NARS2

Summary

NARS2 (asparaginyl-tRNA synthetase 2, mitochondrial, HGNC:26274) is a protein-coding gene on chromosome 11q14.1, encoding Asparaginyl-tRNA synthetase (Q96I59). Mitochondrial aminoacyl-tRNA synthetase that catalyzes the specific attachment of the asparagine amino acid (aa) to the homologous transfer RNA (tRNA), further participating in protein synthesis. It is a selective cancer dependency (DepMap: 24.3% of cell lines).

This gene encodes a putative member of the class II 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 asparagine to tRNA molecules. Mutations in this gene have been associated with combined oxidative phosphorylation deficiency 24 (COXPD24).

Source: NCBI Gene 79731 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Definitive, ClinGen) — +5 more curated relationships
• GWAS associations: 14
• Clinical variants (ClinVar): 411 total — 21 pathogenic, 11 likely-pathogenic
• Phenotypes (HPO): 61
• Cancer dependency (DepMap): dependent in 24.3% of screened cell lines
• MANE Select transcript: NM_024678

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26274
Approved symbol	NARS2
Name	asparaginyl-tRNA synthetase 2, mitochondrial
Location	11q14.1
Locus type	gene with protein product
Status	Approved
Aliases	FLJ23441, SLM5
Ensembl gene	ENSG00000137513
Ensembl biotype	protein_coding
OMIM	612803
Entrez	79731

Gene structure

Transcript identifiers

Ensembl transcripts: 39 — 18 protein_coding, 14 nonsense_mediated_decay, 4 retained_intron, 3 protein_coding_CDS_not_defined

ENST00000281038, ENST00000525345, ENST00000526709, ENST00000528850, ENST00000529771, ENST00000529880, ENST00000695114, ENST00000695115, ENST00000695116, ENST00000695117, ENST00000695341, ENST00000695342, ENST00000695343, ENST00000695344, ENST00000695345, ENST00000695346, ENST00000695347, ENST00000695348, ENST00000695349, ENST00000695350, ENST00000695351, ENST00000695352, ENST00000695353, ENST00000695354, ENST00000695355, ENST00000695356, ENST00000695357, ENST00000695358, ENST00000695359, ENST00000695360, ENST00000695361, ENST00000695362, ENST00000695363, ENST00000695364, ENST00000695365, ENST00000695366, ENST00000935323, ENST00000935324, ENST00000935325

RefSeq mRNA: 18 — MANE Select: NM_024678 NM_001243251, NM_001425299, NM_001425300, NM_001425301, NM_001425302, NM_001425303, NM_001425304, NM_001425305, NM_001425306, NM_001425307, NM_001425308, NM_001425309, NM_001425310, NM_001425311, NM_001425312, NM_001425313, NM_001425314, NM_024678

CCDS: CCDS58164, CCDS8261

Canonical transcript exons

ENST00000281038 — 14 exons

Exon	Start	End
ENSE00001103671	78493063	78493195
ENSE00001151727	78574348	78574864
ENSE00002149511	78435968	78436814
ENSE00003483804	78566132	78566272
ENSE00003513400	78478585	78478683
ENSE00003522365	78559539	78559619
ENSE00003537842	78571335	78571444
ENSE00003580008	78469247	78469313
ENSE00003612752	78478438	78478475
ENSE00003614361	78465876	78466013
ENSE00003618379	78568632	78568752
ENSE00003618694	78528842	78528936
ENSE00003624921	78441091	78441117
ENSE00003655606	78443661	78443758

Expression profiles

Bgee: expression breadth ubiquitous, 278 present calls, max score 94.67.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 13.0762 / max 536.7850, expressed in 1758 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
121516	12.9434	1756
121514	0.0713	21
121515	0.0614	16

