MARS2

Summary

MARS2 (methionyl-tRNA synthetase 2, mitochondrial, HGNC:25133) is a protein-coding gene on chromosome 2q33.1, encoding Methionine–tRNA ligase, mitochondrial (Q96GW9). It is a selective cancer dependency (DepMap: 88.1% of cell lines).

This gene produces a mitochondrial methionyl-tRNA synthetase protein that is encoded by the nuclear genome and imported to the mitochondrion. This protein likely functions as a monomer and is predicted to localize to the mitochondrial matrix. Mutations in this gene are associated with the autosomal recessive neurodegenerative disease spastic ataxia-3 (SPAX3).

Source: NCBI Gene 92935 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 19
• Clinical variants (ClinVar): 269 total — 4 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 54
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 88.1% of screened cell lines
• MANE Select transcript: NM_138395

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25133
Approved symbol	MARS2
Name	methionyl-tRNA synthetase 2, mitochondrial
Location	2q33.1
Locus type	gene with protein product
Status	Approved
Aliases	mtMetRS, SPAX3
Ensembl gene	ENSG00000247626
Ensembl biotype	protein_coding
OMIM	609728
Entrez	92935

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000282276

RefSeq mRNA: 1 — MANE Select: NM_138395 NM_138395

CCDS: CCDS33358

Canonical transcript exons

ENST00000282276 — 1 exons

Exon	Start	End
ENSE00001005147	197705369	197708395

Expression profiles

Bgee: expression breadth ubiquitous, 178 present calls, max score 85.05.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 10.6141 / max 73.6125, expressed in 1730 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
24489	10.6141	1730

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cardiac muscle of right atrium	UBERON:0003379	85.05	gold quality
left ventricle myocardium	UBERON:0006566	85.00	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	83.77	gold quality
tibialis anterior	UBERON:0001385	81.69	gold quality
kidney epithelium	UBERON:0004819	80.99	gold quality
ileal mucosa	UBERON:0000331	80.10	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	78.57	gold quality
adrenal tissue	UBERON:0018303	78.52	gold quality
pancreatic ductal cell	CL:0002079	78.21	silver quality
islet of Langerhans	UBERON:0000006	78.14	gold quality
mucosa of transverse colon	UBERON:0004991	76.85	gold quality
secondary oocyte	CL:0000655	76.34	gold quality
gastrocnemius	UBERON:0001388	75.39	gold quality
right adrenal gland cortex	UBERON:0035827	75.37	gold quality
right adrenal gland	UBERON:0001233	75.27	gold quality
muscle of leg	UBERON:0001383	74.95	gold quality
left adrenal gland	UBERON:0001234	74.92	gold quality
left adrenal gland cortex	UBERON:0035825	74.34	gold quality
rectum	UBERON:0001052	74.30	gold quality
adrenal gland	UBERON:0002369	74.06	gold quality
vermiform appendix	UBERON:0001154	73.82	gold quality
pancreas	UBERON:0001264	73.38	gold quality
esophagus mucosa	UBERON:0002469	73.27	gold quality
skeletal muscle organ	UBERON:0014892	73.06	gold quality
adrenal cortex	UBERON:0001235	73.05	gold quality
lymph node	UBERON:0000029	73.01	gold quality
hindlimb stylopod muscle	UBERON:0004252	72.76	gold quality
cortical plate	UBERON:0005343	72.62	gold quality
heart left ventricle	UBERON:0002084	72.45	gold quality
transverse colon	UBERON:0001157	72.41	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.63

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

78 targeting MARS2, 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-196A-5P	100.00	68.16	684
HSA-MIR-196B-5P	100.00	68.16	681
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-374B-5P	99.90	69.98	2734
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-30A-3P	99.87	69.74	2928

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 88.1% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 4)

