WARS2

Summary

WARS2 (tryptophanyl tRNA synthetase 2, mitochondrial, HGNC:12730) is a protein-coding gene on chromosome 1p12, encoding Tryptophan–tRNA ligase, mitochondrial (Q9UGM6). Catalyzes the attachment of tryptophan to tRNA(Trp) in a two-step reaction: tryptophan is first activated by ATP to form Trp-AMP and then transferred to the acceptor end of tRNA(Trp). It is a selective cancer dependency (DepMap: 32.2% of 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. Two forms of tryptophanyl-tRNA synthetase exist, a cytoplasmic form, named WARS, and a mitochondrial form, named WARS2. This gene encodes the mitochondrial tryptophanyl-tRNA synthetase. Two alternative transcripts encoding different isoforms have been described.

Source: NCBI Gene 10352 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 115
• Clinical variants (ClinVar): 155 total — 7 pathogenic, 8 likely-pathogenic
• Phenotypes (HPO): 101
• Cancer dependency (DepMap): dependent in 32.2% of screened cell lines
• MANE Select transcript: NM_015836

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12730
Approved symbol	WARS2
Name	tryptophanyl tRNA synthetase 2, mitochondrial
Location	1p12
Locus type	gene with protein product
Status	Approved
Aliases	mtTrpRS
Ensembl gene	ENSG00000116874
Ensembl biotype	protein_coding
OMIM	604733
Entrez	10352

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 7 protein_coding, 3 protein_coding_CDS_not_defined

ENST00000235521, ENST00000369426, ENST00000495746, ENST00000497402, ENST00000497761, ENST00000900322, ENST00000900323, ENST00000900324, ENST00000900325, ENST00000928547

RefSeq mRNA: 8 — MANE Select: NM_015836 NM_001378226, NM_001378227, NM_001378228, NM_001378229, NM_001378230, NM_001378231, NM_015836, NM_201263

CCDS: CCDS30817, CCDS900

Canonical transcript exons

ENST00000235521 — 6 exons

Exon	Start	End
ENSE00001122425	119031216	119033359
ENSE00001450011	119140555	119140653
ENSE00003499212	119076350	119076607
ENSE00003532781	119034095	119034213
ENSE00003564282	119045582	119045662
ENSE00003572376	119042264	119042349

Expression profiles

Bgee: expression breadth ubiquitous, 226 present calls, max score 88.52.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 16.0358 / max 136.4492, expressed in 1797 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
14067	16.0282	1797
14060	0.0077	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.52	gold quality
bronchial epithelial cell	CL:0002328	84.52	gold quality
calcaneal tendon	UBERON:0003701	84.14	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.00	gold quality
adrenal tissue	UBERON:0018303	82.69	gold quality
parietal pleura	UBERON:0002400	82.66	gold quality
right adrenal gland cortex	UBERON:0035827	82.28	gold quality
right adrenal gland	UBERON:0001233	81.93	gold quality
tibia	UBERON:0000979	81.72	gold quality
left adrenal gland	UBERON:0001234	81.64	gold quality
body of pancreas	UBERON:0001150	81.03	gold quality
left adrenal gland cortex	UBERON:0035825	80.96	gold quality
tendon	UBERON:0000043	80.77	gold quality
adrenal gland	UBERON:0002369	80.67	gold quality
rectum	UBERON:0001052	80.61	gold quality
islet of Langerhans	UBERON:0000006	80.32	gold quality
pleura	UBERON:0000977	80.30	gold quality
ventricular zone	UBERON:0003053	80.14	gold quality
pancreas	UBERON:0001264	79.92	gold quality
stromal cell of endometrium	CL:0002255	79.90	gold quality
popliteal artery	UBERON:0002250	79.90	gold quality
tibial artery	UBERON:0007610	79.90	gold quality
colonic epithelium	UBERON:0000397	79.86	gold quality
adrenal cortex	UBERON:0001235	79.85	gold quality
ganglionic eminence	UBERON:0004023	79.61	gold quality
muscle of leg	UBERON:0001383	78.92	gold quality
left ovary	UBERON:0002119	78.86	gold quality
hindlimb stylopod muscle	UBERON:0004252	78.61	gold quality
gastrocnemius	UBERON:0001388	78.60	gold quality
mucosa of transverse colon	UBERON:0004991	78.57	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.66
E-GEOD-100618	no	443.81

