, cytoplasmic — P26639 (reviewed: P26639)

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

All UniProt accessions (8): P26639, D6R9F8, D6RBR8, D6RCA5, D6RCS6, D6RDJ6, D6RHV7, D6RJ97

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, at the post-transfer stage.

Subunit / interactions. Homodimer.

Subcellular location. Cytoplasm.

Post-translational modifications. ISGylated.

Disease relevance. Trichothiodystrophy 7, non-photosensitive (TTD7) [MIM:618546] A form of trichothiodystrophy, a disease characterized by sulfur-deficient brittle hair and multisystem variable abnormalities. The spectrum of clinical features varies from mild disease with only hair involvement to severe disease with cutaneous, neurologic and profound developmental defects. Ichthyosis, intellectual and developmental disabilities, decreased fertility, abnormal characteristics at birth, ocular abnormalities, short stature, and infections are common manifestations. There are both photosensitive and non-photosensitive forms of the disorder. TTD7 patients do not manifest cutaneous photosensitivity. They have cysteine- and threonine-deficient hair with alternating light and dark ’tiger-tail’ banding pattern observed under polarization microscopy. Inheritance pattern is autosomal recessive. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Inhibited by borrelidin (BN, IC 50 is 7 nM), which binds to 4 distinct subsites in the protein, preventing binding of all 3 substrates.

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

Isoforms (2)

UniProt ID	Names	Canonical?
P26639-1	1	yes
P26639-2	2

RefSeq proteins (3): NP_001245366, NP_001245367, NP_689508* (*=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

Enzyme classification (BRENDA):

• EC 6.1.1.3 — threonine-tRNA ligase (BRENDA: 36 organisms, 94 substrates, 60 inhibitors, 99 Km, 81 kcat entries)

Substrate kinetics (BRENDA)

12 substrates with measured Km, best-characterized 12. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
L-THREONINE	—	20
TRNA1THR	0.0001–0.0009	17
TRNA2THR	0.0003–0.0014	15
TRNATHR	—	12
L-SERINE	25–939.72	7
ATP	0.267–152	6
2-CHLOROADENOSINE 5’-TRIPHOSPHATE	0.4	2
FORMYCIN 5’-TRIPHOSPHATE	0.5	2
HYDROXYNORVALINE	1.95–7	2
THREONINE	0.0019	1
TRNATHR1	0.0004	1
L-THREONYL-TRNATHR	—	0

Catalyzed reactions (Rhea), 1 shown:

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

UniProt features (80 total): helix 23, strand 23, sequence conflict 9, modified residue 6, mutagenesis site 5, turn 5, sequence variant 4, chain 1, domain 1, splice variant 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
5XLN	X-RAY DIFFRACTION	1.9
4HWT	X-RAY DIFFRACTION	2.3
4P3N	X-RAY DIFFRACTION	2.6
4TTV	X-RAY DIFFRACTION	2.8
1WWT	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P26639-F1	91.09	0.84

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 (6): 39, 243, 246, 298, 453, 702

Mutagenesis-validated functional residues (5):

Position	Phenotype
392	partially restores in vitro translation.
458	partially restores in vitro translation.
462	does not restore in vitro translation, probably does not bind bn.
567	does not restore in vitro translation, does not replace endogenous yeast enzyme.
567	replaces endogenous yeast enzyme.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-379716	Cytosolic tRNA aminoacylation
R-HSA-379724	tRNA Aminoacylation
R-HSA-392499	Metabolism of proteins
R-HSA-72766	Translation

MSigDB gene sets: 442 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_DN, MORF_DNMT1, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_AMINO_ACID_ACTIVATION, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, MORF_BUB1, GOBP_TRNA_METABOLIC_PROCESS, MORF_RRM1, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, MORF_HDAC2, GOBP_TRANSLATION, OUELLET_OVARIAN_CANCER_INVASIVE_VS_LMP_UP, UEDA_PERIFERAL_CLOCK, GNF2_XRCC5

