EARS2

Summary

EARS2 (glutamyl-tRNA synthetase 2, mitochondrial, HGNC:29419) is a protein-coding gene on chromosome 16p12.2, encoding Nondiscriminating glutamyl-tRNA synthetase EARS2, mitochondrial (Q5JPH6). Non-discriminating glutamyl-tRNA synthetase that catalyzes aminoacylation of both mitochondrial tRNA(Glu) and tRNA(Gln) and participates in RNA aminoacylation for mitochondrial protein translation. It is a selective cancer dependency (DepMap: 54.1% of cell lines).

This gene encodes a member of the class I family of aminoacyl-tRNA synthetases. These enzymes play a critical role in protein biosynthesis by charging tRNAs with their cognate amino acids. This protein is encoded by the nuclear genome but is likely to be imported to the mitochondrion where it is thought to catalyze the ligation of glutamate to tRNA molecules. Mutations in this gene have been associated with combined oxidative phosphorylation deficiency 12 (COXPD12). Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 124454 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Leigh syndrome (Definitive, ClinGen) — +2 more curated relationships
• Clinical variants (ClinVar): 389 total — 18 pathogenic, 15 likely-pathogenic
• Phenotypes (HPO): 37
• Cancer dependency (DepMap): dependent in 54.1% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_001083614

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29419
Approved symbol	EARS2
Name	glutamyl-tRNA synthetase 2, mitochondrial
Location	16p12.2
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1970, MSE1, mtGlnRS
Ensembl gene	ENSG00000103356
Ensembl biotype	protein_coding
OMIM	612799
Entrez	124454

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 6 protein_coding_CDS_not_defined, 5 nonsense_mediated_decay, 3 protein_coding, 3 retained_intron

ENST00000449606, ENST00000561859, ENST00000562402, ENST00000562581, ENST00000562799, ENST00000563232, ENST00000563499, ENST00000564461, ENST00000564501, ENST00000564668, ENST00000564759, ENST00000564776, ENST00000564987, ENST00000564997, ENST00000565344, ENST00000566017, ENST00000674054

RefSeq mRNA: 2 — MANE Select: NM_001083614 NM_001083614, NM_001308211

CCDS: CCDS42132, CCDS76844

Canonical transcript exons

ENST00000449606 — 9 exons

Exon	Start	End
ENSE00000677053	23529744	23529897
ENSE00001669479	23520754	23524454
ENSE00003460065	23525244	23525379
ENSE00003464150	23534888	23535360
ENSE00003467841	23532657	23532765
ENSE00003478506	23544514	23544703
ENSE00003487988	23552149	23552304
ENSE00003649365	23529502	23529632
ENSE00003901776	23557205	23557350

Expression profiles

Bgee: expression breadth ubiquitous, 229 present calls, max score 93.57.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 18.8387 / max 94.6110, expressed in 1794 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
156778	18.8387	1794

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
adrenal tissue	UBERON:0018303	93.57	gold quality
right lobe of liver	UBERON:0001114	89.75	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	89.47	gold quality
right adrenal gland	UBERON:0001233	89.35	gold quality
right adrenal gland cortex	UBERON:0035827	89.34	gold quality
left adrenal gland	UBERON:0001234	88.77	gold quality
apex of heart	UBERON:0002098	88.45	gold quality
adrenal gland	UBERON:0002369	88.18	gold quality
left adrenal gland cortex	UBERON:0035825	88.14	gold quality
heart left ventricle	UBERON:0002084	87.43	gold quality
rectum	UBERON:0001052	87.38	gold quality
gastrocnemius	UBERON:0001388	87.34	gold quality
adrenal cortex	UBERON:0001235	87.23	gold quality
muscle of leg	UBERON:0001383	87.06	gold quality
cardiac ventricle	UBERON:0002082	87.04	gold quality
mucosa of transverse colon	UBERON:0004991	86.82	gold quality
right atrium auricular region	UBERON:0006631	86.42	gold quality
cortical plate	UBERON:0005343	85.90	gold quality
islet of Langerhans	UBERON:0000006	85.84	gold quality
stromal cell of endometrium	CL:0002255	85.80	gold quality
heart	UBERON:0000948	85.58	gold quality
cardiac atrium	UBERON:0002081	85.49	gold quality
smooth muscle tissue	UBERON:0001135	85.28	gold quality
hindlimb stylopod muscle	UBERON:0004252	85.19	gold quality
skin of leg	UBERON:0001511	85.14	gold quality
liver	UBERON:0002107	85.11	gold quality
right lobe of thyroid gland	UBERON:0001119	84.90	gold quality
adult mammalian kidney	UBERON:0000082	84.79	gold quality
pancreas	UBERON:0001264	84.68	gold quality
body of pancreas	UBERON:0001150	84.55	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.16