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ATF4, CREB1, NCOR1, QRICH1

miRNA regulators (miRDB)

84 targeting WARS2, 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-4500	99.99	72.72	2367
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-548AN	99.97	70.91	2817
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-3658	99.96	73.87	4379
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-22-3P	99.93	68.13	917
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-7162-3P	99.89	68.16	1682
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-6857-5P	99.87	65.32	985
HSA-MIR-137-3P	99.87	74.74	2401
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-544A	99.84	68.66	1965
HSA-MIR-7157-5P	99.66	69.33	1829
HSA-MIR-10394-5P	99.65	66.83	1852
HSA-MIR-1205	99.65	66.76	1826

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 32.2% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 12)

• tandem promoters provide a dual system to regulate expression and alternative splicing of human TrpRS in vivo (PMID:14757836)
• Mutations located at the appended beta1-beta2 hairpin and the AIDQ sequence of human TrpRS switch this enzyme to a tRNA-dependent mode in the tryptophan activation step. (PMID:17726052)
• The data demonstrate a pro-angiogenic function for Wars2 both within and outside the heart. (PMID:27389904)
• first genome-wide scan for selection in Inuit from Greenland. A region, with a deeply divergent haplotype that is closely related to the sequence in the Denisovan genome contains two genes, WARS2 and TBX15. our study suggests a complex multi-factorial regulation of TBX15 and WARS2. We show that the introgressed region is associated with regional changes in methylation and expression levels (PMID:28007980)
• we found a compound heterozygous genotype of the mitochondrial tryptophanyl-tRNA synthetase (WARS2) gene, comprising a nonsense mutation (c.325delA, p.Ser109Alafs*15), which very likely entails nonsense-mediated mRNA decay and a missense mutation (PMID:28236339)
• Here we substantially extend and consolidate the symptomatology of WARS2 by presenting a patient with severe infantile-onset leukoencephalopathy, profound intellectual disability, spastic quadriplegia, epilepsy, microcephaly, short stature, failure to thrive, cerebral atrophy, and periventricular white matter abnormalities (PMID:28650581)
• This confidently implicates that mutations in WARS2 cause mitochondrial disease with a broad spectrum of clinical presentation. (PMID:28905505)
• An alternative conformation of human TrpRS suggests a role of zinc in activating non-enzymatic function. (PMID:28910573)
• This case expands the phenotypic spectrum of WARS2 deficiency and emphasizes the importance of mitochondrial protein synthesis in the pathogenesis of Parkinsonism. (PMID:29120065)
• A lead candidate functional single nucleotide polymorphism within the WARS2 gene associated with waist-hip-ratio does not alter RNA stability. (PMID:33007465)
• Mini-TrpRS is essential for IFNgamma-induced monocyte-derived giant cell formation. (PMID:33721618)
• The Expanding Phenotypical Spectrum of WARS2-Related Disorder: Four Novel Cases with a Common Recurrent Variant. (PMID:37107582)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	wars2	ENSDARG00000011801
mus_musculus	Wars2	ENSMUSG00000004233
rattus_norvegicus	Wars2	ENSRNOG00000019508
drosophila_melanogaster	TrpRS-m	FBGN0036763
caenorhabditis_elegans		WBGENE00006946

Paralogs (1): WARS1 (ENSG00000140105)

Protein

Protein identifiers

Tryptophan–tRNA ligase, mitochondrial — Q9UGM6 (reviewed: Q9UGM6)

Alternative names: (Mt)TrpRS, Tryptophanyl-tRNA synthetase

All UniProt accessions (2): B7Z6G7, Q9UGM6

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the attachment of tryptophan to tRNA(Trp) in a two-step reaction: tryptophan is first activated by ATP to form Trp-AMP and then transferred to the acceptor end of tRNA(Trp).

Subcellular location. Mitochondrion matrix. Mitochondrion.

Tissue specificity. Brain.