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	94.67	gold quality
oocyte	CL:0000023	94.37	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	92.02	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	91.83	gold quality
biceps brachii	UBERON:0001507	91.67	gold quality
vastus lateralis	UBERON:0001379	91.53	gold quality
ventricular zone	UBERON:0003053	91.48	gold quality
pigmented layer of retina	UBERON:0001782	91.46	gold quality
embryo	UBERON:0000922	90.99	gold quality
quadriceps femoris	UBERON:0001377	90.98	gold quality
ganglionic eminence	UBERON:0004023	90.53	gold quality
hair follicle	UBERON:0002073	90.44	silver quality
cortical plate	UBERON:0005343	89.98	gold quality
deltoid	UBERON:0001476	89.47	gold quality
skeletal muscle tissue	UBERON:0001134	89.34	gold quality
diaphragm	UBERON:0001103	88.94	silver quality
hindlimb stylopod muscle	UBERON:0004252	88.90	gold quality
stromal cell of endometrium	CL:0002255	88.47	gold quality
triceps brachii	UBERON:0001509	88.40	gold quality
gluteal muscle	UBERON:0002000	88.22	gold quality
heart right ventricle	UBERON:0002080	88.19	gold quality
islet of Langerhans	UBERON:0000006	88.18	gold quality
muscle organ	UBERON:0001630	88.06	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	87.64	gold quality
muscle tissue	UBERON:0002385	87.34	gold quality
muscle of leg	UBERON:0001383	87.19	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	87.13	gold quality
right lobe of liver	UBERON:0001114	87.07	gold quality
germinal epithelium of ovary	UBERON:0001304	87.03	gold quality
gastrocnemius	UBERON:0001388	87.03	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-CURD-114	yes	12.04
E-ANND-3	yes	8.86
E-GEOD-81383	no	1083.65

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ATF4

miRNA regulators (miRDB)

34 targeting NARS2, 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-4668-3P	100.00	68.74	2635
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-8062	99.88	68.43	995
HSA-MIR-544A	99.84	68.66	1965
HSA-MIR-5003-5P	99.61	69.13	1624
HSA-MIR-488-3P	99.61	68.79	1731
HSA-MIR-1252-3P	99.55	67.71	2862
HSA-MIR-7159-3P	99.51	70.17	1920
HSA-MIR-4672	99.50	71.58	2893
HSA-MIR-20A-3P	99.44	69.10	1575
HSA-MIR-183-5P	99.31	72.27	1164
HSA-MIR-580-5P	99.28	70.94	1776
HSA-MIR-593-3P	99.22	67.28	1327
HSA-MIR-4263	99.18	69.25	2236
HSA-MIR-6071	99.16	67.77	1780
HSA-MIR-6809-5P	99.13	68.45	1223
HSA-MIR-219A-1-3P	98.91	67.87	639
HSA-MIR-6760-5P	98.87	66.73	1515
HSA-MIR-4709-5P	98.51	67.25	1335
HSA-MIR-6878-5P	98.49	67.91	2142
HSA-MIR-541-5P	98.24	67.77	1181
HSA-MIR-4275	97.96	68.42	1549
HSA-MIR-5585-5P	97.95	68.80	1024
HSA-MIR-4769-3P	97.95	68.17	1002
HSA-MIR-6817-5P	97.95	67.86	1026
HSA-MIR-1279	97.83	67.50	1898
HSA-MIR-1255B-2-3P	97.80	67.04	880
HSA-MIR-1278	97.75	67.55	628

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 24.3% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 9)