• Sequence analysis of mitochondrial MetRS indicates that this protein contains consensus motifs characteristic of class I aminoacyl-tRNA synthetase but lacks Zn2+ binding motif and C-terminal dimerization region found in MetRSs from various organisms. (PMID:15274629)
• MARS2 is mutated in Autosomal Recessive Spastic Ataxia with Leukoencephalopathy patients. (PMID:22448145)
• Novel, compound heterozygous, single-nucleotide variants in MARS2 associated with developmental delay, poor growth, and sensorineural hearing loss (PMID:25754315)
• Increased Mars2 expression upon microRNA-4661-5p-mediated KDM5D downregulation is correlated with malignant degree of gastric cancer cells. (PMID:34273914)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	mars2	ENSDARG00000009218
mus_musculus	Mars2	ENSMUSG00000046994
rattus_norvegicus	Mars2	ENSRNOG00000065339
drosophila_melanogaster	MetRS-m	FBGN0027083

Paralogs (7): LARS2 (ENSG00000011376), IARS2 (ENSG00000067704), LARS1 (ENSG00000133706), VARS2 (ENSG00000137411), MARS1 (ENSG00000166986), IARS1 (ENSG00000196305), VARS1 (ENSG00000204394)

Protein

Protein identifiers

Methionine–tRNA ligase, mitochondrial — Q96GW9 (reviewed: Q96GW9)

Alternative names: Methionyl-tRNA synthetase 2, Mitochondrial methionyl-tRNA synthetase

All UniProt accessions (1): Q96GW9

UniProt curated annotations — full annotation on UniProt →

Subcellular location. Mitochondrion matrix.

Disease relevance. Spastic ataxia 3, autosomal recessive (SPAX3) [MIM:611390] A neurologic disorder characterized by cerebellar ataxia, ataxic gait, spasticity, and hyperreflexia. Other variable features include dysarthria, dysmetria, mild cognitive impairment, urinary urgency and dystonic positioning. The disease is caused by variants affecting the gene represented in this entry. Combined oxidative phosphorylation deficiency 25 (COXPD25) [MIM:616430] A mitochondrial disorder resulting in developmental delay, growth failure, and sensorineural hearing loss. The disease is caused by variants affecting the gene represented in this entry.

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

RefSeq proteins (1): NP_612404* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR009080	tRNAsynth_Ia_anticodon-bd	Homologous_superfamily
IPR014729	Rossmann-like_a/b/a_fold	Homologous_superfamily
IPR014758	Met-tRNA_synth	Family
IPR015413	Methionyl/Leucyl_tRNA_Synth	Domain
IPR023457	Met-tRNA_synth_2	Family
IPR033911	MetRS_core	Domain
IPR041872	Anticodon_Met	Domain

Pfam: PF09334, PF19303

Catalyzed reactions (Rhea), 1 shown:

• tRNA(Met) + L-methionine + ATP = L-methionyl-tRNA(Met) + AMP + diphosphate (RHEA:13481)

UniProt features (7 total): short sequence motif 2, transit peptide 1, chain 1, binding site 1, sequence variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96GW9-F1	89.66	0.81

Functional residue map

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

Ligand- & substrate-binding residues (1): 350

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: 186 (showing top): GOBP_AMINO_ACID_ACTIVATION, GOBP_TRNA_METABOLIC_PROCESS, GOBP_TRANSLATION, DODD_NASOPHARYNGEAL_CARCINOMA_UP, KEGG_AMINOACYL_TRNA_BIOSYNTHESIS, REACTOME_MITOCHONDRIAL_TRNA_AMINOACYLATION, IVANOVA_HEMATOPOIESIS_EARLY_PROGENITOR, GOCC_MITOCHONDRIAL_MATRIX, MARSON_BOUND_BY_E2F4_UNSTIMULATED, GOMF_LIGASE_ACTIVITY_FORMING_CARBON_OXYGEN_BONDS, GOMF_ADENYL_NUCLEOTIDE_BINDING, TORCHIA_TARGETS_OF_EWSR1_FLI1_FUSION_UP, KUMAR_PATHOGEN_LOAD_BY_MACROPHAGES, ZWANG_CLASS_1_TRANSIENTLY_INDUCED_BY_EGF, GOMF_CATALYTIC_ACTIVITY_ACTING_ON_RNA

GO Biological Process (3): tRNA aminoacylation for protein translation (GO:0006418), methionyl-tRNA aminoacylation (GO:0006431), translation (GO:0006412)