Disease relevance. Neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures (NEMMLAS) [MIM:617710] An autosomal recessive, mitochondrial disorder with a broad phenotypic spectrum ranging from severe neonatal lactic acidosis, encephalomyopathy and early death to an attenuated course with milder manifestations. Clinical features include delayed psychomotor development, intellectual disability, hypotonia, dystonia, ataxia, and spasticity. Severe combined respiratory chain deficiency may be found in severely affected individuals. The disease is caused by variants affecting the gene represented in this entry. Parkinsonism-dystonia 3, childhood-onset (PKDYS3) [MIM:619738] An autosomal recessive neurodegenerative disorder with onset in infancy or early childhood. Affected individuals present with progressive movement abnormalities, including parkinsonism with tremor, dystonia, myoclonus ataxia, and hyperkinetic movements such as ballismus. The parkinsonism features may be responsive to treatment with levodopa, although many patients develop levodopa-induced dyskinesia. Some patients may have mild cognitive impairment or psychiatric disturbances. The disease is caused by variants affecting the gene represented in this entry.

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

Isoforms (2)

UniProt ID	Names	Canonical?
Q9UGM6-1	1	yes
Q9UGM6-2	2

RefSeq proteins (8): NP_001365155, NP_001365156, NP_001365157, NP_001365158, NP_001365159, NP_001365160, NP_056651, NP_957715 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001412	aa-tRNA-synth_I_CS	Conserved_site
IPR002305	aa-tRNA-synth_Ic	Family
IPR002306	Trp-tRNA-ligase	Family
IPR014729	Rossmann-like_a/b/a_fold	Homologous_superfamily
IPR024109	Trp-tRNA-ligase_bac-type	Family
IPR050203	Trp-tRNA_synthetase	Family

Pfam: PF00579

Enzyme classification (BRENDA):

• EC 6.1.1.2 — tryptophan-tRNA ligase (BRENDA: 36 organisms, 113 substrates, 74 inhibitors, 112 Km, 92 kcat entries)

Substrate kinetics (BRENDA)

40 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
TRNATRP	0.0001–0.0248	30
ATP	0.03–2	19
TRP	0.0004–0.128	12
L-TRYPTOPHAN	0.0007–0.027	10
P1,P3-BIS(5’-ADENOSYL)TRIPHOSPHATE	1	2
ARCHEOGLOBUS FULGIDUS TRNATRP(A73, WILD-TYPE)	0.0001	1
ARCHEOGLOBUS FULGIDUS TRNATRP(A73C)	0.0001	1
ARCHEOGLOBUS FULGIDUS TRNATRP(A73G)	0.0001	1
ARCHEOGLOBUS FULGIDUS TRNATRP(A73U)	0.0001	1
BACILLUS SUBTILIS TRNATRP(A73, WILD-TYPE)	0.0001	1
BACILLUS SUBTILIS TRNATRP(A73C)	0.0001	1
BACILLUS SUBTILIS TRNATRP(A73G)	0.0001	1
BACILLUS SUBTILIS TRNATRP(A73U)	0.0001	1
BOVINE TRNATRP(G73, WILD-TYPE)	0.0002	1
BOVINE TRNATRP(G73A)	0.0002	1

Catalyzed reactions (Rhea), 1 shown:

• tRNA(Trp) + L-tryptophan + ATP = L-tryptophyl-tRNA(Trp) + AMP + diphosphate + H(+) (RHEA:24080)

UniProt features (55 total): helix 18, sequence variant 15, binding site 6, strand 6, turn 5, splice variant 2, transit peptide 1, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
5EKD	X-RAY DIFFRACTION	1.82

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UGM6-F1	89.78	0.80

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 (6): 42; 48–51; 167; 179–181; 217; 226–230

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: 273 (showing top): GOBP_AMINO_ACID_ACTIVATION, GOBP_TRNA_METABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_VASCULATURE_DEVELOPMENT, GOBP_MITOCHONDRIAL_TRANSLATION, EFC_Q6, GOBP_TRANSLATION, GOBP_BLOOD_VESSEL_MORPHOGENESIS, GOBP_MITOCHONDRIAL_RNA_METABOLIC_PROCESS, GOBP_VASCULOGENESIS, KEGG_AMINOACYL_TRNA_BIOSYNTHESIS, chr1p12, REACTOME_MITOCHONDRIAL_TRNA_AMINOACYLATION, WONG_MITOCHONDRIA_GENE_MODULE, GGTGAAG_MIR412, GOBP_POSITIVE_REGULATION_OF_DEVELOPMENTAL_PROCESS