• A variant in NARS2 results in a combined OXPHOS complex deficiency involving complex I and IV, making NARS2 a new member of disease-associated aminoacyl-tRNA synthetases. (PMID:25385316)
• Genome-wide SNP analysis identified multiple suggestive novel loci and two of them were also significant in gene-based analysis (CCDC85C and NARS2) that survived after controlling for false-discovery rate at 0.05. (PMID:25649651)
• In these cells we show that a decrease in oxygen consumption rates (OCR) and electron transport chain (ETC) activity can be rescued by overexpression of wild type NARS2 (PMID:25807530)
• The individuals with PARS2 and NARS2 mutations demonstrate similar neurological features as those previously reported, with diversity in clinical presentation such as hearing loss and seizure type. (PMID:28077841)
• The AARS2 variant accounts for a significant number of cases with Non-immune Hydrops Fetalis in the cohort of pregnancies Omani patients. (PMID:28822227)
• NARS2 expression is reduced in AD brain tissue compared with controls. NARS2 expression in brain is associated with GAB2 AD risk variant rs2373115. (PMID:30088171)
• The phenotypic variability and natural history of NARS2 associated disease. (PMID:33596490)
• Splicing variants in NARS2 are associated with milder phenotypes and intra-familial variability. (PMID:36252909)
• Novel NARS2 variants in a patient with early-onset status epilepticus: case study and literature review. (PMID:38310242)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	nars2	ENSDARG00000098441
mus_musculus	Nars2	ENSMUSG00000018995
rattus_norvegicus	Nars2	ENSRNOG00000011476
drosophila_melanogaster	AsnRS-m	FBGN0034177
caenorhabditis_elegans		WBGENE00013447

Paralogs (4): KARS1 (ENSG00000065427), DARS1 (ENSG00000115866), DARS2 (ENSG00000117593), NARS1 (ENSG00000134440)

Protein

Protein identifiers

Asparaginyl-tRNA synthetase — Q96I59 (reviewed: Q96I59)

Alternative names: Asparagine–tRNA ligase, mitochondrial

All UniProt accessions (23): A0A8Q3SHL5, A0A8Q3SHN4, A0A8Q3SHN6, A0A8Q3SHP1, A0A8Q3SHS9, A0A8Q3SHT5, A0A8Q3SHT7, A0A8Q3SHU1, A0A8Q3SHV4, A0A8Q3SIK4, A0A8Q3WKD2, A0A8Q3WKD4, A0A8Q3WKD8, A0A8Q3WKD9, A0A8Q3WKE5, A0A8Q3WKF4, A0A8Q3WKI6, A0A8Q3WKX6, Q96I59, A0A8Q3WLI0, A0A8Q3WLT2, E9PRK2, H0YE96

UniProt curated annotations — full annotation on UniProt →

Function. Mitochondrial aminoacyl-tRNA synthetase that catalyzes the specific attachment of the asparagine amino acid (aa) to the homologous transfer RNA (tRNA), further participating in protein synthesis. The reaction occurs in a two steps: asparagine is first activated by ATP to form Asn-AMP and then transferred to the acceptor end of tRNA(Asn).

Subunit / interactions. Homodimer.

Subcellular location. Mitochondrion matrix. Mitochondrion.

Disease relevance. Combined oxidative phosphorylation deficiency 24 (COXPD24) [MIM:616239] An autosomal recessive mitochondrial disorder with wide phenotypic variability. Some patients have a milder form affecting only skeletal muscle, whereas others may have a more severe disorder, reminiscent of Alpers syndrome. Alpers syndrome is a progressive neurodegenerative disorder that presents in infancy or early childhood and is characterized by diffuse degeneration of cerebral gray matter. The disease is caused by variants affecting the gene represented in this entry. Deafness, autosomal recessive, 94 (DFNB94) [MIM:618434] A form of non-syndromic, sensorineural deafness characterized by prelingual, profound, bilateral hearing impairment. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. The disease may be caused by variants affecting the gene represented in this entry.

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

Isoforms (2)

UniProt ID	Names	Canonical?
Q96I59-1	1	yes
Q96I59-2	2

RefSeq proteins (18): NP_001230180, NP_001412228, NP_001412229, NP_001412230, NP_001412231, NP_001412232, NP_001412233, NP_001412234, NP_001412235, NP_001412236, NP_001412237, NP_001412238, NP_001412239, NP_001412240, NP_001412241, NP_001412242, NP_001412243, NP_078954* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002312	Asp/Asn-tRNA-synth_IIb	Family
IPR004364	Aa-tRNA-synt_II	Domain
IPR004365	NA-bd_OB_tRNA	Domain
IPR004522	Asn-tRNA-ligase	Family
IPR006195	aa-tRNA-synth_II	Domain
IPR012340	NA-bd_OB-fold	Homologous_superfamily
IPR045864	aa-tRNA-synth_II/BPL/LPL	Homologous_superfamily