GO Biological Process (4): threonyl-tRNA aminoacylation (GO:0006435), translation (GO:0006412), tRNA aminoacylation for protein translation (GO:0006418), tRNA aminoacylation (GO:0043039)

GO Molecular Function (10): tRNA binding (GO:0000049), threonine-tRNA ligase activity (GO:0004829), ATP binding (GO:0005524), zinc ion binding (GO:0008270), identical protein binding (GO:0042802), nucleotide binding (GO:0000166), RNA binding (GO:0003723), aminoacyl-tRNA ligase activity (GO:0004812), protein binding (GO:0005515), ligase activity (GO:0016874)

GO Cellular Component (3): cytoplasm (GO:0005737), cytosol (GO:0005829), extracellular exosome (GO:0070062)

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
cellular anatomical structure	2
tRNA aminoacylation for 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
tRNA metabolic process	1
amino acid activation	1
RNA binding	1
aminoacyl-tRNA ligase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
transition metal ion binding	1
protein binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
nucleic acid binding	1
ligase activity, forming carbon-oxygen bonds	1
catalytic activity, acting on a tRNA	1
binding	1
catalytic activity	1
intracellular anatomical structure	1
cytoplasm	1
extracellular vesicle	1

Protein interactions and networks

STRING

2476 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TARS1	LARS2	Q15031	977
TARS1	LARS1	Q9P2J5	970
TARS1	AARS1	P49588	894
TARS1	NARS1	O43776	875
TARS1	NARS2	Q96I59	871
TARS1	EPRS1	P07814	862
TARS1	IARS2	Q9NSE4	861
TARS1	VARS1	P26640	845
TARS1	IARS1	P41252	844
TARS1	YARS1	P54577	843
TARS1	MAP3K12	Q12852	829
TARS1	PARS2	Q7L3T8	825
TARS1	HARS1	P12081	821
TARS1	GARS1	P41250	820
TARS1	HARS2	P49590	813

IntAct

91 interactions, top by confidence:

A	B	Type	Score
PRKAG1	PRKAB2	psi-mi:“MI:0914”(association)	0.940
TARS1	TARS3	psi-mi:“MI:0915”(physical association)	0.720
TARS3	TARS1	psi-mi:“MI:0915”(physical association)	0.720
TARS1	C7orf25	psi-mi:“MI:0915”(physical association)	0.560
TARS1	SULT1B1	psi-mi:“MI:0915”(physical association)	0.560
TARS1	OPTN	psi-mi:“MI:0915”(physical association)	0.560
VCAM1	PSMD11	psi-mi:“MI:0914”(association)	0.530
gag	SDCBP	psi-mi:“MI:0914”(association)	0.460
NDRG1	TARS1	psi-mi:“MI:0915”(physical association)	0.400
	GNAT3	psi-mi:“MI:0915”(physical association)	0.400
TARS1	iglC2	psi-mi:“MI:0915”(physical association)	0.370
HSPB1	TARS1	psi-mi:“MI:0915”(physical association)	0.370
OTUB1	EPM2A	psi-mi:“MI:0914”(association)	0.350
Brwd3	WDR91	psi-mi:“MI:0914”(association)	0.350
Max	PABPN1	psi-mi:“MI:0914”(association)	0.350
JUN		psi-mi:“MI:0914”(association)	0.350
JUN	TPM3	psi-mi:“MI:0914”(association)	0.350
RIPK4	VWA8	psi-mi:“MI:0914”(association)	0.350
Prdm16	ESYT2	psi-mi:“MI:0914”(association)	0.350
Mecom	ESYT2	psi-mi:“MI:0914”(association)	0.350