GO Biological Process (6): vasculogenesis (GO:0001570), tRNA aminoacylation for protein translation (GO:0006418), positive regulation of angiogenesis (GO:0045766), mitochondrial tryptophanyl-tRNA aminoacylation (GO:0070183), translation (GO:0006412), tryptophanyl-tRNA aminoacylation (GO:0006436)

GO Molecular Function (5): tryptophan-tRNA ligase activity (GO:0004830), ATP binding (GO:0005524), nucleotide binding (GO:0000166), aminoacyl-tRNA ligase activity (GO:0004812), ligase activity (GO:0016874)

GO Cellular Component (4): nucleoplasm (GO:0005654), mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), plasma membrane (GO:0005886)

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
cell differentiation	1
blood vessel morphogenesis	1
translation	1
tRNA aminoacylation	1
angiogenesis	1
regulation of angiogenesis	1
positive regulation of vasculature development	1
tryptophanyl-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
tRNA aminoacylation for protein translation	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
nuclear lumen	1
cellular anatomical structure	1
cytoplasm	1
intracellular membrane-bounded organelle	1
intracellular organelle lumen	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

1912 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
WARS2	YARS1	P54577	986
WARS2	YARS2	Q9Y2Z4	926
WARS2	WARS1	P23381	923
WARS2	PARS2	Q7L3T8	882
WARS2	MARS2	Q96GW9	881
WARS2	MARS1	P56192	879
WARS2	VARS2	Q5ST30	879
WARS2	QARS1	P47897	878
WARS2	VARS1	P26640	877
WARS2	AARS1	P49588	857
WARS2	AARS2	Q5JTZ9	848
WARS2	IARS2	Q9NSE4	841
WARS2	NARS2	Q96I59	816
WARS2	LARS2	Q15031	814
WARS2	RARS2	Q5T160	811
WARS2	LARS1	Q9P2J5	811

IntAct

10 interactions, top by confidence:

A	B	Type	Score
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350
RMND5A	HTRA2	psi-mi:“MI:0914”(association)	0.350
CLPP	NDUFA4	psi-mi:“MI:2364”(proximity)	0.270
	VWA8	psi-mi:“MI:2364”(proximity)	0.270
MGST3	VWA8	psi-mi:“MI:2364”(proximity)	0.270
PDK1	VWA8	psi-mi:“MI:2364”(proximity)	0.270
TRMT61B	VWA8	psi-mi:“MI:2364”(proximity)	0.270
FHIP2B	VWA8	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (48): WARS2 (Affinity Capture-MS), WARS2 (Affinity Capture-MS), WARS2 (Affinity Capture-MS), WARS2 (Negative Genetic), WARS2 (Affinity Capture-MS), WARS2 (Proximity Label-MS), WARS2 (Proximity Label-MS), WARS2 (Proximity Label-MS), WARS2 (Synthetic Lethality), WARS2 (Affinity Capture-MS), WARS2 (Proximity Label-MS), WARS2 (Proximity Label-MS), WARS2 (Proximity Label-MS), WARS2 (Proximity Label-MS), WARS2 (Proximity Label-MS)

ESM2 similar proteins: C0HKD6, J9VVW8, O13775, O14000, O14055, O42875, O51038, O74634, O74890, O82462, O84589, P04803, P13188, P13503, P14325, P22438, P28241, P48526, P48527, P67586, P67587, Q04SB0, Q050D6, Q1RIE3, Q319F8, Q3T099, Q54MZ8, Q54WD9, Q5UPJ7, Q72QT1, Q7NAT8, Q7V286, Q7VBM9, Q821H9, Q83FN1, Q83HC3, Q86A90, Q8F525, Q8RXE9, Q8SRV7