GO Molecular Function (5): methionine-tRNA ligase activity (GO:0004825), ATP binding (GO:0005524), nucleotide binding (GO:0000166), aminoacyl-tRNA ligase activity (GO:0004812), ligase activity (GO:0016874)

GO Cellular Component (2): mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759)

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
translation	1
tRNA aminoacylation	1
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
aminoacyl-tRNA ligase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
ligase activity, forming carbon-oxygen bonds	1
catalytic activity, acting on a tRNA	1
catalytic activity	1
cytoplasm	1
intracellular membrane-bounded organelle	1
mitochondrion	1
intracellular organelle lumen	1

Protein interactions and networks

STRING

2048 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MARS2	IARS1	P41252	995
MARS2	IARS2	Q9NSE4	994
MARS2	LARS2	Q15031	988
MARS2	LARS1	Q9P2J5	988
MARS2	KARS1	Q15046	987
MARS2	QARS1	P47897	981
MARS2	EPRS1	P07814	975
MARS2	EEF1E1	O43324	966
MARS2	EARS2	Q5JPH6	962
MARS2	RARS2	Q5T160	960
MARS2	RARS1	P54136	933
MARS2	YARS2	Q9Y2Z4	910
MARS2	YARS1	P54577	907
MARS2	PARS2	Q7L3T8	896
MARS2	AIMP2	Q13155	882

IntAct

42 interactions, top by confidence:

A	B	Type	Score
CDKN2C	CDK4	psi-mi:“MI:0914”(association)	0.970
HSPD1	NUDT19	psi-mi:“MI:0914”(association)	0.710
NDUFS7	NDUFS8	psi-mi:“MI:0914”(association)	0.640
SMURF2	NEDD4	psi-mi:“MI:0914”(association)	0.590
MARS2	CLUH	psi-mi:“MI:0914”(association)	0.530
BCKDHB	DBT	psi-mi:“MI:0914”(association)	0.530
FAM219A	OBSL1	psi-mi:“MI:0914”(association)	0.530
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350
MRPL4	ZSWIM8	psi-mi:“MI:0914”(association)	0.350
YBEY	NUDT19	psi-mi:“MI:0914”(association)	0.350
NDUFS7		psi-mi:“MI:0914”(association)	0.350
FAM219A	NBN	psi-mi:“MI:0914”(association)	0.350
HROB	ZPR1	psi-mi:“MI:0914”(association)	0.350
FCGR2B	FCGR2A	psi-mi:“MI:0914”(association)	0.350
GCDH	MARS2	psi-mi:“MI:0914”(association)	0.350
UQCRFS1	VWA8	psi-mi:“MI:0914”(association)	0.350
MALSU1	VWA8	psi-mi:“MI:0914”(association)	0.350
GPR182	METTL15	psi-mi:“MI:0914”(association)	0.350
NDUFB11	NDUFS8	psi-mi:“MI:0914”(association)	0.350
MTSS2	CHEK1	psi-mi:“MI:0914”(association)	0.350
SIPA1L2	N4BP3	psi-mi:“MI:0914”(association)	0.350
GCSAML	SPAG9	psi-mi:“MI:0914”(association)	0.350
ACSM5	CLUH	psi-mi:“MI:0914”(association)	0.350
TAFA2	ERN1	psi-mi:“MI:0914”(association)	0.350

BioGRID (63): MARS2 (Affinity Capture-MS), MARS2 (Affinity Capture-MS), MARS2 (Affinity Capture-MS), MARS2 (Affinity Capture-MS), MARS2 (Co-fractionation), MARS2 (Co-fractionation), MARS2 (Affinity Capture-MS), MARS2 (Affinity Capture-MS), MARS2 (Affinity Capture-MS), MARS2 (Affinity Capture-MS), MARS2 (Affinity Capture-MS), MARS2 (Affinity Capture-MS), MARS2 (Affinity Capture-MS), MARS2 (Affinity Capture-MS), MARS2 (Affinity Capture-MS)

ESM2 similar proteins: A0A1D6LAG9, A2YQ56, A6H7E1, B3LFA4, B8B4H5, B9FK36, B9FSH5, F4I1L3, F4IPY2, F4KE63, O23247, O24357, O75005, P49589, P49696, P93736, Q0IZQ2, Q2KIF8, Q2QMG2, Q43727, Q43768, Q43794, Q43839, Q499X9, Q4R646, Q5M7N8, Q5ZKA2, Q69UZ3, Q6DJ95, Q6GQJ7, Q6PA41, Q7T0Z0, Q8BIJ6, Q8BYM8, Q8L743, Q8L785, Q8RXE9, Q8RXK8, Q8S6N5, Q90YI3

Diamond homologs: A1APS3, A5ITI8, A6H7E1, A6QHJ8, A6U2D1, A7X383, A8Z2I4, B5EE39, C6E100, O14000, O26687, O27428, O33925, O67298, O67411, O74634, P0DG48, P0DG49, P22438, P23395, P23920, P37465, P56127, P59078, P59079, P59081, P59952, P67578, P67579, P67580, P67581, P75091, P93736, P9WFU4, P9WFU5, Q1RJZ5, Q2FG72, Q2FXR8, Q2YTA0, Q465G4

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	2
Uncertain significance	190
Likely benign	52
Benign	6

Top pathogenic / likely-pathogenic (6)

Variant ID	HGVS	Classification
100659	NM_138395.4(MARS2):c.682_949del (p.Gly228fs)	Pathogenic
100661	MARS2, DUP2	Pathogenic
1032415	NM_138395.4(MARS2):c.1032_1033del (p.Cys344fs)	Pathogenic
193027	NM_138395.4(MARS2):c.550C>T (p.Gln184Ter)	Pathogenic
214632	NM_138395.4(MARS2):c.145A>G (p.Thr49Ala)	Likely pathogenic
3779834	NM_138395.4(MARS2):c.837G>A (p.Trp279Ter)	Likely pathogenic

SpliceAI

10 predictions. Top by Δscore:

Variant	Effect	Δscore
2:197706514:T:TA	acceptor_gain	0.5600
2:197706515:C:CA	acceptor_gain	0.3400
2:197706505:TG:T	acceptor_gain	0.3000
2:197706506:GG:G	acceptor_gain	0.3000
2:197706426:T:A	acceptor_gain	0.2900
2:197706530:TCG:T	acceptor_gain	0.2900
2:197706503:CGTGG:C	acceptor_gain	0.2700
2:197706511:G:A	acceptor_gain	0.2700
2:197706432:GTCT:G	acceptor_gain	0.2100
2:197706502:CCGTG:C	acceptor_gain	0.2000

AlphaMissense

3821 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:197706348:T:C	F315L	0.996
2:197706350:C:A	F315L	0.996
2:197706350:C:G	F315L	0.996
2:197706240:T:A	W279R	0.995
2:197706240:T:C	W279R	0.995
2:197705766:T:C	F121L	0.992
2:197705768:C:A	F121L	0.992
2:197705768:C:G	F121L	0.992
2:197706426:T:A	W341R	0.992
2:197706426:T:C	W341R	0.992
2:197705931:T:C	F176L	0.991
2:197705933:C:A	F176L	0.991
2:197705933:C:G	F176L	0.991
2:197706363:T:A	W320R	0.991
2:197706363:T:C	W320R	0.991
2:197706448:T:C	M348T	0.991
2:197705589:C:G	H62D	0.990
2:197706043:T:C	F213S	0.990
2:197706351:C:G	H316D	0.990
2:197706336:G:C	D311H	0.989
2:197706455:G:C	K350N	0.989
2:197706455:G:T	K350N	0.989
2:197705580:C:G	H59D	0.988
2:197706331:G:T	G309V	0.988
2:197706415:T:A	V337D	0.988
2:197705559:T:C	F52L	0.987
2:197705561:C:A	F52L	0.987
2:197705561:C:G	F52L	0.987
2:197705747:C:G	C114W	0.987
2:197706172:C:T	S256F	0.987

dbSNP variants (sampled 300 via entrez): RS1000093837 (2:197705104 G>A), RS1000464224 (2:197706588 C>G,T), RS1000550421 (2:197706629 C>T), RS1001889530 (2:197705841 G>A), RS1002228329 (2:197708485 C>T), RS1003356346 (2:197705189 G>A,T), RS1003623102 (2:197704506 A>G), RS1003819701 (2:197705037 A>G), RS1004023004 (2:197707712 C>T), RS1004055646 (2:197707475 A>G), RS1004943124 (2:197706759 G>A,T), RS1005062967 (2:197705642 A>G,T), RS1005616169 (2:197703819 T>G), RS1007577672 (2:197705350 G>A,C), RS1007673336 (2:197704747 CTT>C)

Disease associations

OMIM: gene MIM:609728 | disease phenotypes: MIM:611390, MIM:616430

GenCC curated gene-disease

Disease	Classification	Inheritance
mitochondrial disease	Strong	Autosomal recessive
spastic ataxia 3	Moderate	Autosomal recessive
combined oxidative phosphorylation defect type 25	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
mitochondrial disease	Definitive	AR

Mondo (3): spastic ataxia 3 (MONDO:0012664), combined oxidative phosphorylation defect type 25 (MONDO:0014636), mitochondrial disease (MONDO:0044970)

Orphanet (2): Autosomal recessive spastic ataxia with leukoencephalopathy (Orphanet:314603), Combined oxidative phosphorylation defect type 25 (Orphanet:447954)

HPO phenotypes

54 total (30 of 54 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000011	Neurogenic bladder
HP:0000012	Urinary urgency
HP:0000316	Hypertelorism
HP:0000319	Smooth philtrum
HP:0000343	Long philtrum
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000407	Sensorineural hearing impairment
HP:0000431	Wide nasal bridge
HP:0000463	Anteverted nares
HP:0000666	Horizontal nystagmus
HP:0000768	Pectus carinatum
HP:0001159	Syndactyly
HP:0001251	Ataxia
HP:0001256	Mild intellectual disability
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001272	Cerebellar atrophy
HP:0001290	Generalized hypotonia
HP:0001310	Dysmetria
HP:0001321	Cerebellar hypoplasia
HP:0001332	Dystonia
HP:0001347	Hyperreflexia
HP:0001508	Failure to thrive
HP:0002059	Cerebral atrophy
HP:0002066	Gait ataxia
HP:0002073	Progressive cerebellar ataxia
HP:0002119	Ventriculomegaly

GWAS associations

19 associations (top):

Study	Trait	p-value
GCST002539_41	Schizophrenia	2.000000e-11
GCST004132_35	Crohn’s disease	7.000000e-08
GCST004521_180	Autism spectrum disorder or schizophrenia	3.000000e-11
GCST004521_275	Autism spectrum disorder or schizophrenia	7.000000e-09
GCST005588_15	Idiopathic dilated cardiomyopathy	7.000000e-06
GCST006803_21	Schizophrenia	4.000000e-13
GCST007293_117	Body fat distribution (arm fat ratio)	1.000000e-06
GCST007293_18	Body fat distribution (arm fat ratio)	2.000000e-07
GCST007293_44	Body fat distribution (arm fat ratio)	8.000000e-11
GCST007294_108	Body fat distribution (trunk fat ratio)	4.000000e-06
GCST007294_27	Body fat distribution (trunk fat ratio)	3.000000e-09
GCST007565_194	Morning person	1.000000e-27
GCST010698_25	Subcortical volume (min-P)	2.000000e-08
GCST010699_24	Brain morphology (min-P)	1.000000e-09
GCST010700_25	Cortical thickness (MOSTest)	2.000000e-10
GCST010701_25	Cortical surface area (MOSTest)	2.000000e-37
GCST010702_65	Subcortical volume (MOSTest)	1.000000e-11
GCST010703_197	Brain morphology (MOSTest)	1.000000e-11
GCST011176_21	Stroke	8.000000e-07

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0009094	idiopathic dilated cardiomyopathy
EFO:0004341	body fat distribution
EFO:0008328	chronotype measurement
EFO:0004346	neuroimaging measurement
EFO:0004840	cortical thickness

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C566956	Ataxia, Spastic, 3, Autosomal Recessive (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4739700 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 194,583 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL130	CHLORAMPHENICOL	4	194,583

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

ChEMBL bioactivities

12 potent at pChembl≥5 of 12 total, top 12 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.41	EC50	39	nM	CHEMBL4757779
7.38	EC50	42	nM	CHEMBL4791458
7.12	EC50	75	nM	CHEMBL4762630
6.76	EC50	175	nM	CHEMBL4777699
6.71	EC50	195	nM	CHEMBL4761163
6.54	EC50	290	nM	CHEMBL4781504
6.50	EC50	316	nM	CHEMBL4795266
6.37	EC50	430	nM	CHEMBL4742903
6.32	EC50	478	nM	CHEMBL4745092
6.29	EC50	507	nM	CHEMBL4740481
5.76	EC50	1750	nM	CHEMBL4750041
5.10	EC50	7900	nM	CHLORAMPHENICOL

PubChem BioAssay actives

12 with measured affinity, of 12 total; 12 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
1-[(5-chloro-1H-imidazo[4,5-b]pyridin-2-yl)methyl]-4-[(2-chloro-4-methoxyphenyl)methyl]-3-ethylimidazol-2-one	1695256: Inhibition of mitochondrial MetRS-mediated mitochondrial protein synthesis in human HepG2 cells measured after 6 days by ELISA	ec50	0.0390	uM
1-[(5-chloro-1H-imidazo[4,5-b]pyridin-2-yl)methyl]-4-[(2,4-dichlorophenyl)methyl]-3-ethylimidazol-2-one	1695256: Inhibition of mitochondrial MetRS-mediated mitochondrial protein synthesis in human HepG2 cells measured after 6 days by ELISA	ec50	0.0420	uM
4-[(2-chloro-4-methoxyphenyl)methyl]-3-ethyl-1-[(5-fluoro-1H-imidazo[4,5-b]pyridin-2-yl)methyl]imidazol-2-one	1695256: Inhibition of mitochondrial MetRS-mediated mitochondrial protein synthesis in human HepG2 cells measured after 6 days by ELISA	ec50	0.0750	uM
4-[(2,4-dichlorophenyl)methyl]-3-(2,2-difluoroethyl)-1-[(5-fluoro-1H-imidazo[4,5-b]pyridin-2-yl)methyl]imidazol-2-one	1695256: Inhibition of mitochondrial MetRS-mediated mitochondrial protein synthesis in human HepG2 cells measured after 6 days by ELISA	ec50	0.1750	uM
4-[(2,4-dichlorophenyl)methyl]-1-[(5-fluoro-1H-imidazo[4,5-b]pyridin-2-yl)methyl]-3-propylimidazol-2-one	1695256: Inhibition of mitochondrial MetRS-mediated mitochondrial protein synthesis in human HepG2 cells measured after 6 days by ELISA	ec50	0.1950	uM
4-[(2,4-dichlorophenyl)methyl]-3-ethyl-1-[(5-fluoro-1H-imidazo[4,5-b]pyridin-2-yl)methyl]imidazol-2-one	1695256: Inhibition of mitochondrial MetRS-mediated mitochondrial protein synthesis in human HepG2 cells measured after 6 days by ELISA	ec50	0.2900	uM
2-[[5-(2-chloro-4,5-dimethoxyphenyl)imidazo[1,2-a]pyridin-2-yl]methyl]-5-fluoro-1H-imidazo[4,5-b]pyridine	1695256: Inhibition of mitochondrial MetRS-mediated mitochondrial protein synthesis in human HepG2 cells measured after 6 days by ELISA	ec50	0.3160	uM
1-[(5-chloro-1H-imidazo[4,5-b]pyridin-2-yl)methyl]-4-[(2,4-dichlorophenyl)methyl]-3-(2,2-difluoroethyl)imidazol-2-one	1695256: Inhibition of mitochondrial MetRS-mediated mitochondrial protein synthesis in human HepG2 cells measured after 6 days by ELISA	ec50	0.4300	uM
5-chloro-2-[[5-(2-chloro-4,5-dimethoxyphenyl)imidazo[1,2-a]pyridin-2-yl]methyl]-1H-imidazo[4,5-b]pyridine	1695256: Inhibition of mitochondrial MetRS-mediated mitochondrial protein synthesis in human HepG2 cells measured after 6 days by ELISA	ec50	0.4780	uM
5-chloro-2-[[5-(2,4-dichloro-5-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl]methyl]-1H-imidazo[4,5-b]pyridine	1695256: Inhibition of mitochondrial MetRS-mediated mitochondrial protein synthesis in human HepG2 cells measured after 6 days by ELISA	ec50	0.5070	uM
2-[[5-(2,4-dichloro-5-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl]methyl]-5-fluoro-1H-imidazo[4,5-b]pyridine	1695256: Inhibition of mitochondrial MetRS-mediated mitochondrial protein synthesis in human HepG2 cells measured after 6 days by ELISA	ec50	1.7500	uM
Chloramphenicol	1695256: Inhibition of mitochondrial MetRS-mediated mitochondrial protein synthesis in human HepG2 cells measured after 6 days by ELISA	ec50	7.9000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	3
Estradiol	increases expression	2
Formaldehyde	decreases expression	2
Tetrachlorodibenzodioxin	decreases expression	2
Valproic Acid	increases expression	2
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
dicrotophos	increases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
pirinixic acid	increases activity, increases expression, affects binding	1
sulindac sulfide	increases expression	1
cupric chloride	increases expression	1
di-n-butylphosphoric acid	affects expression	1
K 7174	decreases expression	1
Atrazine	decreases expression	1
Benzo(a)pyrene	decreases methylation	1
Cadmium	increases expression	1
Cisplatin	decreases expression	1
Dichlorodiphenyl Dichloroethylene	increases expression	1
Demecolcine	decreases expression	1
Ethyl Methanesulfonate	decreases expression	1
Hydrogen Peroxide	affects expression	1
Methyl Methanesulfonate	decreases expression	1
Oxygen	decreases expression	1
Plant Extracts	decreases expression	1
Quercetin	decreases expression	1
Ribonucleotides	affects binding	1
Silicon Dioxide	increases expression	1
Silver	decreases expression	1
Dronabinol	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4700078	ADMET	Inhibition of mitochondrial MetRS-mediated mitochondrial protein synthesis in human HepG2 cells measured after 6 days by ELISA	Structure-guided discovery of selective methionyl-tRNA synthetase inhibitors with potent activity against Trypanosoma brucei — RSC Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03351998	PHASE4	COMPLETED	Impact of Statin Therapy on Muscle Mitochondrial Function and Aerobic Capacity
NCT00432744	PHASE3	COMPLETED	Phase III Trial of Coenzyme Q10 in Mitochondrial Disease
NCT05162768	PHASE3	COMPLETED	Study to Evaluate Efficacy and Safety of Elamipretide in Subjects With Primary Mitochondrial Disease From Nuclear DNA Mutations (nPMD)
NCT06451757	PHASE3	RECRUITING	KHENERFIN Study: A Trial to Evaluate the Efficacy and Safety of Sonlicromanol in Primary Mitochondrial Diseases
NCT02398201	PHASE2	COMPLETED	A Study of Bezafibrate in Mitochondrial Myopathy
NCT02473445	PHASE2	TERMINATED	A Long-term Extension of Study RP103-MITO-001 (NCT02023866) to Assess Cysteamine Bitartrate Delayed-release Capsules (RP103) in Children With Inherited Mitochondrial Disease
NCT02500628	PHASE2	COMPLETED	Heart Rate Variability in Response to Metformin Challenge
NCT02805790	PHASE2	COMPLETED	Safety, Tolerability, Efficacy of MTP-131 for Treatment of Mitochondrial Disease in Subjects From the MMPOWER Study
NCT02909400	PHASE2	COMPLETED	The KHENERGY Study
NCT02976038	PHASE2	TERMINATED	Open-Label Extension Trial to Characterize the Long-term Safety and Tolerability of Elamipretide in Subjects With Genetically Confirmed Primary Mitochondrial Myopathy (PMM)
NCT03177798	PHASE2	COMPLETED	Mitochondria and Chronic Kidney Disease