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): QRICH1, STAT1

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 54.1% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 5)

• Studies showed in vitro Gln-tRNA(Gln) formation catalyzed by the recombinant mtGluRS and hGatCAB. (PMID:19805282)
• Strong candidate gene for mitochondrial disease, based on recessive mutations detected in infantile patients (PMID:22277967)
• This study presented that a new neurological disease, early-onset leukoencephalopathy with thalamus and brainstem involvement and high lactate, defined by a peculiar biphasic clinical course and caused by mutations in a single gene, EARS2. (PMID:22492562)
• EARS2 significantly coexpresses with PALB2 in breast and pancreatic cancer. (PMID:35779338)
• Phenotyping mitochondrial glutamyl-tRNA synthetase deficiency (EARS2): A case series and systematic literature review. (PMID:39173847)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ears2	ENSDARG00000103099
mus_musculus	Ears2	ENSMUSG00000030871
rattus_norvegicus	Ears2l1	ENSRNOG00000067512
drosophila_melanogaster	GluRS-m	FBGN0036629
caenorhabditis_elegans		WBGENE00001338

Paralogs (2): EPRS1 (ENSG00000136628), QARS1 (ENSG00000172053)

Protein

Protein identifiers

Nondiscriminating glutamyl-tRNA synthetase EARS2, mitochondrial — Q5JPH6 (reviewed: Q5JPH6)

Alternative names: Glutamate–tRNA(Gln) ligase EARS2, mitochondrial, Glutamyl-tRNA synthetase, Mitochondrial glutamyl-tRNA synthetase

All UniProt accessions (6): Q5JPH6, H3BPY3, H3BQI0, H3BQP8, H3BTB7, I3L166

UniProt curated annotations — full annotation on UniProt →

Function. Non-discriminating glutamyl-tRNA synthetase that catalyzes aminoacylation of both mitochondrial tRNA(Glu) and tRNA(Gln) and participates in RNA aminoacylation for mitochondrial protein translation. Attachs glutamate to tRNA(Glu) or tRNA(Gln) in a two-step reaction: glutamate is first activated by ATP to form Glu-AMP and then transferred to the acceptor end of tRNA(Glu) or tRNA(Gln). In vitro, cytoplasmic tRNA(Gln) is slightly glutamylated, but with low activity.

Subcellular location. Mitochondrion matrix.

Disease relevance. Combined oxidative phosphorylation deficiency 12 (COXPD12) [MIM:614924] An autosomal recessive, mitochondrial, neurologic disorder characterized by onset in infancy of hypotonia and delayed psychomotor development, or early developmental regression, associated with T2-weighted hyperintensities in the deep cerebral white matter, brainstem, and cerebellar white matter. Serum lactate is increased due to a defect in mitochondrial respiration. There are 2 main phenotypic groups: those with a milder disease course and some recovery of skills after age 2 years, and those with a severe disease course resulting in marked disability. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the class-I aminoacyl-tRNA synthetase family. Glutamate–tRNA ligase type 1 subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q5JPH6-1	1	yes
Q5JPH6-2	2