Diamond homologs: C0HKD6, O42875, P00953, P00954, P04803, P0A2P2, P0A2P3, P21656, P43835, P47372, P56396, P57602, P57956, P59466, P67586, P67587, P67588, P67589, P67591, P67592, P67593, P67594, P73655, P75510, P9WFT2, P9WFT3, Q1RIE3, Q3T099, Q46127, Q49901, Q4UL98, Q5E2G5, Q5HH88, Q5HQH4, Q68WR2, Q6AGQ7, Q6GAT0, Q6GI89, Q71XG7, Q7MAE0

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
QRICH1	“up-regulates quantity by expression”	WARS2	“transcriptional regulation”
ATF4	“up-regulates quantity by expression”	WARS2	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	7
Likely pathogenic	8
Uncertain significance	75
Likely benign	38
Benign	12

Top pathogenic / likely-pathogenic (15)

Variant ID	HGVS	Classification
1341956	NG_050658.1:g.(5235_69181)_(69440_100126)del	Pathogenic
2339126	NM_015836.4(WARS2):c.313_317delinsG (p.Asn105fs)	Pathogenic
3773821	NM_015836.4(WARS2):c.348+1G>T	Pathogenic
440919	NM_015836.4(WARS2):c.134G>T (p.Gly45Val)	Pathogenic
440920	NM_015836.4(WARS2):c.532G>C (p.Val178Leu)	Pathogenic
4847080	NM_015836.4(WARS2):c.604del (p.Glu202fs)	Pathogenic
976753	NM_015836.4(WARS2):c.622G>T (p.Glu208Ter)	Pathogenic
1341955	NM_015836.4(WARS2):c.833T>G (p.Val278Gly)	Likely pathogenic
1685473	NM_015836.4(WARS2):c.680T>C (p.Met227Thr)	Likely pathogenic
1685474	NM_015836.4(WARS2):c.526G>T (p.Val176Phe)	Likely pathogenic
1690649	NM_015836.4(WARS2):c.148G>T (p.Gly50Cys)	Likely pathogenic
1709258	NM_015836.4(WARS2):c.368T>G (p.Leu123Ter)	Likely pathogenic
224152	NM_015836.4(WARS2):c.715C>T (p.Arg239Ter)	Likely pathogenic
2663724	NM_015836.4(WARS2):c.116C>G (p.Ser39Cys)	Likely pathogenic
807717	NM_015836.4(WARS2):c.149G>A (p.Gly50Asp)	Likely pathogenic

SpliceAI

1325 predictions. Top by Δscore:

Variant	Effect	Δscore
1:119033355:GGATG:G	acceptor_gain	1.0000
1:119033357:ATG:A	acceptor_gain	1.0000
1:119033358:TG:T	acceptor_gain	1.0000
1:119033359:GCT:G	acceptor_loss	1.0000
1:119033360:C:CC	acceptor_gain	1.0000
1:119033376:A:T	acceptor_gain	1.0000
1:119033378:C:CT	acceptor_gain	1.0000
1:119033382:C:CT	acceptor_gain	1.0000
1:119033385:A:C	acceptor_gain	1.0000
1:119033390:C:T	acceptor_gain	1.0000
1:119034089:A:AC	donor_gain	1.0000
1:119034090:C:CC	donor_gain	1.0000
1:119034090:CTTA:C	donor_gain	1.0000
1:119034091:TTA:T	donor_loss	1.0000
1:119034092:TACTG:T	donor_loss	1.0000
1:119034093:A:AC	donor_gain	1.0000
1:119034094:C:CT	donor_gain	1.0000
1:119034094:CT:C	donor_gain	1.0000
1:119034094:CTG:C	donor_gain	1.0000
1:119034094:CTGA:C	donor_gain	1.0000
1:119034094:CTGAG:C	donor_gain	1.0000
1:119034134:T:TA	donor_gain	1.0000
1:119034214:C:CC	acceptor_gain	1.0000
1:119042262:A:AC	donor_gain	1.0000
1:119042263:C:CC	donor_gain	1.0000
1:119045660:CAC:C	acceptor_gain	1.0000
1:119045663:C:CC	acceptor_gain	1.0000
1:119045664:T:A	acceptor_loss	1.0000
1:119033356:GATG:G	acceptor_gain	0.9900
1:119033364:G:C	acceptor_gain	0.9900

AlphaMissense

2340 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:119033085:C:A	K303N	0.994
1:119033085:C:G	K303N	0.994
1:119034202:A:T	V176D	0.994
1:119042283:C:G	A166P	0.993
1:119076469:G:C	H77D	0.992
1:119042279:T:A	D167V	0.991
1:119042282:G:T	A166D	0.991
1:119033234:C:G	A254P	0.990
1:119033281:A:T	V238D	0.990
1:119042280:C:G	D167H	0.990
1:119076482:G:C	S72R	0.989
1:119076482:G:T	S72R	0.989
1:119076484:T:G	S72R	0.989
1:119033087:T:C	K303E	0.987
1:119034187:T:G	D181A	0.987
1:119042286:C:G	A165P	0.987
1:119045638:A:G	W125R	0.987
1:119045638:A:T	W125R	0.987
1:119076362:G:C	F112L	0.987
1:119076362:G:T	F112L	0.987
1:119076364:A:G	F112L	0.987
1:119042279:T:G	D167A	0.986
1:119033233:G:T	A254D	0.985
1:119034142:A:G	F196S	0.985
1:119034188:C:G	D181H	0.985
1:119042273:A:G	L169P	0.985
1:119033225:C:G	D257H	0.984
1:119034187:T:A	D181V	0.984
1:119033189:G:T	R269S	0.983
1:119033223:G:C	D257E	0.983

dbSNP variants (sampled 300 via entrez): RS1000015781 (1:119078278 A>G), RS1000048886 (1:119121451 A>G), RS1000146457 (1:119125614 C>G), RS1000165314 (1:119038246 A>G), RS1000175880 (1:119109241 G>A), RS1000196860 (1:119037932 G>C), RS1000205605 (1:119087197 C>G,T), RS1000207695 (1:119127103 C>G), RS1000209360 (1:119132216 T>C), RS1000243779 (1:119102053 G>A), RS1000286687 (1:119115948 T>A,C,G), RS1000296693 (1:119093937 A>G), RS1000318838 (1:119070936 G>A), RS1000347726 (1:119138724 T>C), RS1000364822 (1:119062363 T>C)

Disease associations

OMIM: gene MIM:604733 | disease phenotypes: MIM:617710, MIM:619738

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures	Strong	Autosomal recessive
parkinsonism-dystonia 3, childhood-onset	Strong	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): neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures (MONDO:0060578), parkinsonism-dystonia 3, childhood-onset (MONDO:0030676), mitochondrial disease (MONDO:0044970)

Orphanet (2): WARS2-related combined oxidative phosphorylation defect (Orphanet:572798), Mitochondrial disease (Orphanet:68380)

HPO phenotypes

101 total (30 of 101 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000218	High palate
HP:0000219	Thin upper lip vermilion
HP:0000316	Hypertelorism
HP:0000338	Hypomimic face
HP:0000343	Long philtrum
HP:0000369	Low-set ears
HP:0000431	Wide nasal bridge
HP:0000486	Strabismus
HP:0000510	Rod-cone dystrophy
HP:0000577	Exotropia
HP:0000639	Nystagmus
HP:0000646	Amblyopia
HP:0000648	Optic atrophy
HP:0000709	Psychosis
HP:0000716	Depression
HP:0000718	Aggressive behavior
HP:0000737	Irritability
HP:0000739	Anxiety
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001272	Cerebellar atrophy
HP:0001276	Hypertonia
HP:0001288	Gait disturbance
HP:0001300	Parkinsonism
HP:0001310	Dysmetria
HP:0001320	Cerebellar vermis hypoplasia

GWAS associations

115 associations (top):

Study	Trait	p-value
GCST000829_3	Waist-hip ratio	9.000000e-25
GCST002782_1	Waist-to-hip ratio adjusted for body mass index	1.000000e-07
GCST002782_2	Waist-to-hip ratio adjusted for body mass index	2.000000e-19
GCST002782_211	Waist-to-hip ratio adjusted for body mass index	2.000000e-14
GCST002782_3	Waist-to-hip ratio adjusted for body mass index	7.000000e-08
GCST002782_4	Waist-to-hip ratio adjusted for body mass index	7.000000e-15
GCST002782_5	Waist-to-hip ratio adjusted for body mass index	2.000000e-20
GCST003996_15	Monobrow	4.000000e-11
GCST004063_79	Waist circumference adjusted for body mass index	1.000000e-12
GCST004063_81	Waist circumference adjusted for body mass index	1.000000e-24
GCST004063_82	Waist circumference adjusted for body mass index	2.000000e-15
GCST004064_3	Waist-hip ratio	3.000000e-10
GCST004064_49	Waist-hip ratio	1.000000e-12
GCST004500_113	Waist circumference adjusted for BMI (adjusted for smoking behaviour)	2.000000e-25
GCST004500_37	Waist circumference adjusted for BMI (adjusted for smoking behaviour)	2.000000e-11
GCST004500_70	Waist circumference adjusted for BMI (adjusted for smoking behaviour)	9.000000e-18
GCST004501_69	Waist circumference adjusted for BMI (joint analysis main effects and smoking interaction)	2.000000e-25
GCST004501_70	Waist circumference adjusted for BMI (joint analysis main effects and smoking interaction)	3.000000e-17
GCST004501_71	Waist circumference adjusted for BMI (joint analysis main effects and smoking interaction)	3.000000e-11
GCST004504_104	Waist circumference adjusted for BMI in non-smokers	2.000000e-10
GCST004504_105	Waist circumference adjusted for BMI in non-smokers	8.000000e-23
GCST004504_106	Waist circumference adjusted for BMI in non-smokers	1.000000e-15
GCST004505_114	Waist-to-hip ratio adjusted for BMI (adjusted for smoking behaviour)	7.000000e-10
GCST004505_115	Waist-to-hip ratio adjusted for BMI (adjusted for smoking behaviour)	1.000000e-21
GCST004505_116	Waist-to-hip ratio adjusted for BMI (adjusted for smoking behaviour)	6.000000e-14
GCST004507_37	Waist-to-hip ratio adjusted for BMI (joint analysis main effects and smoking interaction)	4.000000e-06
GCST004507_5	Waist-to-hip ratio adjusted for BMI (joint analysis main effects and smoking interaction)	1.000000e-09
GCST004508_28	Waist-to-hip ratio adjusted for BMI in non-smokers	1.000000e-08
GCST004508_29	Waist-to-hip ratio adjusted for BMI in non-smokers	6.000000e-06
GCST004567_112	Waist-to-hip ratio adjusted for BMI (joint analysis for main effect and physical activity interaction)	5.000000e-19

EFO canonical traits (11, from GWAS)

EFO ID	Trait name
EFO:0004343	waist-hip ratio
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0007906	synophrys measurement
EFO:0007789	BMI-adjusted waist circumference
EFO:0004318	smoking behavior
EFO:0008002	physical activity measurement
EFO:0004340	body mass index
EFO:0004346	neuroimaging measurement
EFO:0004840	cortical thickness
EFO:0004327	electrocardiography
EFO:0008039	BMI-adjusted hip circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

26 total (human), top 26 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Acetaminophen	affects cotreatment, decreases expression, increases expression	3
Valproic Acid	decreases methylation, affects expression, decreases expression	3
Arsenic	affects methylation, increases methylation	2
Benzo(a)pyrene	increases methylation, decreases expression	2
Aflatoxin B1	decreases expression, increases methylation	2
aristolochic acid I	decreases expression	1
arsenite	increases methylation	1
perfluorooctanoic acid	increases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
aflatoxin B2	increases methylation	1
vanadyl sulfate	increases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
2,3,5-(triglutathion-S-yl)hydroquinone	increases ADP-ribosylation	1
torcetrapib	increases expression	1
abrine	increases expression	1
bisphenol S	affects expression	1
Temozolomide	increases expression	1
Ascorbic Acid	decreases expression	1
Doxorubicin	decreases expression	1
Formaldehyde	decreases expression	1
Lipopolysaccharides	decreases expression, affects cotreatment	1
Potassium Dichromate	decreases expression	1
Tretinoin	decreases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	1
Cyclosporine	increases expression	1
Antirheumatic Agents	increases expression	1

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