Pfam: PF00152, PF01336

Enzyme classification (BRENDA):

• EC 6.1.1.22 — asparagine-tRNA ligase (BRENDA: 20 organisms, 26 substrates, 46 inhibitors, 36 Km, 27 kcat entries)

Substrate kinetics (BRENDA)

7 substrates with measured Km, best-characterized 7. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ASN	0.015–0.77	17
ATP	0.0306–7	11
TRNAASN	0.0001–0.002	3
3-CYANOALANINE	5.8	1
ASPARTATE-3-HYDROXAMATE	0.78	1
ISOASPARAGINE	0.26	1
L-ASPARAGINE	0.04	1

Catalyzed reactions (Rhea), 1 shown:

• tRNA(Asn) + L-asparagine + ATP = L-asparaginyl-tRNA(Asn) + AMP + diphosphate + H(+) (RHEA:11180)

UniProt features (11 total): sequence variant 7, transit peptide 1, chain 1, modified residue 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96I59-F1	91.59	0.82

Functional residue map

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

Post-translational modifications (1): 353

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: 240 (showing top): GOBP_AMINO_ACID_ACTIVATION, GOBP_TRNA_METABOLIC_PROCESS, GOBP_TRANSLATION, GROSS_ELK3_TARGETS_UP, LASTOWSKA_NEUROBLASTOMA_COPY_NUMBER_DN, KEGG_AMINOACYL_TRNA_BIOSYNTHESIS, CREB_Q3, YRTCANNRCGC_UNKNOWN, NIKOLSKY_BREAST_CANCER_11Q12_Q14_AMPLICON, REACTOME_MITOCHONDRIAL_TRNA_AMINOACYLATION, WALLACE_PROSTATE_CANCER_RACE_DN, NUYTTEN_EZH2_TARGETS_DN, GOCC_MITOCHONDRIAL_MATRIX, MARSON_BOUND_BY_FOXP3_STIMULATED, MANALO_HYPOXIA_DN

GO Biological Process (3): asparaginyl-tRNA aminoacylation (GO:0006421), translation (GO:0006412), tRNA aminoacylation for protein translation (GO:0006418)

GO Molecular Function (6): nucleic acid binding (GO:0003676), asparagine-tRNA ligase activity (GO:0004816), 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), cytosol (GO:0005829)

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
cytoplasm	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
binding	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
intracellular membrane-bounded organelle	1
mitochondrion	1
intracellular organelle lumen	1

Protein interactions and networks

STRING

2034 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NARS2	TARS2	Q9BW92	880
NARS2	TARS3	A2RTX5	873
NARS2	TARS1	P26639	871
NARS2	QARS1	P47897	863
NARS2	EARS2	Q5JPH6	863
NARS2	IARS2	Q9NSE4	858
NARS2	AARS1	P49588	847
NARS2	PARS2	Q7L3T8	847
NARS2	YARS2	Q9Y2Z4	846
NARS2	CARS2	Q9HA77	844
NARS2	HARS1	P12081	844
NARS2	RARS2	Q5T160	841
NARS2	WARS2	Q9UGM6	816
NARS2	IARS1	P41252	816
NARS2	HARS2	P49590	816
NARS2	MARS2	Q96GW9	816

IntAct

105 interactions, top by confidence:

A	B	Type	Score
HSPD1	NUDT19	psi-mi:“MI:0914”(association)	0.710
rep	MPHOSPH10	psi-mi:“MI:0914”(association)	0.660
YWHAG	BLTP3B	psi-mi:“MI:2364”(proximity)	0.640
NDUFS7	NDUFS8	psi-mi:“MI:0914”(association)	0.640
NP	KPNA6	psi-mi:“MI:0914”(association)	0.550
RAB8B	BLTP3B	psi-mi:“MI:0914”(association)	0.530
BPNT1	GTPBP10	psi-mi:“MI:0914”(association)	0.530
LAMP3	METTL15	psi-mi:“MI:0914”(association)	0.530
OTC	RTL8C	psi-mi:“MI:0914”(association)	0.530
SLC25A41	NUDT19	psi-mi:“MI:0914”(association)	0.530
GATC	NME4	psi-mi:“MI:0914”(association)	0.530
CD70	METTL15	psi-mi:“MI:0914”(association)	0.530
UQCRFS1	NDUFAB1	psi-mi:“MI:0914”(association)	0.530
gag	SDCBP	psi-mi:“MI:0914”(association)	0.460
TRNT1	NARS2	psi-mi:“MI:0915”(physical association)	0.400
NP	KPNA4	psi-mi:“MI:0914”(association)	0.350
NP	HNRNPDL	psi-mi:“MI:0914”(association)	0.350
NP	HNRNPAB	psi-mi:“MI:0914”(association)	0.350
NP	KPNA6	psi-mi:“MI:0914”(association)	0.350

BioGRID (109): NARS2 (Affinity Capture-MS), NARS2 (Affinity Capture-MS), DARS2 (Co-fractionation), NARS2 (Co-fractionation), NARS2 (Affinity Capture-MS), NARS2 (Affinity Capture-MS), NARS2 (Affinity Capture-MS), NARS2 (Affinity Capture-MS), NARS2 (Affinity Capture-MS), NARS2 (Affinity Capture-MS), NARS2 (Affinity Capture-MS), NARS2 (Affinity Capture-MS), NARS2 (Affinity Capture-MS), NARS2 (Affinity Capture-MS), NARS2 (Affinity Capture-MS)

ESM2 similar proteins: A0AVT1, A2RTX5, A6QNM8, F4IFC5, O04630, O13914, O13969, O16129, O75879, P04801, P07236, P13642, P21894, P26636, P26638, P26639, P41250, P49588, P49591, P50475, P52709, P87144, Q0V9S0, Q3ZBV8, Q4R4U9, Q4R646, Q54J66, Q5R9K9, Q5RC02, Q5XHY5, Q5ZKA2, Q6DRC0, Q6P799, Q8BGQ7, Q8BGV0, Q8BIJ6, Q8BLY2, Q8CFX8, Q8GZ45, Q8H104

Diamond homologs: A0KXL6, A0LL53, A0PY64, A1APP8, A1JMN8, A3D3V7, A3DBI2, A3QE68, A5G5R2, A5HZE1, A5N4F7, A5UCB9, A6L0U5, A6LIA1, A6LPI6, A6TVS9, A6WMP4, A7FRK8, A7GB01, A7GTK8, A8FVU8, A8H467, A8MJ91, A9KZ30, A9NE58, B0JN99, B0TUU1, B1V8X4, B1XKH1, B2S3J9, B2TI01, B2UXS0, B3PNG8, B3R0I1, B6YRL1, O51128, O83618, P25345, P43829, P47359

SIGNOR signaling

7 interactions.

A	Effect	B	Mechanism
ATF4	“up-regulates quantity by expression”	NARS2	“transcriptional regulation”
NARS2	“down-regulates quantity”	tRNA(Asn)	“chemical modification”
NARS2	“down-regulates quantity”	asparagine	“chemical modification”
NARS2	“down-regulates quantity”	ATP(4-)	“chemical modification”
NARS2	“up-regulates quantity”	Asn-tRNA(Asn)	“chemical modification”
NARS2	“up-regulates quantity”	diphosphate(3-)	“chemical modification”
NARS2	“up-regulates quantity”	AMP	“chemical modification”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 102 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Mitochondrial protein import	5	12.5×	3e-03
Complex I biogenesis	5	12.3×	3e-03
Mitochondrial protein degradation	6	10.2×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	21
Likely pathogenic	11
Uncertain significance	150
Likely benign	134
Benign	48