RefSeq proteins (2): NP_001077083, NP_001295140 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000924	Glu/Gln-tRNA-synth	Family
IPR001412	aa-tRNA-synth_I_CS	Conserved_site
IPR004527	Glu-tRNA-ligase_bac/mito	Family
IPR008925	aa_tRNA-synth_I_cd-bd_sf	Homologous_superfamily
IPR014729	Rossmann-like_a/b/a_fold	Homologous_superfamily
IPR020058	Glu/Gln-tRNA-synth_Ib_cat-dom	Domain
IPR020751	aa-tRNA-synth_I_codon-bd_sub2	Homologous_superfamily
IPR033910	GluRS_core	Domain
IPR045462	aa-tRNA-synth_I_cd-bd	Domain
IPR049940	GluQ/Sye	Family

Pfam: PF00749, PF19269

Catalyzed reactions (Rhea), 3 shown:

• tRNA(Glx) + L-glutamate + ATP = L-glutamyl-tRNA(Glx) + AMP + diphosphate (RHEA:18397)
• tRNA(Glu) + L-glutamate + ATP = L-glutamyl-tRNA(Glu) + AMP + diphosphate (RHEA:23540)
• tRNA(Gln) + L-glutamate + ATP = L-glutamyl-tRNA(Gln) + AMP + diphosphate (RHEA:64612)

UniProt features (30 total): sequence variant 16, binding site 7, modified residue 2, short sequence motif 2, transit peptide 1, chain 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5JPH6-F1	89.84	0.79

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 (7): 284–288; 40–42; 50; 76; 228–232; 246; 249

Post-translational modifications (2): 256, 486

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: 217 (showing top): GOBP_AMINO_ACID_ACTIVATION, MODULE_255, GOBP_TRNA_METABOLIC_PROCESS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_MITOCHONDRIAL_TRANSLATION, MODULE_317, MODULE_128, GOBP_TRANSLATION, GOBP_MITOCHONDRIAL_RNA_METABOLIC_PROCESS, DODD_NASOPHARYNGEAL_CARCINOMA_UP, KEGG_AMINOACYL_TRNA_BIOSYNTHESIS, REACTOME_MITOCHONDRIAL_TRNA_AMINOACYLATION, chr16p12, GOCC_MITOCHONDRIAL_MATRIX

GO Biological Process (5): glutamyl-tRNA aminoacylation (GO:0006424), tRNA aminoacylation for mitochondrial protein translation (GO:0070127), translation (GO:0006412), tRNA aminoacylation for protein translation (GO:0006418), tRNA aminoacylation (GO:0043039)

GO Molecular Function (9): tRNA binding (GO:0000049), glutamate-tRNA ligase activity (GO:0004818), ATP binding (GO:0005524), zinc ion binding (GO:0008270), glutamate-tRNA(Gln) ligase activity (GO:0050561), nucleotide binding (GO:0000166), RNA binding (GO:0003723), 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
tRNA aminoacylation for protein translation	2
aminoacyl-tRNA ligase activity	2
mitochondrial RNA metabolic process	1
mitochondrial 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
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
transition metal ion 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
catalytic activity	1
cytoplasm	1
intracellular membrane-bounded organelle	1
mitochondrion	1
intracellular organelle lumen	1

Protein interactions and networks

STRING

3488 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EARS2	MARS2	Q96GW9	962
EARS2	MARS1	P56192	953
EARS2	PARS2	Q7L3T8	881
EARS2	LARS2	Q15031	880
EARS2	LARS1	Q9P2J5	867
EARS2	NARS2	Q96I59	863
EARS2	RARS2	Q5T160	860
EARS2	AARS1	P49588	858
EARS2	YARS2	Q9Y2Z4	846
EARS2	NARS1	O43776	844
EARS2	VARS2	Q5ST30	842
EARS2	IARS2	Q9NSE4	839
EARS2	DARS2	Q6PI48	838
EARS2	KARS1	Q15046	816
EARS2	VARS1	P26640	815