BioGRID (244): TARS (Affinity Capture-MS), C7orf25 (Two-hybrid), TARSL2 (Two-hybrid), TARS (Affinity Capture-MS), TARS (Affinity Capture-MS), TARS (Affinity Capture-MS), TARS (Two-hybrid), PTGES3L-AARSD1 (Co-fractionation), AARSD1 (Co-fractionation), AHNAK (Co-fractionation), CHEK1 (Co-fractionation), EIF2AK4 (Co-fractionation), FARSA (Co-fractionation), FARSB (Co-fractionation), GARS (Co-fractionation)

ESM2 similar proteins: A0MTA1, A1YES6, A1YFZ3, A2T6Y4, A2T7I6, A3M208, A8J2Z9, A8XL25, B0V4U0, B0X4N8, B2I3E2, B7I5G4, O26314, O43049, P00388, P00389, P04175, P08967, P0A2X3, P0A2X4, P0C1I1, P13217, P23196, P26639, P26882, P27695, P28352, P36776, P37039, P37040, P37454, P43138, P51173, P93655, Q0UI56, Q16775, Q16T79, Q28333, Q388N2, Q3SYT8

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

7 interactions.

A	Effect	B	Mechanism
TARS1	“down-regulates quantity”	tRNA(Thr)	“chemical modification”
TARS1	“down-regulates quantity”	threonine	“chemical modification”
TARS1	“down-regulates quantity”	ATP(4-)	“chemical modification”
TARS1	“up-regulates quantity”	diphosphate(3-)	“chemical modification”
TARS1	“up-regulates quantity”	AMP	“chemical modification”
TARS1	“up-regulates quantity”	Thr-tRNA(Thr)	“chemical modification”
TARS1	“up-regulates quantity”	alpha-aminoacyl-tRNA	“chemical modification”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 94 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
Activation of AMPK downstream of NMDARs	5	29.3×	1e-04
MTOR signalling	5	20.4×	5e-04
AMPK-induced ERAD and lysosome mediated degradation of PD-L1(CD274)	5	14.9×	2e-03
Translocation of SLC2A4 (GLUT4) to the plasma membrane	5	11.9×	4e-03
Autophagy	5	11.4×	4e-03
TP53 Regulates Metabolic Genes	5	10.0×	6e-03
Macroautophagy	5	8.9×	9e-03
Transcriptional Regulation by TP53	7	6.7×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	2
Uncertain significance	98
Likely benign	11
Benign	13

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
689397	NM_152295.5(TARS1):c.1912C>T (p.Arg638Ter)	Pathogenic
689398	NM_152295.5(TARS1):c.826A>G (p.Lys276Glu)	Pathogenic
689399	NM_152295.5(TARS1):c.680T>C (p.Leu227Pro)	Pathogenic
3899295	NM_152295.5(TARS1):c.1829dup (p.Lys611fs)	Likely pathogenic
4075461	NM_152295.5(TARS1):c.1820del (p.Asn607fs)	Likely pathogenic

SpliceAI

2386 predictions. Top by Δscore:

Variant	Effect	Δscore
5:33448539:A:AG	acceptor_gain	1.0000
5:33448540:G:GG	acceptor_gain	1.0000
5:33448725:GAAT:G	donor_gain	1.0000
5:33453286:A:AG	acceptor_gain	1.0000
5:33453287:A:AG	acceptor_gain	1.0000
5:33453288:G:GC	acceptor_gain	1.0000
5:33453288:GTCAA:G	acceptor_gain	1.0000
5:33453395:GA:G	donor_gain	1.0000
5:33453401:G:GT	donor_gain	1.0000
5:33453408:AGGCA:A	donor_gain	1.0000
5:33453409:GGCAG:G	donor_gain	1.0000
5:33453410:GCA:G	donor_gain	1.0000
5:33453411:CA:C	donor_gain	1.0000
5:33453412:AG:A	donor_loss	1.0000
5:33453413:G:GG	donor_gain	1.0000
5:33453413:GT:G	donor_loss	1.0000
5:33454939:TTTCA:T	acceptor_loss	1.0000
5:33454940:TTCA:T	acceptor_loss	1.0000
5:33454941:TCA:T	acceptor_loss	1.0000
5:33454942:CAG:C	acceptor_loss	1.0000
5:33454943:A:AC	acceptor_loss	1.0000
5:33454944:G:GA	acceptor_loss	1.0000
5:33454944:GGTGT:G	acceptor_gain	1.0000
5:33455062:GAAGG:G	donor_gain	1.0000
5:33455065:GG:G	donor_gain	1.0000
5:33455066:GG:G	donor_gain	1.0000
5:33455583:TCA:T	acceptor_loss	1.0000
5:33455584:CA:C	acceptor_loss	1.0000
5:33455585:A:AG	acceptor_gain	1.0000
5:33455585:AGG:A	acceptor_gain	1.0000

AlphaMissense

4824 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:33454954:C:G	H155D	1.000
5:33454956:C:A	H155Q	1.000
5:33454956:C:G	H155Q	1.000
5:33454958:C:T	S156F	1.000
5:33454960:A:C	S157R	1.000
5:33454962:T:A	S157R	1.000
5:33454962:T:G	S157R	1.000
5:33454964:C:A	A158D	1.000
5:33454966:C:G	H159D	1.000
5:33454968:C:A	H159Q	1.000
5:33454968:C:G	H159Q	1.000
5:33455018:G:A	G176D	1.000
5:33456014:A:G	K236E	1.000
5:33456016:A:C	K236N	1.000
5:33456016:A:T	K236N	1.000
5:33456166:A:T	D259V	1.000
5:33456171:T:C	C261R	1.000
5:33456172:G:A	C261Y	1.000
5:33456173:C:G	C261W	1.000
5:33456183:C:G	H265D	1.000
5:33456187:T:A	V266D	1.000
5:33457300:T:C	L294P	1.000
5:33457306:G:C	R296T	1.000
5:33457307:A:C	R296S	1.000
5:33457307:A:T	R296S	1.000
5:33457315:G:A	G299D	1.000
5:33457381:G:C	R321P	1.000
5:33457391:G:C	R324S	1.000
5:33457391:G:T	R324S	1.000
5:33457399:G:A	G327D	1.000

dbSNP variants (sampled 300 via entrez): RS1000068110 (5:33462508 A>G), RS1000081682 (5:33448011 G>A,T), RS1000121512 (5:33462836 T>A,C), RS1000518298 (5:33457738 T>C), RS1000534134 (5:33452778 T>A), RS1000605509 (5:33467573 A>G), RS1000687111 (5:33446585 G>A), RS1000835052 (5:33440657 C>G,T), RS1000841386 (5:33439017 A>C), RS1000881365 (5:33444281 T>C), RS1000906794 (5:33440430 T>G), RS1000976172 (5:33467261 A>G), RS1001004921 (5:33450090 C>G), RS1001444532 (5:33463160 A>T), RS1001563034 (5:33443985 C>A,T)

Disease associations

OMIM: gene MIM:187790 | disease phenotypes: MIM:618546, MIM:601675

GenCC curated gene-disease

Disease	Classification	Inheritance
trichothiodystrophy 7, nonphotosensitive	Moderate	Autosomal recessive
trichothiodystrophy	Supportive	Autosomal recessive

Mondo (2): trichothiodystrophy 7, nonphotosensitive (MONDO:0032806), trichothiodystrophy (MONDO:0018053)

Orphanet (1): Trichothiodystrophy (Orphanet:33364)

HPO phenotypes

94 total (30 of 94 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000133	Gonadal dysgenesis
HP:0000252	Microcephaly
HP:0000278	Retrognathia
HP:0000280	Coarse facial features
HP:0000286	Epicanthus
HP:0000316	Hypertelorism
HP:0000320	Bird-like facies
HP:0000411	Protruding ear
HP:0000482	Microcornea
HP:0000483	Astigmatism
HP:0000486	Strabismus
HP:0000509	Conjunctivitis
HP:0000519	Developmental cataract
HP:0000545	Myopia
HP:0000546	Retinal degeneration
HP:0000565	Esotropia
HP:0000601	Hypotelorism
HP:0000608	Macular degeneration
HP:0000613	Photophobia
HP:0000639	Nystagmus
HP:0000656	Ectropion
HP:0000670	Carious teeth
HP:0000938	Osteopenia
HP:0000958	Dry skin
HP:0000964	Eczematoid dermatitis
HP:0000992	Cutaneous photosensitivity
HP:0001097	Keratoconjunctivitis sicca
HP:0001197	Abnormality of prenatal development or birth

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST004184_9	Lung function (FVC)	4.000000e-13
GCST006624_86	Systolic blood pressure	2.000000e-09
GCST007102_12	Seasonality and depression	2.000000e-06
GCST007367_1	Meconium ileus in cystic fibrosis	3.000000e-07
GCST007429_8	Lung function (FVC)	3.000000e-17
GCST007432_134	FEV1	2.000000e-14
GCST008839_168	Height	2.000000e-09
GCST012305_10	Major depressive disorder x sex interaction	6.000000e-06
GCST90013466_28	Height	1.000000e-09
GCST90013466_5	Height	8.000000e-17
GCST90013467_10	Height	1.000000e-06

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0004312	vital capacity
EFO:0006335	systolic blood pressure
EFO:0006876	seasonality measurement
EFO:0004314	forced expiratory volume
EFO:0008343	sex interaction measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3391 (SINGLE PROTEIN)

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

ChEMBL bioactivities

26 potent at pChembl≥5 of 28 total, top 26 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.92	Ki	1.2	nM	CHEMBL2311920
8.74	Ki	1.8	nM	CHEMBL2311926
8.52	Ki	3	nM	CHEMBL2311924
8.48	Ki	3.3	nM	CHEMBL2311918
8.39	Ki	4.1	nM	CHEMBL2311925
8.28	Ki	5.2	nM	CHEMBL2311927
8.28	Kd	5.311	nM	CHEMBL3752910
8.28	ED50	5.311	nM	CHEMBL3752910
8.00	Ki	10.1	nM	CHEMBL2311919
7.87	Ki	13.4	nM	CHEMBL2311917
7.82	IC50	15	nM	CHEMBL1163068
7.50	Ki	32	nM	CHEMBL2316966
7.31	Kd	49	nM	CHEMBL5405159
7.24	Kd	57.65	nM	CHEMBL5653589
7.24	ED50	57.65	nM	CHEMBL5653589
7.14	Ki	72	nM	CHEMBL2311921
7.04	Ki	91	nM	CHEMBL2311928
6.94	Kd	115	nM	CHEMBL5430875
6.90	Kd	126	nM	CHEMBL5424310
6.40	Ki	399	nM	CHEMBL2316963
6.33	Ki	463	nM	CHEMBL2311922
6.22	Ki	601	nM	CHEMBL2316967
6.03	Ki	935	nM	CHEMBL2316962
5.82	Ki	1518	nM	CHEMBL2311929
5.65	Ki	2242	nM	CHEMBL2311923
5.24	Ki	5820	nM	CHEMBL2316960

PubChem BioAssay actives

24 with measured affinity, of 95 total; 24 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
(2S,3R)-2-amino-N-[3-(4-amino-2-chloroquinazolin-7-yl)phenyl]sulfonyl-3-hydroxybutanamide	723280: Binding affinity to human cytoplasmic ThrRS by coupled spectrophotometry	ki	0.0012	uM
(2S,3R)-2-amino-3-hydroxy-N-[7-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)naphthalen-2-yl]sulfonylbutanamide	723280: Binding affinity to human cytoplasmic ThrRS by coupled spectrophotometry	ki	0.0018	uM
(2S,3R)-2-amino-N-[7-(6-aminopyrimidin-4-yl)naphthalen-2-yl]sulfonyl-3-hydroxybutanamide	723280: Binding affinity to human cytoplasmic ThrRS by coupled spectrophotometry	ki	0.0030	uM
(2S,3R)-2-amino-N-[3-(4-aminoquinazolin-7-yl)phenyl]sulfonyl-3-hydroxybutanamide	723280: Binding affinity to human cytoplasmic ThrRS by coupled spectrophotometry	ki	0.0033	uM
(2S,3R)-2-amino-N-[(E)-2-[3-(6-aminopyrimidin-4-yl)phenyl]ethenyl]sulfonyl-3-hydroxybutanamide	723280: Binding affinity to human cytoplasmic ThrRS by coupled spectrophotometry	ki	0.0041	uM
(2S,3R)-2-amino-3-hydroxy-N-[[7-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-1H-isoquinolin-2-yl]sulfonyl]butanamide	723280: Binding affinity to human cytoplasmic ThrRS by coupled spectrophotometry	ki	0.0052	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149548: Binding affinity to human TARS incubated for 45 mins by Kinobead based pull down assay	kd	0.0053	uM
(2S,3R)-2-amino-N-[3-(2,4-diaminoquinazolin-7-yl)phenyl]sulfonyl-3-hydroxybutanamide	723280: Binding affinity to human cytoplasmic ThrRS by coupled spectrophotometry	ki	0.0101	uM
[(2S,3R,4S,5S)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl N-[(2S,3R)-2-amino-3-hydroxybutanoyl]sulfamate	723280: Binding affinity to human cytoplasmic ThrRS by coupled spectrophotometry	ki	0.0134	uM
[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl N-[(2S,3R)-2-amino-3-hydroxybutanoyl]sulfamate	213252: Inhibitory activity against cognate Staphylococcus aureus threonyl tRNA synthetase	ic50	0.0150	uM
(2S,3R)-2-amino-N-[(E)-2-[3-(6-aminopyrimidin-4-yl)phenyl]ethenyl]sulfonyl-3-hydroxypentanamide	723280: Binding affinity to human cytoplasmic ThrRS by coupled spectrophotometry	ki	0.0320	uM
(2S,3R)-2-amino-N-[[5-(6-aminopyrimidin-4-yl)-1,3-benzothiazol-2-yl]sulfonyl]-3-hydroxybutanamide	2005811: Inhibition of human cytosolic ThrRS assessed as dissociation constant by isothermal titration calorimetry	kd	0.0490	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149548: Binding affinity to human TARS incubated for 45 mins by Kinobead based pull down assay	kd	0.0576	uM
(2S,3R)-2-amino-N-[3-(4-amino-2-methylquinazolin-7-yl)phenyl]sulfonyl-3-hydroxybutanamide	723280: Binding affinity to human cytoplasmic ThrRS by coupled spectrophotometry	ki	0.0720	uM
(2S,3R)-2-amino-3-hydroxy-N-[3-(1-oxo-2,3-dihydroisoindol-5-yl)phenyl]sulfonylbutanamide	723280: Binding affinity to human cytoplasmic ThrRS by coupled spectrophotometry	ki	0.0910	uM
[4-(6-aminopyrimidin-4-yl)phenyl] N-[(2S,3R)-2-amino-3-hydroxybutanoyl]sulfamate	2005811: Inhibition of human cytosolic ThrRS assessed as dissociation constant by isothermal titration calorimetry	kd	0.1150	uM
[2-(6-aminopyrimidin-4-yl)indazol-4-yl] N-[(2S,3R)-2-amino-3-hydroxybutanoyl]sulfamate	2005811: Inhibition of human cytosolic ThrRS assessed as dissociation constant by isothermal titration calorimetry	kd	0.1260	uM
(2S,3R)-2-amino-N’-[3-(4-amino-2-chloroquinazolin-7-yl)phenyl]-3-hydroxybutanehydrazide	723280: Binding affinity to human cytoplasmic ThrRS by coupled spectrophotometry	ki	0.3990	uM
(2S,3R)-2-amino-N-[3-(1-amino-3-chloroisoquinolin-6-yl)phenyl]sulfonyl-3-hydroxybutanamide	723280: Binding affinity to human cytoplasmic ThrRS by coupled spectrophotometry	ki	0.4630	uM
(2S,3R)-2-amino-N-[(E)-2-[3-(6-aminopyrimidin-4-yl)phenyl]ethenyl]sulfonyl-3-hydroxy-4-methylpentanamide	723280: Binding affinity to human cytoplasmic ThrRS by coupled spectrophotometry	ki	0.6010	uM
(2S,3R)-2-amino-N-[[3-(4-amino-2-chloroquinazolin-7-yl)phenyl]methyl]-3-hydroxybutanamide	723280: Binding affinity to human cytoplasmic ThrRS by coupled spectrophotometry	ki	0.9350	uM
(2S,3R)-2-amino-N-[3-(3-chloro-2H-indazol-5-yl)phenyl]sulfonyl-3-hydroxybutanamide	723280: Binding affinity to human cytoplasmic ThrRS by coupled spectrophotometry	ki	1.5180	uM
(2S,3R)-2-amino-N-[3-(1-aminoisoquinolin-6-yl)phenyl]sulfonyl-3-hydroxybutanamide	723280: Binding affinity to human cytoplasmic ThrRS by coupled spectrophotometry	ki	2.2420	uM
(2S,3R)-2-amino-3-hydroxy-N-[3-(3-methyl-2H-indazol-5-yl)phenyl]sulfonylbutanamide	723280: Binding affinity to human cytoplasmic ThrRS by coupled spectrophotometry	ki	5.8200	uM

CTD chemical–gene interactions

79 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, decreases expression, increases expression	6
Valproic Acid	decreases expression, decreases methylation, affects cotreatment, increases expression, affects expression	5
sodium arsenite	decreases expression, increases abundance, increases expression	4
borrelidin	affects folding, decreases activity, affects binding	3
trichostatin A	increases expression, affects cotreatment	3
Tobacco Smoke Pollution	affects expression, increases expression	3
Cyclosporine	increases expression	3
entinostat	increases expression, affects cotreatment	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression, increases expression	2
Panobinostat	affects cotreatment, increases expression	2
Cisplatin	decreases expression	2
Estradiol	increases expression	2
aristolochic acid I	decreases expression, increases expression	1
bisphenol F	increases expression	1
dicrotophos	decreases expression	1
chloroacetaldehyde	decreases expression	1
methylmercuric chloride	increases expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, increases expression, decreases expression	1
decabromobiphenyl ether	increases expression	1
4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone	increases expression	1
afimoxifene	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
perfluorooctanoic acid	increases expression	1
ochratoxin A	decreases expression	1
1-nitropyrene	increases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
perfluorooctane sulfonic acid	increases expression	1
chloropicrin	affects expression	1
perfluoro-n-nonanoic acid	increases expression	1

ChEMBL screening assays

53 unique, capped per target: 53 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2317882	Binding	Binding affinity to human cytoplasmic ThrRS by coupled spectrophotometry	Identification of bacteria-selective threonyl-tRNA synthetase substrate inhibitors by structure-based design. — J Med Chem

Cellosaurus cell lines

2 cell lines: 2 finite cell line

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

Cellosaurus	Name	Category	Sex
CVCL_ZP25	TTD5VI	Finite cell line	Female
CVCL_ZP49	TTD18PV	Finite cell line

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00001813	Not specified	COMPLETED	Examination of Clinical and Laboratory Abnormalities in Patients With Defective DNA Repair: Xeroderma Pigmentosum, Cockayne Syndrome, or Trichothiodystrophy
NCT05484570	Not specified	RECRUITING	Natural History Study for DNA Repair Disorders