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1323326	NM_024678.6(NARS2):c.1236C>G (p.Tyr412Ter)	Pathogenic
1460220	NC_000011.9:g.(?78189464)(78189749_?)del	Pathogenic
1690304	NM_024678.6(NARS2):c.922-21_922-19del	Pathogenic
183150	NM_024678.6(NARS2):c.822G>C (p.Gln274His)	Pathogenic
2413140	NM_024678.6(NARS2):c.595-1G>A	Pathogenic
2431370	NC_000011.10:g.(78476711_78486359)del	Pathogenic
2682376	NC_000011.9:g.(78180360_78189483)_(78189730_78204108)del	Pathogenic
280243	NM_024678.6(NARS2):c.822+2T>G	Pathogenic
2986511	NM_024678.6(NARS2):c.157del (p.Val53fs)	Pathogenic
3254561	NM_024678.6(NARS2):c.936_949dup (p.Asn317delinsIleCysTer)	Pathogenic
3653641	NM_024678.6(NARS2):c.343dup (p.Ile115fs)	Pathogenic
3674378	NM_024678.6(NARS2):c.172G>T (p.Glu58Ter)	Pathogenic
391671	NM_024678.6(NARS2):c.418C>T (p.Arg140Ter)	Pathogenic
4526064	NM_024678.6(NARS2):c.947dup (p.Asn316fs)	Pathogenic
4718832	NM_024678.6(NARS2):c.893_894del (p.Cys298fs)	Pathogenic
4782256	NM_024678.6(NARS2):c.228del (p.Ala77fs)	Pathogenic
522915	NM_024678.6(NARS2):c.10del (p.Val4fs)	Pathogenic
632573	NM_024678.6(NARS2):c.594+1G>A	Pathogenic
632577	NM_024678.6(NARS2):c.707T>G (p.Phe236Cys)	Pathogenic
632578	NM_024678.6(NARS2):c.1184T>G (p.Leu395Arg)	Pathogenic
872894	NM_024678.6(NARS2):c.545T>A (p.Ile182Lys)	Pathogenic
1190071	NM_024678.6(NARS2):c.788T>C (p.Ile263Thr)	Likely pathogenic
1341731	NM_024678.6(NARS2):c.822+6704_959+1727del	Likely pathogenic
183151	NM_024678.6(NARS2):c.641C>T (p.Pro214Leu)	Likely pathogenic
2413142	NM_024678.6(NARS2):c.959+1505T>G	Likely pathogenic
2413143	NM_024678.6(NARS2):c.822+6703_959+1726del	Likely pathogenic
3600372	NM_024678.6(NARS2):c.252-2A>G	Likely pathogenic
3613682	NM_024678.6(NARS2):c.951C>T (p.Asn317=)	Likely pathogenic
4056828	NM_024678.6(NARS2):c.325G>C (p.Glu109Gln)	Likely pathogenic
423956	NM_024678.6(NARS2):c.124del (p.Glu42fs)	Likely pathogenic

SpliceAI

3250 predictions. Top by Δscore:

Variant	Effect	Δscore
11:78443656:AGTAC:A	donor_loss	1.0000
11:78443657:GTAC:G	donor_loss	1.0000
11:78443658:TAC:T	donor_loss	1.0000
11:78443659:A:AT	donor_loss	1.0000
11:78443757:ACCTA:A	acceptor_loss	1.0000
11:78443759:C:CC	acceptor_gain	1.0000
11:78465871:CTTA:C	donor_loss	1.0000
11:78465872:TTA:T	donor_loss	1.0000
11:78465874:A:AC	donor_gain	1.0000
11:78465874:ACC:A	donor_loss	1.0000
11:78465875:C:CA	donor_loss	1.0000
11:78465875:C:CC	donor_gain	1.0000
11:78466009:CCCCA:C	acceptor_gain	1.0000
11:78466010:CCCA:C	acceptor_gain	1.0000
11:78466010:CCCAC:C	acceptor_gain	1.0000
11:78466011:CCA:C	acceptor_gain	1.0000
11:78466011:CCAC:C	acceptor_gain	1.0000
11:78466012:CA:C	acceptor_gain	1.0000
11:78466012:CACTG:C	acceptor_gain	1.0000
11:78466013:ACT:A	acceptor_loss	1.0000
11:78466014:C:A	acceptor_loss	1.0000
11:78466014:C:CC	acceptor_gain	1.0000
11:78466015:T:G	acceptor_loss	1.0000
11:78466019:A:C	acceptor_gain	1.0000
11:78478581:TTA:T	donor_loss	1.0000
11:78478582:TACCT:T	donor_loss	1.0000
11:78478583:A:C	donor_loss	1.0000
11:78478584:C:A	donor_loss	1.0000
11:78478681:AACC:A	acceptor_loss	1.0000
11:78493058:CCTA:C	donor_loss	1.0000