IntAct

69 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
MAS1	POTEF	psi-mi:“MI:0914”(association)	0.530
TNFSF8	LGALS8	psi-mi:“MI:0914”(association)	0.530
UQCRFS1	NDUFAB1	psi-mi:“MI:0914”(association)	0.530
NPTN	TNPO2	psi-mi:“MI:0914”(association)	0.530
BSG	BTAF1	psi-mi:“MI:0914”(association)	0.530
LPAR1	TMEM223	psi-mi:“MI:0914”(association)	0.530
EARS2	CTAG1A	psi-mi:“MI:0915”(physical association)	0.400
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350
LRRK2		psi-mi:“MI:0914”(association)	0.350
BSG	METTL15	psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
HTRA2	VWA8	psi-mi:“MI:0914”(association)	0.350
IMMP1L	EIF1AY	psi-mi:“MI:0914”(association)	0.350
IMMP2L	ANKHD1-EIF4EBP3	psi-mi:“MI:0914”(association)	0.350
ITM2B	ILVBL	psi-mi:“MI:0914”(association)	0.350
SMIM26	METTL15	psi-mi:“MI:0914”(association)	0.350
ATG16L1	ESYT2	psi-mi:“MI:0914”(association)	0.350
ATG16L1		psi-mi:“MI:0914”(association)	0.350
HCST	TMEM120B	psi-mi:“MI:0914”(association)	0.350
P2RY10	POTEF	psi-mi:“MI:0914”(association)	0.350
NPTN	RTL8C	psi-mi:“MI:0914”(association)	0.350
GPR182	SLC12A8	psi-mi:“MI:0914”(association)	0.350
TRIM43	VWA8	psi-mi:“MI:0914”(association)	0.350
YARS2	VWA8	psi-mi:“MI:0914”(association)	0.350
AMACR	VWA8	psi-mi:“MI:0914”(association)	0.350
ACSM5	VWA8	psi-mi:“MI:0914”(association)	0.350

BioGRID (110): EARS2 (Affinity Capture-MS), EARS2 (Affinity Capture-MS), EARS2 (Affinity Capture-MS), EARS2 (Affinity Capture-MS), EARS2 (Affinity Capture-MS), EARS2 (Affinity Capture-MS), EARS2 (Affinity Capture-MS), EARS2 (Affinity Capture-MS), EARS2 (Proximity Label-MS), EARS2 (Proximity Label-MS), EARS2 (Proximity Label-MS), EARS2 (Proximity Label-MS), EARS2 (Proximity Label-MS), EARS2 (Proximity Label-MS), EARS2 (Proximity Label-MS)

ESM2 similar proteins: A2C764, A2C7H0, A5GMU7, A5W968, A7MGQ9, A8GIZ1, A9N925, B0KHV8, B4RJ69, B5BL68, B5EL11, B6J4I8, Q0I858, Q0P499, Q1IZL1, Q1LK68, Q3AHV1, Q3J8Y8, Q4K5Z0, Q57T70, Q5F6E8, Q5JPH6, Q5N4F9, Q5PAG8, Q5PD33, Q5QVQ6, Q5ZJ66, Q60BF9, Q66JG3, Q6A7Y1, Q6NJY9, Q7N866, Q7TUT1, Q7TUT7, Q7U8M8, Q7UHE2, Q7W2N4, Q83BL6, Q83GH3, Q83GP4

Diamond homologs: A0AF36, A0M6K0, A0PZ93, A1BDK8, A4IJG6, A4SGA5, A4XHE0, A5FL73, A5FPX2, A5G3W1, A5I0T6, A5N867, A6H2H7, A6L0E8, A6LEA1, A6TWK7, A7FSY9, A7GCD9, A7Z0L4, A7ZFB9, A8F960, A8MLB5, A9KRX7, B0B818, B0BC83, B0K403, B0KAA6, B0S0W2, B1HNM5, B1IIG7, B1KYV1, B2A4B3, B2KAV3, B2RI67, B2S076, B2TND7, B2V5H4, B2V5J1, B3EFG9, B3EMG1

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
QRICH1	“up-regulates quantity by expression”	EARS2	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	18
Likely pathogenic	15
Uncertain significance	185
Likely benign	91
Benign	33