NCT03866954	PHASE2	WITHDRAWN	Trial of Erythrocyte Encapsulated Thymidine Phosphorylase In Mitochondrial Neurogastrointestinal Encephalomyopathy
NCT04165239	PHASE2	COMPLETED	The KHENERGYZE Study
NCT04604548	PHASE2	COMPLETED	The KHENEREXT Study
NCT04802707	PHASE2	RECRUITING	Deoxynucleosides Pyrimidines as Treatment for Mitochondrial Depletion Syndrome
NCT04846036	PHASE2	SUSPENDED	The KHENERGYC Study
NCT05650229	PHASE2	RECRUITING	Efficacy of KL1333 in Adult Patients With Primary Mitochondrial Disease
NCT05972954	PHASE2	COMPLETED	OMT-28 in Patients With Primary Mitochondrial Disease (PMD) (PMD-OPTION)
NCT06017869	PHASE2	RECRUITING	Evaluate the Safety and Therapeutic Effects of a Single Intravenous Infusion (IV) of Autologous CD34+ Cells Enriched With Allogenic Placenta-derived Mitochondria in Patients With a Diagnosis of Pearson Syndrome (PS)
NCT07514338	PHASE2	NOT_YET_RECRUITING	Open Label Extension to Assess Long Term Safety and Efficacy of KL1333 in Patients With Primary Mitochondrial Disease
NCT00060515	PHASE1	TERMINATED	RG2133 (2’,3’,5’-Tri-O-Acetyluridine) in Mitochondrial Disease
NCT02348125	PHASE1	UNKNOWN	Does Clinical Treatment of Mitochondrial Dysfunction Impact Autism Spectrum Disorder (ASD)?
NCT02544217	PHASE1	COMPLETED	A Dose-escalating Clinical Trial With KH176
NCT03888716	PHASE1	COMPLETED	A Phase Ia/Ib, SAD and MAD Study of of KL1333 in Healthy Subjects and Patients With Primary Mitochondrial Disease
NCT04086329	PHASE1	RECRUITING	Validation of Oxygen Nanosensor in Mitochondrial Myopathy
NCT04643249	PHASE1	COMPLETED	Drug-drug Interaction Study of KL1333 in Healthy Subjects
NCT05241262	PHASE1	RECRUITING	Study of N-acetylcysteine in the Treatment of Patients With the m.3243A>G Mutation and Low Brain Glutathione Levels
NCT05569122	PHASE1	RECRUITING	Applying pGz in Mitochondrial Disease
NCT06819683	PHASE1	RECRUITING	Validation of Nanosensor Oxygen Measurement
NCT07258667	PHASE1	NOT_YET_RECRUITING	Pilot Study of the Efficacy of Nicotinamide (Vitamin B3) in Leber’s Hereditary Optic Neuropathy
NCT04378075	PHASE2/PHASE3	TERMINATED	A Study to Evaluate Efficacy and Safety of Vatiquinone for Treating Mitochondrial Disease in Participants With Refractory Epilepsy
NCT01642056	PHASE1/PHASE2	COMPLETED	EPI-743 for Metabolism or Mitochondrial Disorders
NCT03384420	PHASE1/PHASE2	COMPLETED	A Study to Evaluate the Safety and Therapeutic Effects of Transplantation of MNV-BM-BLD in Pediatric Patients With Pearson Syndrome
NCT06051448	PHASE1/PHASE2	COMPLETED	Promoting Resilience in Stress Management (PRISM) and Clinical-focused Narrative (CFN) Pilot in Adults With Primary Mitochondrial Disease (PMD).
NCT01252979	EARLY_PHASE1	COMPLETED	Ketones & Mitochondrial Heteroplasmy
NCT00786539	Not specified	COMPLETED	Mitochondria Inborn Errors of Metabolism and ANT Defects in Mitochondria Diseases
NCT00829270	Not specified	COMPLETED	Economic and Medical Evaluation of the Whole Mitochondrial DNA Screening by Surveyor and Mitochips Techniques
NCT00831948	Not specified	UNKNOWN	Identification of Large-Scale Mutations of POLG Gene by QMPSF in Patients With Mitochondrial DNA Instability.
NCT01001585	Not specified	TERMINATED	Anesthetic Effects in Mitochondrial Disease
NCT01148550	Not specified	SUSPENDED	Longitudinal Study of Mitochondrial Hepatopathies