AlphaMissense

3129 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:78571403:G:C	F61L	0.996
11:78571403:G:T	F61L	0.996
11:78571405:A:G	F61L	0.996
11:78568675:A:G	L110P	0.992
11:78566161:C:G	A162P	0.989
11:78571404:A:G	F61S	0.988
11:78568729:A:T	V92E	0.987
11:78571441:A:G	W49R	0.987
11:78571441:A:T	W49R	0.987
11:78571443:C:T	G48E	0.987
11:78566226:C:G	R140P	0.986
11:78568718:C:G	G96R	0.986
11:78568718:C:T	G96R	0.986
11:78566169:C:G	R159P	0.985
11:78571444:C:G	G48R	0.985
11:78571444:C:T	G48R	0.985
11:78571362:A:T	V75D	0.984
11:78571390:C:G	D66H	0.984
11:78493117:A:C	F256L	0.983
11:78493117:A:T	F256L	0.983
11:78493119:A:G	F256L	0.983
11:78568717:C:T	G96E	0.983
11:78436679:G:C	C475W	0.982
11:78568718:C:A	G96W	0.982
11:78571386:C:T	G67E	0.982
11:78571425:C:G	R54P	0.982
11:78571388:A:C	D66E	0.980
11:78571388:A:T	D66E	0.980
11:78571401:A:G	L62P	0.980
11:78436715:T:A	K463N	0.979

dbSNP variants (sampled 300 via entrez): RS1000013185 (11:78574031 T>C), RS1000018864 (11:78497319 C>T), RS1000026953 (11:78537816 A>G), RS1000034421 (11:78459791 T>C,G), RS1000037430 (11:78543530 C>A,T), RS1000044136 (11:78499196 G>A,T), RS1000090040 (11:78464899 C>T), RS1000127342 (11:78467029 G>A), RS1000128079 (11:78540897 G>A), RS1000135130 (11:78503074 A>G,T), RS1000138203 (11:78576851 C>A,T), RS1000185326 (11:78464675 G>A), RS1000217335 (11:78511231 C>T), RS1000233713 (11:78532218 G>A), RS1000235752 (11:78540593 T>G)

Disease associations

OMIM: gene MIM:612803 | disease phenotypes: MIM:616239, MIM:618434, MIM:609060

GenCC curated gene-disease

Disease	Classification	Inheritance
combined oxidative phosphorylation defect type 24	Definitive	Autosomal recessive
mitochondrial disease	Moderate	Autosomal recessive
hearing loss, autosomal recessive	Supportive	Autosomal recessive
nonsyndromic genetic hearing loss	Limited	Autosomal recessive
hearing loss, autosomal recessive 94	Limited	Autosomal recessive

ClinGen Gene-Disease Validity (3)

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

Disease	Classification	Inheritance
Leigh syndrome	Limited	AR
nonsyndromic genetic hearing loss	Limited	AR
mitochondrial disease	Definitive	AR

Mondo (8): combined oxidative phosphorylation defect type 24 (MONDO:0014547), hearing loss, autosomal recessive 94 (MONDO:0032749), mitochondrial disease (MONDO:0044970), intellectual disability (MONDO:0001071), hepatoencephalopathy due to combined oxidative phosphorylation defect type 1 (MONDO:0012191), sensorineural hearing loss disorder (MONDO:0020678), nonsyndromic genetic hearing loss (MONDO:0019497), hearing loss, autosomal recessive (MONDO:0019588)