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1454232	NM_001083614.2(EARS2):c.1240C>T (p.Gln414Ter)	Pathogenic
1705024	NM_001083614.2(EARS2):c.376C>T (p.Gln126Ter)	Pathogenic
2002675	NM_001083614.2(EARS2):c.197del (p.Lys66fs)	Pathogenic
2052934	NM_001083614.2(EARS2):c.1270_1277del (p.Leu424fs)	Pathogenic
2137797	NM_001083614.2(EARS2):c.1413del (p.Lys471fs)	Pathogenic
2423669	NC_000016.9:g.(?23555815)(23556044_?)del	Pathogenic
2423670	NC_000016.9:g.(?23543958)(23619353_?)del	Pathogenic
2988193	NM_001083614.2(EARS2):c.1159C>T (p.Gln387Ter)	Pathogenic
318550	NM_001083614.2(EARS2):c.949G>T (p.Gly317Cys)	Pathogenic
3243603	NC_000016.9:g.(?23535692)(23546701_?)del	Pathogenic
3339818	NM_001083614.2(EARS2):c.428C>G (p.Ser143Ter)	Pathogenic
3385233	NM_001083614.2:c.(?_-8)_65del	Pathogenic
39791	NM_001083614.2(EARS2):c.286G>A (p.Glu96Lys)	Pathogenic
39793	NM_001083614.2(EARS2):c.193A>G (p.Lys65Glu)	Pathogenic
4804720	NM_001083614.2(EARS2):c.744dup (p.Glu249Ter)	Pathogenic
488831	NM_001083614.2(EARS2):c.1194C>G (p.Tyr398Ter)	Pathogenic
803228	NM_001083614.2(EARS2):c.684C>A (p.Tyr228Ter)	Pathogenic
973189	NM_001083614.2(EARS2):c.1283del (p.Pro428fs)	Pathogenic
2083151	NM_001083614.2(EARS2):c.920T>C (p.Leu307Ser)	Likely pathogenic
2440017	NM_001083614.2(EARS2):c.451A>T (p.Lys151Ter)	Likely pathogenic
2444670	NM_001083614.2(EARS2):c.202C>T (p.Gln68Ter)	Likely pathogenic
2584491	NM_001083614.2(EARS2):c.349C>T (p.Gln117Ter)	Likely pathogenic
2627742	NM_001083614.2(EARS2):c.947C>G (p.Ser316Ter)	Likely pathogenic
3340707	NM_001083614.2(EARS2):c.295+2T>C	Likely pathogenic
3381145	NM_001083614.2(EARS2):c.958+1G>A	Likely pathogenic
3731523	NM_001083614.2(EARS2):c.719del (p.Gly240fs)	Likely pathogenic
392792	NM_001083614.2(EARS2):c.700G>C (p.Val234Leu)	Likely pathogenic
426388	NM_001083614.2(EARS2):c.949G>A (p.Gly317Ser)	Likely pathogenic
440959	NM_001083614.2(EARS2):c.334G>C (p.Ala112Pro)	Likely pathogenic
452150	NM_001083614.2(EARS2):c.293C>T (p.Ala98Val)	Likely pathogenic

SpliceAI

1777 predictions. Top by Δscore:

Variant	Effect	Δscore
16:23529496:ACTC:A	donor_loss	1.0000
16:23529497:CTC:C	donor_loss	1.0000
16:23529498:TCA:T	donor_loss	1.0000
16:23529499:CA:C	donor_loss	1.0000
16:23529500:A:AC	donor_gain	1.0000
16:23529500:A:AT	donor_loss	1.0000
16:23529500:AC:A	donor_gain	1.0000
16:23529500:ACC:A	donor_gain	1.0000
16:23529501:C:CC	donor_gain	1.0000
16:23529501:CC:C	donor_gain	1.0000
16:23529501:CCC:C	donor_gain	1.0000
16:23529631:CC:C	acceptor_gain	1.0000
16:23529632:CC:C	acceptor_gain	1.0000
16:23529743:CCTGT:C	donor_gain	1.0000
16:23529791:C:A	donor_gain	1.0000
16:23529893:GCAGT:G	acceptor_gain	1.0000
16:23529894:CAGT:C	acceptor_gain	1.0000
16:23529894:CAGTC:C	acceptor_gain	1.0000
16:23529895:AGT:A	acceptor_gain	1.0000
16:23529896:GT:G	acceptor_gain	1.0000
16:23529898:C:CC	acceptor_gain	1.0000
16:23529898:C:T	acceptor_loss	1.0000
16:23529899:T:G	acceptor_loss	1.0000
16:23532653:TCAC:T	donor_loss	1.0000
16:23532654:CAC:C	donor_loss	1.0000
16:23532655:A:AC	donor_gain	1.0000
16:23532655:A:AT	donor_loss	1.0000
16:23532655:AC:A	donor_gain	1.0000
16:23532656:C:A	donor_loss	1.0000
16:23532656:C:CC	donor_gain	1.0000

AlphaMissense

3381 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:23534985:C:A	K287N	0.998
16:23534985:C:G	K287N	0.998
16:23535139:T:A	D236V	0.998
16:23535098:A:G	W250R	0.997
16:23535098:A:T	W250R	0.997
16:23535140:C:G	D236H	0.997
16:23535143:C:G	D235H	0.997
16:23552296:G:C	H50D	0.997
16:23557212:G:C	S44R	0.997
16:23557212:G:T	S44R	0.997
16:23557214:T:G	S44R	0.997
16:23535139:T:G	D236A	0.996
16:23535142:T:A	D235V	0.996
16:23552223:C:A	R74M	0.996
16:23552223:C:G	R74T	0.996
16:23535029:G:C	H273D	0.995
16:23535143:C:A	D235Y	0.995
16:23557221:G:C	F41L	0.995
16:23557221:G:T	F41L	0.995
16:23557223:A:G	F41L	0.995
16:23535248:C:G	D200H	0.994
16:23552217:T:A	E76V	0.994
16:23552222:C:A	R74S	0.994
16:23552222:C:G	R74S	0.994
16:23552274:G:T	A57D	0.994
16:23557213:C:T	S44N	0.994
16:23529581:A:G	W425R	0.993
16:23529581:A:T	W425R	0.993
16:23532722:G:C	F334L	0.993
16:23532722:G:T	F334L	0.993

dbSNP variants (sampled 300 via entrez): RS1000019930 (16:23539707 T>C), RS1000104015 (16:23534389 G>A), RS1000149431 (16:23533867 A>G,T), RS1000162112 (16:23528202 T>C,G), RS1000236025 (16:23528562 T>C), RS1000267066 (16:23529434 A>G), RS1000284579 (16:23527304 C>T), RS1000432766 (16:23550539 G>A), RS1000650268 (16:23550125 C>A,T), RS1000684659 (16:23522399 C>T), RS1000717617 (16:23522313 G>A), RS1000851440 (16:23535332 G>C), RS1000902173 (16:23538600 T>C), RS1001237659 (16:23545458 G>C), RS1001238759 (16:23545122 G>A,T)

Disease associations

OMIM: gene MIM:612799 | disease phenotypes: MIM:614924, MIM:617468, MIM:208150

GenCC curated gene-disease

Disease	Classification	Inheritance
leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome	Strong	Autosomal recessive
Leigh syndrome	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
Leigh syndrome	Definitive	AR
mitochondrial disease	Definitive	AR

Mondo (5): leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome (MONDO:0013971), mitochondrial disease (MONDO:0044970), arthrogryposis multiplex congenita (MONDO:0015168), fetal akinesia deformation sequence 1 (MONDO:0100101), Leigh syndrome (MONDO:0009723)

Orphanet (4): Leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome (Orphanet:314051), Mitochondrial disease (Orphanet:68380), Arthrogryposis multiplex congenita (Orphanet:1037), Fetal akinesia deformation sequence (Orphanet:994)

HPO phenotypes

37 total (30 of 37 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000175	Cleft palate
HP:0000505	Visual impairment
HP:0000508	Ptosis
HP:0000602	Ophthalmoplegia
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001274	Agenesis of corpus callosum
HP:0001285	Spastic tetraparesis
HP:0001319	Neonatal hypotonia
HP:0001332	Dystonia
HP:0001344	Absent speech
HP:0001396	Cholestasis
HP:0001403	Macrovesicular hepatic steatosis
HP:0001508	Failure to thrive
HP:0002067	Bradykinesia
HP:0002079	Hypoplasia of the corpus callosum
HP:0002151	Increased circulating lactate concentration
HP:0002188	Delayed CNS myelination
HP:0002240	Hepatomegaly
HP:0002352	Leukoencephalopathy
HP:0002376	Developmental regression
HP:0002421	Poor head control
HP:0003128	Lactic acidosis
HP:0003200	Ragged-red muscle fibers
HP:0003487	Babinski sign
HP:0003593	Infantile onset
HP:0006254	Elevated circulating alpha-fetoprotein concentration
HP:0006989	Dysplastic corpus callosum

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D007888	Leigh Disease	C10.228.140.163.100.412; C16.320.565.189.412; C16.320.565.202.810.444; C18.452.132.100.412; C18.452.648.189.412; C18.452.648.202.810.444; C18.452.660.520

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
methacrylaldehyde	affects cotreatment, decreases expression, increases oxidation, increases abundance	2
entinostat	increases expression, affects cotreatment	2
Acetaminophen	decreases expression	2
Acrolein	affects cotreatment, decreases expression, increases oxidation, increases abundance	2
Ozone	affects cotreatment, decreases expression, increases oxidation, increases abundance	2
Valproic Acid	increases expression, increases methylation	2
Cyclosporine	decreases expression, increases expression	2
aristolochic acid I	decreases expression, increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, decreases expression, increases oxidation, increases abundance	1
bisphenol A	affects cotreatment, increases methylation	1
sodium arsenite	decreases expression	1
aflatoxin B2	decreases methylation	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
ICG 001	decreases expression	1
bisphenol B	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
bisphenol S	increases expression	1
NSC 689534	affects binding, decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Air Pollutants	increases oxidation, affects cotreatment, decreases expression, increases abundance	1
Arsenic	affects methylation	1
Cadmium	increases abundance, increases expression	1
Cisplatin	decreases expression	1
Copper	affects binding, decreases expression	1
Dichlorodiphenyl Dichloroethylene	increases expression	1
Ivermectin	decreases expression	1
Smoke	decreases expression	1
Theophylline	increases expression	1
Thiram	decreases expression	1

Clinical trials (associated diseases)

112 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
NCT01721733	PHASE2	COMPLETED	Safety and Efficacy Study of EPI-743 in Children With Leigh Syndrome
NCT02352896	PHASE2	COMPLETED	Long-Term Safety and Efficacy Evaluation of EPI-743 in Children With Leigh Syndrome
NCT03747328	PHASE2	WITHDRAWN	ABI-009 (Nab-sirolimus) in Patients With Genetically-confirmed Leigh or Leigh-like Syndrome
NCT06843811	PHASE2	ENROLLING_BY_INVITATION	Sirolimus for Leigh Syndrome
NCT06990984	PHASE2	NOT_YET_RECRUITING	A Dose-ranging Study of TTI-0102 in Adults and Children With Leigh Syndrome Spectrum (LSS)
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
NCT02544217	PHASE1	COMPLETED	A Dose-escalating Clinical Trial With KH176
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)?
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
NCT01780168	Not specified	RECRUITING	The NIH MINI Study: Metabolism, Infection, and Immunity in Inborn Errors of Metabolism
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT01803906	Not specified	ENROLLING_BY_INVITATION	Tissue Sample Study for Mitochondrial Disorders
NCT03137355	Not specified	RECRUITING	The International Registry for Leigh Syndrome