Orphanet (4): Combined oxidative phosphorylation defect type 24 (Orphanet:444458), Mitochondrial disease (Orphanet:68380), Hepatoencephalopathy due to combined oxidative phosphorylation defect type 1 (Orphanet:137681), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

61 total (30 of 61 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000097	Focal segmental glomerulosclerosis
HP:0000252	Microcephaly
HP:0000343	Long philtrum
HP:0000365	Hearing impairment
HP:0000463	Anteverted nares
HP:0000508	Ptosis
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001256	Mild intellectual disability
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001265	Hyporeflexia
HP:0001272	Cerebellar atrophy
HP:0001274	Agenesis of corpus callosum
HP:0001284	Areflexia
HP:0001290	Generalized hypotonia
HP:0001324	Muscle weakness
HP:0001347	Hyperreflexia
HP:0001488	Bilateral ptosis
HP:0001751	Abnormal vestibular function
HP:0001944	Dehydration
HP:0002013	Vomiting
HP:0002079	Hypoplasia of the corpus callosum
HP:0002133	Status epilepticus
HP:0002151	Increased circulating lactate concentration
HP:0002171	Gliosis

GWAS associations

14 associations (top):

Study	Trait	p-value
GCST002701_2	Verbal declarative memory	8.000000e-07
GCST002701_7	Verbal declarative memory	6.000000e-07
GCST002775_5	Alzheimer’s disease (survival time)	3.000000e-06
GCST007277_15	Tourette syndrome	5.000000e-06
GCST007656_10	Chronic obstructive pulmonary disease or resting heart rate (pleiotropy)	4.000000e-12
GCST008747_31	Estimated glomerular filtration rate	1.000000e-07
GCST009391_113	Metabolite levels	3.000000e-07
GCST009391_1472	Metabolite levels	2.000000e-06
GCST009391_72	Metabolite levels	4.000000e-07
GCST009391_969	Metabolite levels	4.000000e-06
GCST90002385_208	High light scatter reticulocyte count	2.000000e-11
GCST90002389_366	Lymphocyte percentage of white cells	4.000000e-11
GCST90002405_287	Reticulocyte count	5.000000e-12
GCST90002406_373	Reticulocyte fraction of red cells	3.000000e-09

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0004874	memory performance
EFO:0006805	word list delayed recall measurement
EFO:0000714	survival time
EFO:0010354	diacylglycerol 36:1 measurement
EFO:0010407	triacylglycerol 48:4 measurement
EFO:0009767	glycine measurement
EFO:0007986	reticulocyte count
EFO:0007993	lymphocyte percentage of leukocytes

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
C563797	Combined Oxidative Phosphorylation Deficiency 1 (supp.)
C564609	Deafness, Autosomal Recessive (supp.)
C580334	Nonsyndromic Deafness (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Acetaminophen	affects cotreatment, increases expression, decreases expression	3
Air Pollutants	increases abundance, increases expression, decreases expression	2
Particulate Matter	increases abundance, increases expression, decreases expression	2
beauvericin	affects cotreatment, increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
sodium arsenite	decreases expression	1
cobaltous chloride	decreases expression	1
perfluorooctanoic acid	increases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
M-VAC protocol	increases response to substance	1
beta-methylcholine	affects expression	1
epigallocatechin gallate	decreases expression, affects cotreatment	1
CGP 52608	affects binding, increases reaction	1
enniatins	affects cotreatment, increases expression	1
bisphenol B	increases expression	1
bisphenol AF	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Temozolomide	increases expression	1
Sunitinib	increases expression	1
Arsenic	affects methylation	1
Benzo(a)pyrene	decreases expression	1
Carbamazepine	affects expression	1
Doxorubicin	increases expression	1
Ethyl Methanesulfonate	decreases expression	1
Formaldehyde	decreases expression	1
Lipopolysaccharides	affects cotreatment, increases expression	1
Methyl Methanesulfonate	decreases expression	1
Plant Extracts	affects cotreatment, increases expression	1
Tretinoin	decreases expression	1

Clinical trials (associated diseases)

301 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
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
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
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
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
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
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
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities