DARS2

Summary

DARS2 (aspartyl-tRNA synthetase 2, mitochondrial, HGNC:25538) is a protein-coding gene on chromosome 1q25.1, encoding Aspartate–tRNA ligase, mitochondrial (Q6PI48). Catalyzes the attachment of aspartate to tRNA(Asp) in a two-step reaction: aspartate is first activated by ATP to form Asp-AMP and then transferred to the acceptor end of tRNA(Asp). It is a selective cancer dependency (DepMap: 24.8% of cell lines).

The protein encoded by this gene belongs to the class-II aminoacyl-tRNA synthetase family. It is a mitochondrial enzyme that specifically aminoacylates aspartyl-tRNA. Mutations in this gene are associated with leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL).

Source: NCBI Gene 55157 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 4
• Clinical variants (ClinVar): 510 total — 33 pathogenic, 29 likely-pathogenic
• Phenotypes (HPO): 90
• Cancer dependency (DepMap): dependent in 24.8% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_018122

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25538
Approved symbol	DARS2
Name	aspartyl-tRNA synthetase 2, mitochondrial
Location	1q25.1
Locus type	gene with protein product
Status	Approved
Aliases	FLJ10514, mtAspRS
Ensembl gene	ENSG00000117593
Ensembl biotype	protein_coding
OMIM	610956
Entrez	55157

Gene structure

Transcript identifiers

Ensembl transcripts: 30 — 24 protein_coding, 4 nonsense_mediated_decay, 2 retained_intron

ENST00000471476, ENST00000647645, ENST00000647730, ENST00000647788, ENST00000648055, ENST00000648271, ENST00000648458, ENST00000648807, ENST00000648960, ENST00000649067, ENST00000649106, ENST00000649689, ENST00000650297, ENST00000893354, ENST00000893355, ENST00000893356, ENST00000893357, ENST00000893358, ENST00000893359, ENST00000893360, ENST00000893361, ENST00000893362, ENST00000893363, ENST00000919979, ENST00000919980, ENST00000919981, ENST00000919982, ENST00000919983, ENST00000966171, ENST00000966172

RefSeq mRNA: 3 — MANE Select: NM_018122 NM_001365212, NM_001365213, NM_018122

CCDS: CCDS1311, CCDS91108, CCDS91109

Canonical transcript exons

ENST00000649689 — 17 exons

Exon	Start	End
ENSE00000789903	173853795	173853905
ENSE00001889588	173857518	173858546
ENSE00003479956	173840866	173840973
ENSE00003505430	173839367	173839546
ENSE00003531830	173831535	173831630
ENSE00003577904	173833376	173833499
ENSE00003593572	173830660	173830761
ENSE00003596584	173850327	173850479
ENSE00003617241	173856666	173856741
ENSE00003624909	173826687	173826786
ENSE00003632588	173845229	173845291
ENSE00003643612	173853349	173853567
ENSE00003680351	173836940	173837046
ENSE00003686116	173838190	173838259
ENSE00003687460	173834473	173834519
ENSE00003692024	173828333	173828399
ENSE00003834272	173824673	173825356

Expression profiles

Bgee: expression breadth ubiquitous, 180 present calls, max score 89.17.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 22.4731 / max 192.5535, expressed in 1807 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
6742	16.1815	1791
6740	2.5469	1403
6747	1.2988	679
6743	0.8036	510
6746	0.7418	424
6741	0.5736	344
6744	0.1784	54
6745	0.1486	44

Top tissues by expression

280 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	89.17	gold quality
rectum	UBERON:0001052	86.93	gold quality
adrenal tissue	UBERON:0018303	86.15	gold quality
right adrenal gland	UBERON:0001233	84.71	gold quality
ventricular zone	UBERON:0003053	84.56	gold quality
mucosa of transverse colon	UBERON:0004991	84.42	gold quality
right adrenal gland cortex	UBERON:0035827	84.24	gold quality
islet of Langerhans	UBERON:0000006	83.88	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.70	gold quality
left adrenal gland	UBERON:0001234	83.31	gold quality
left adrenal gland cortex	UBERON:0035825	82.41	gold quality
calcaneal tendon	UBERON:0003701	82.28	gold quality
adrenal gland	UBERON:0002369	82.11	gold quality
ganglionic eminence	UBERON:0004023	81.69	gold quality
stromal cell of endometrium	CL:0002255	80.98	gold quality
adrenal cortex	UBERON:0001235	80.08	gold quality
transverse colon	UBERON:0001157	79.76	gold quality
monocyte	CL:0000576	79.26	gold quality
leukocyte	CL:0000738	79.18	gold quality
mononuclear cell	CL:0000842	79.09	gold quality
heart left ventricle	UBERON:0002084	78.94	gold quality
pancreas	UBERON:0001264	78.73	gold quality
body of stomach	UBERON:0001161	78.37	gold quality
cardiac ventricle	UBERON:0002082	78.34	gold quality
body of pancreas	UBERON:0001150	78.27	gold quality
muscle of leg	UBERON:0001383	78.18	gold quality
hindlimb stylopod muscle	UBERON:0004252	78.08	gold quality
gastrocnemius	UBERON:0001388	78.04	gold quality
adult mammalian kidney	UBERON:0000082	77.73	gold quality
right atrium auricular region	UBERON:0006631	77.68	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.45

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ATF4, GLI1

miRNA regulators (miRDB)

59 targeting DARS2, 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-3163	100.00	77.23	8605
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-432-3P	100.00	67.86	705
HSA-MIR-4668-3P	100.00	68.74	2635
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-3605-5P	99.96	67.12	932
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-570-3P	99.96	72.41	4910
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-544A	99.84	68.66	1965
HSA-MIR-7161-5P	99.68	68.92	1592

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 24.8% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 24)

• The gene for mitochondrial aspartyl-tRNA synthetase is described and the initial characterization of the enzyme is reported. Genes for the remaining missing human synthetases have also been found with the exception of glutaminyl-tRNA synthetase. (PMID:15779907)
• Mutations in DARS2, which encodes mitochondrial aspartyl-tRNA synthetase, in affected individuals with leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation. (PMID:17384640)
• DARS2 mutations cause childhood-to-adolescence onset leucoencephalopathy, but they do not seem to be associated with multiple sclerosis. (PMID:19592391)
• This report describes two novel heterozygote composite mutations in the DARS2 gene (PMID:20878420)
• Case demonstrates that DARS2 mutation homozygosity is not lethal, as suggested earlier, but compatible with a rather benign disease course. (PMID:21749991)
• We describe two new cases of Leukoencephalopathy with brainstem and spinal cord involvement and elevated lactate with a novel pathogenic mutation in the DARS2 gene (PMID:21792730)
• A novel homozygous mutation of DARS2 may cause a severe LBSL (Leukoencephalopathy with brain stem and spinal cord involvement with lactate elevation) variant. (PMID:21815884)
• Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation is associated with cell-type-dependent splicing of mtAspRS mRNA. (PMID:22023289)
• Pathogenic mutations causing LBSL affect mitochondrial aspartyl-tRNA synthetase in diverse way (PMID:23216004)
• A comparison of biophysical properties of human mitochondrial aspartyl-tRNA synthetase, HsaDRS2, with them to those of a bacterial (E. coli) homolog, EcoDRS. (PMID:23275545)
• Cognitive impairment seems to be common among patients with leukoencephalopathy with brainstem and spinal cord involvement and elevated lactate and DARS2 mutations (PMID:23652419)
• 60 different DARS2 mutations were identified in 78 patients with leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation, 13 of which have not been reported before (PMID:24566671)
• This study identified DARS2-associated leukoencephalopathy with hypomyelination with brainstem and spinal cord involvement and leg spasticity. (PMID:25527264)
• Mutations with mild effects on solubility occur in patients as allelic combinations whereas those with strong effects on solubility or on aminoacylation are necessarily associated with a partially functional allele. (PMID:26620921)
• Results show that DARS2 is strongly upregulated in hepatocellular carcinoma (HCC) and is associated with HCC progression. DARS2 promotes HCC tumorigenesis by accelerating cell cycle progression and attenuating cell apoptosis. (PMID:29052520)
• Whole exome sequencing of the proband identified two compound heterozygous variants (NM_018122.4:c.1762C > G and c.563G > A) in DARS2 (PMID:30352563)
• DARS2 is indispensable for Purkinje cell survival and protects against cerebellar ataxia. (PMID:32766765)
• Phenotypic diversity of brain MRI patterns in mitochondrial aminoacyl-tRNA synthetase mutations. (PMID:33972171)
• High expression of DARS2 indicates poor prognosis in lung adenocarcinoma. (PMID:36085578)
• Mutations in DARS2 result in global dysregulation of mRNA metabolism and splicing. (PMID:37563224)
• DARS2 overexpression is associated with PET/CT metabolic parameters and affects glycolytic activity in lung adenocarcinoma. (PMID:37626419)
• DARS2 promotes the occurrence of lung adenocarcinoma via the ERK/c-Myc signaling pathway. (PMID:37950542)
• Functional enrichment analysis reveals the involvement of DARS2 in multiple biological pathways and its potential as a therapeutic target in esophageal carcinoma. (PMID:38382106)
• Identification of a Novel Indel Variant in the DARS2 Gene in Russian Patients with Leukoencephalopathy with Brainstem and Spinal Cord Involvement and Lactate Elevation. (PMID:38790244)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	dars2	ENSDARG00000060861
mus_musculus	Dars2	ENSMUSG00000026709
rattus_norvegicus	Dars2	ENSRNOG00000002813
drosophila_melanogaster	AspRS-m	FBGN0051739
caenorhabditis_elegans		WBGENE00001095

Paralogs (4): KARS1 (ENSG00000065427), DARS1 (ENSG00000115866), NARS1 (ENSG00000134440), NARS2 (ENSG00000137513)

Protein

Protein identifiers

Aspartate–tRNA ligase, mitochondrial — Q6PI48 (reviewed: Q6PI48)

Alternative names: Aspartyl-tRNA synthetase

All UniProt accessions (8): A0A3B3IS01, A0A3B3IS54, A0A3B3ISK7, A0A3B3IT01, A0A3B3IT89, A0A3B3ITK9, A0A3B3ITS3, Q6PI48

UniProt curated annotations — full annotation on UniProt →

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

Subunit / interactions. Homodimer. Interacts with FBXO24.

Subcellular location. Mitochondrion matrix. Mitochondrion membrane.

Post-translational modifications. Acetylated; acetylation protects from ubiquitin-mediated degradation. Ubiquitinated by the SCF-FBXO24 E3 ubiquitin ligase, leading to proteasomal degradation.

Disease relevance. Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) [MIM:611105] Autosomal recessive disease and is defined on the basis of a highly characteristic constellation of abnormalities observed by magnetic resonance imaging and spectroscopy. Affected individuals develop slowly progressive cerebellar ataxia, spasticity, and dorsal column dysfunction, sometimes with a mild cognitive deficit or decline. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the class-II aminoacyl-tRNA synthetase family. Type 1 subfamily.

RefSeq proteins (3): NP_001352141, NP_001352142, NP_060592* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002312	Asp/Asn-tRNA-synth_IIb	Family
IPR004115	GAD-like_sf	Homologous_superfamily
IPR004364	Aa-tRNA-synt_II	Domain
IPR004365	NA-bd_OB_tRNA	Domain
IPR004524	Asp-tRNA-ligase_1	Family
IPR006195	aa-tRNA-synth_II	Domain
IPR012340	NA-bd_OB-fold	Homologous_superfamily
IPR029351	GAD_dom	Domain
IPR045864	aa-tRNA-synth_II/BPL/LPL	Homologous_superfamily
IPR047089	Asp-tRNA-ligase_1_N	Domain
IPR047090	AspRS_core	Domain

Pfam: PF00152, PF01336, PF02938

Enzyme classification (BRENDA):

• EC 6.1.1.12 — aspartate-tRNA ligase (BRENDA: 31 organisms, 64 substrates, 51 inhibitors, 107 Km, 53 kcat entries)

Substrate kinetics (BRENDA)

13 substrates with measured Km, best-characterized 13. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
TRNAASP	—	33
ATP	0.023–1.11	22
ASP	0.003–4.6	13
L-ASPARTATE	0.0015–13.76	10
TRNAASN	0.0001–0.0091	10
ASPARTATE	1.2–1.4	5
2-AMINOMALONIC ACID	8	1
ASPARTIC ACID	0.03	1
L-ASP	0.32	1
L-ASPARTIC ACID	0.005	1
THREO-3-HYDROXYASPARTIC ACID	24	1
TRNAASPA73	1.3	1
ASPARTYL-TRNA	—	0

Catalyzed reactions (Rhea), 1 shown:

• tRNA(Asp) + L-aspartate + ATP = L-aspartyl-tRNA(Asp) + AMP + diphosphate (RHEA:19649)

UniProt features (35 total): sequence variant 13, mutagenesis site 7, binding site 5, modified residue 4, cross-link 3, transit peptide 1, chain 1, region of interest 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
4AH6	X-RAY DIFFRACTION	3.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6PI48-F1	88.91	0.77

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 (5): 266–268; 266; 535; 542; 584–587

Post-translational modifications (7): 368, 382, 153, 558, 640, 219, 242

Mutagenesis-validated functional residues (7):

Position	Phenotype
58	no effect on its mitochondria localization.
136	no effect on its mitochondria localization.
153	displays low levels of polyubiquitylation.
338	no effect on its mitochondria localization.
368	displays decreased acetylation and high-levels of polyubiquitylation.
558	displays low levels of polyubiquitylation.
640	displays low levels of polyubiquitylation.

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: 231 (showing top): GSE45365_NK_CELL_VS_CD8_TCELL_DN, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GOBP_AMINO_ACID_ACTIVATION, GOBP_TRNA_METABOLIC_PROCESS, GOBP_MITOCHONDRIAL_TRANSLATION, GOBP_TRANSLATION, GOCC_MITOCHONDRIAL_ENVELOPE, GOBP_MITOCHONDRIAL_RNA_METABOLIC_PROCESS, KEGG_AMINOACYL_TRNA_BIOSYNTHESIS, FISCHER_DREAM_TARGETS, REACTOME_MITOCHONDRIAL_TRNA_AMINOACYLATION, ACEVEDO_LIVER_CANCER_UP, GOCC_MITOCHONDRIAL_MATRIX, MARSON_BOUND_BY_FOXP3_STIMULATED, MARSON_BOUND_BY_FOXP3_UNSTIMULATED

GO Biological Process (5): aspartyl-tRNA aminoacylation (GO:0006422), tRNA aminoacylation (GO:0043039), mitochondrial asparaginyl-tRNA aminoacylation (GO:0070145), translation (GO:0006412), tRNA aminoacylation for protein translation (GO:0006418)

GO Molecular Function (10): tRNA binding (GO:0000049), aspartate-tRNA ligase activity (GO:0004815), ATP binding (GO:0005524), protein homodimerization activity (GO:0042803), aspartate-tRNA(Asn) ligase activity (GO:0050560), nucleotide binding (GO:0000166), nucleic acid binding (GO:0003676), aminoacyl-tRNA ligase activity (GO:0004812), protein binding (GO:0005515), ligase activity (GO:0016874)

GO Cellular Component (6): nucleoplasm (GO:0005654), mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), mitochondrial membrane (GO:0031966), cytoplasm (GO:0005737), membrane (GO:0016020)

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	3
cellular anatomical structure	3
aminoacyl-tRNA ligase activity	2
binding	2
tRNA aminoacylation for protein translation	1
tRNA metabolic process	1
amino acid activation	1
asparaginyl-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
translation	1
tRNA aminoacylation	1
RNA binding	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
identical protein binding	1
protein dimerization activity	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
cytoplasm	1
intracellular membrane-bounded organelle	1
intracellular organelle lumen	1
mitochondrial envelope	1
organelle membrane	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

2962 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DARS2	AARS2	Q5JTZ9	870
DARS2	EARS2	Q5JPH6	838
DARS2	RARS2	Q5T160	811
DARS2	FARS2	O95363	793
DARS2	YARS2	Q9Y2Z4	770
DARS2	AARS1	P49588	722
DARS2	VARS1	P26640	719
DARS2	LARS2	Q15031	717
DARS2	VARS2	Q5ST30	713
DARS2	PARS2	Q7L3T8	710
DARS2	WARS2	Q9UGM6	709
DARS2	CARS2	Q9HA77	709
DARS2	IARS2	Q9NSE4	708
DARS2	MARS2	Q96GW9	705
DARS2	TARS2	Q9BW92	674

IntAct

133 interactions, top by confidence:

A	B	Type	Score
DARS2	HSPD1	psi-mi:“MI:0915”(physical association)	0.730
HSPD1	NUDT19	psi-mi:“MI:0914”(association)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CDC123	EIF2S2	psi-mi:“MI:0914”(association)	0.710
DARS2	GAPDHS	psi-mi:“MI:0915”(physical association)	0.560
ALDH18A1	DARS2	psi-mi:“MI:0915”(physical association)	0.560
TMEM239	DARS2	psi-mi:“MI:0915”(physical association)	0.560
FETUB	DARS2	psi-mi:“MI:0915”(physical association)	0.560
UNC50	DARS2	psi-mi:“MI:0915”(physical association)	0.560
TSPAN33	DARS2	psi-mi:“MI:0915”(physical association)	0.560
CDIPT	DARS2	psi-mi:“MI:0915”(physical association)	0.560
THSD7B	DARS2	psi-mi:“MI:0915”(physical association)	0.560
COL8A2	DARS2	psi-mi:“MI:0915”(physical association)	0.560
CYB561	DARS2	psi-mi:“MI:0915”(physical association)	0.560
DARS2	TMEM239	psi-mi:“MI:0915”(physical association)	0.560
PLP2	DARS2	psi-mi:“MI:0915”(physical association)	0.560
DARS2	FETUB	psi-mi:“MI:0915”(physical association)	0.560
AOC3	DARS2	psi-mi:“MI:0915”(physical association)	0.560
DARS2	TSPAN33	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (193): DARS2 (Affinity Capture-MS), DARS2 (Affinity Capture-MS), DARS2 (Affinity Capture-MS), DARS2 (Co-fractionation), DARS2 (Co-fractionation), FNTA (Co-fractionation), POR (Co-fractionation), RPA2 (Co-fractionation), DARS2 (Affinity Capture-MS), DARS2 (Affinity Capture-MS), DARS2 (Affinity Capture-MS), DARS2 (Affinity Capture-MS), DARS2 (Affinity Capture-MS), DARS2 (Affinity Capture-MS), GAPDHS (Affinity Capture-MS)

ESM2 similar proteins: A1L258, B5DEQ3, B7ZMP1, B8B7X6, D4AAT7, F1QXM5, O00116, O04015, O04226, O23240, O45218, O46504, O65361, P31754, P32232, P32296, P46681, P52624, P54887, P54888, P84850, P87228, P97275, Q01415, Q1JPD3, Q3KRD0, Q5M7W7, Q5R6J8, Q5R824, Q68FH4, Q6PI48, Q7TNG8, Q7TSQ8, Q7XI14, Q86WU2, Q8BIP0, Q8C0I1, Q8CIM3, Q8IW45, Q8NCN5

Diamond homologs: A4J2J2, A5D3E3, A5FKJ2, A5FRE3, A5G3L5, A5UUR3, A6GWB6, A6QPU5, A6VXD0, A7NQH9, A7Z750, A8ZUR7, A9B392, A9KF44, A9MUB9, A9N999, A9WGJ7, B0K0N5, B0K978, B0TF89, B1ZSW8, B2A2G0, B2J116, B2RHE0, B2V713, B3DX01, B3EUH5, B3WEM2, B4SVF1, B4T7Z9, B4TYS4, B4U7P3, B5EIV1, B5F3I9, B5FSN0, B5R1V2, B5R8D6, B5YDT0, B5YJP5, B7GFR1

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
ATF4	“up-regulates quantity by expression”	DARS2	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 122 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 ribosome-associated quality control	7	9.9×	9e-04
Mitochondrial protein degradation	7	9.2×	9e-04

GO biological processes:

GO term	Partners	Fold	FDR
mitochondrial large ribosomal subunit assembly	6	54.6×	4e-07

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	33
Likely pathogenic	29
Uncertain significance	187
Likely benign	141
Benign	51

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1027436	NM_018122.5(DARS2):c.233del (p.Asn78fs)	Pathogenic
1057	NM_018122.5(DARS2):c.228-21_228-20delinsC	Pathogenic
1059	NM_018122.5(DARS2):c.787C>T (p.Arg263Ter)	Pathogenic
1061	NM_018122.5(DARS2):c.455G>T (p.Cys152Phe)	Pathogenic
1062	NM_018122.5(DARS2):c.492+2T>C	Pathogenic
1063	NM_018122.5(DARS2):c.133A>G (p.Ser45Gly)	Pathogenic
1075158	NM_018122.5(DARS2):c.1352dup (p.Leu451fs)	Pathogenic
1453218	NM_018122.5(DARS2):c.6C>G (p.Tyr2Ter)	Pathogenic
1455328	NM_018122.5(DARS2):c.1395_1396del (p.Gly467fs)	Pathogenic
1964202	NM_018122.5(DARS2):c.728del (p.Pro243fs)	Pathogenic
2426445	NC_000001.10:g.(?173794368)(173800788_?)del	Pathogenic
2426446	NC_000001.10:g.(?173806058)(173810131_?)del	Pathogenic
2691462	NM_018122.5(DARS2):c.161dup (p.Cys54fs)	Pathogenic
2819918	NM_018122.5(DARS2):c.1065del (p.Leu356fs)	Pathogenic
2888230	NM_018122.5(DARS2):c.1552G>T (p.Glu518Ter)	Pathogenic
3006077	NM_018122.5(DARS2):c.1011dup (p.Gly338fs)	Pathogenic
3013251	NM_018122.5(DARS2):c.1366C>T (p.Arg456Ter)	Pathogenic
3024559	NM_018122.5(DARS2):c.1675-1256_*115delinsGCAACATTTCGGCAACATTCCAACC	Pathogenic
3027397	GRCh37/hg19 1q25.1(chr1:173803611-173803657)x1	Pathogenic
3063594	NM_018122.5(DARS2):c.109del (p.Ser37fs)	Pathogenic
3251557	NM_018122.5(DARS2):c.119_120dup (p.Ile41fs)	Pathogenic
3725558	NM_018122.5(DARS2):c.1427dup (p.Ser477fs)	Pathogenic
4688052	NM_018122.5(DARS2):c.1006C>T (p.Arg336Cys)	Pathogenic
4688053	NM_018122.5(DARS2):c.713C>T (p.Ser238Phe)	Pathogenic
4688054	NM_018122.5(DARS2):c.74del (p.Ile25fs)	Pathogenic
4688055	NM_018122.5(DARS2):c.1508C>T (p.Pro503Leu)	Pathogenic
4727096	NM_018122.5(DARS2):c.910del (p.Ser304fs)	Pathogenic
4728270	NC_000001.11:g.173834473_173834507del	Pathogenic
4760117	NM_018122.5(DARS2):c.535_536del (p.Leu178_Arg179insTer)	Pathogenic
4847009	NM_018122.5(DARS2):c.566dup (p.Arg190fs)	Pathogenic

SpliceAI

2607 predictions. Top by Δscore:

Variant	Effect	Δscore
1:173826683:A:AG	acceptor_gain	1.0000
1:173826684:A:G	acceptor_gain	1.0000
1:173826685:A:G	acceptor_gain	1.0000
1:173826685:AG:A	acceptor_loss	1.0000
1:173826686:G:GA	acceptor_loss	1.0000
1:173826686:G:GG	acceptor_gain	1.0000
1:173826686:GA:G	acceptor_gain	1.0000
1:173830658:A:AG	acceptor_gain	1.0000
1:173830658:AGTC:A	acceptor_gain	1.0000
1:173830659:G:GG	acceptor_gain	1.0000
1:173830659:GTCG:G	acceptor_gain	1.0000
1:173830757:ATCCA:A	donor_gain	1.0000
1:173830762:G:GG	donor_gain	1.0000
1:173830762:GTAG:G	donor_loss	1.0000
1:173830763:T:A	donor_loss	1.0000
1:173831525:A:AG	acceptor_gain	1.0000
1:173831532:A:AG	acceptor_gain	1.0000
1:173831533:A:G	acceptor_gain	1.0000
1:173831534:GAAA:G	acceptor_gain	1.0000
1:173833374:A:AG	acceptor_gain	1.0000
1:173833374:A:G	acceptor_loss	1.0000
1:173833375:G:GA	acceptor_gain	1.0000
1:173833375:GA:G	acceptor_gain	1.0000
1:173833495:GCATG:G	donor_gain	1.0000
1:173833496:CATGG:C	donor_loss	1.0000
1:173833498:TGG:T	donor_loss	1.0000
1:173833500:G:GC	donor_loss	1.0000
1:173833500:G:GG	donor_gain	1.0000
1:173833501:T:A	donor_loss	1.0000
1:173834467:TTTTA:T	acceptor_loss	1.0000

AlphaMissense

4214 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:173837017:G:C	K247N	0.998
1:173837017:G:T	K247N	0.998
1:173838211:T:G	C264W	0.998
1:173837000:A:C	S242R	0.997
1:173837002:T:A	S242R	0.997
1:173837002:T:G	S242R	0.997
1:173838251:T:C	F278L	0.997
1:173838253:T:A	F278L	0.997
1:173838253:T:G	F278L	0.997
1:173830705:T:C	S114P	0.996
1:173830730:T:A	V122D	0.996
1:173833476:G:C	R198P	0.996
1:173834475:T:C	F207L	0.995
1:173834477:T:A	F207L	0.995
1:173834477:T:G	F207L	0.995
1:173837008:A:C	Q244H	0.995
1:173837008:A:T	Q244H	0.995
1:173857575:C:A	A603D	0.995
1:173857577:T:C	F604L	0.995
1:173857579:C:A	F604L	0.995
1:173857579:C:G	F604L	0.995
1:173830738:C:A	R125S	0.994
1:173836952:T:C	F226L	0.994
1:173836954:T:A	F226L	0.994
1:173836954:T:G	F226L	0.994
1:173853514:T:C	F504L	0.994
1:173853516:T:A	F504L	0.994
1:173853516:T:G	F504L	0.994
1:173826768:G:A	G70E	0.993
1:173826770:T:A	W71R	0.993

dbSNP variants (sampled 300 via entrez): RS1000001878 (1:173851638 G>A), RS1000023807 (1:173829811 A>G), RS1000054945 (1:173829583 C>T), RS1000118429 (1:173843572 A>G,T), RS1000208924 (1:173824302 CA>C), RS1000661229 (1:173823157 A>T), RS1000722333 (1:173824563 G>A), RS1000780590 (1:173857759 C>T), RS1000917593 (1:173837167 G>A), RS1000949762 (1:173822815 G>A), RS1001029728 (1:173843007 A>G), RS1001049257 (1:173829727 G>C), RS1001129185 (1:173852232 G>A), RS1001203823 (1:173842583 G>A,T), RS1001371500 (1:173836862 T>C)

Disease associations

OMIM: gene MIM:610956 | disease phenotypes: MIM:611105, MIM:108600, MIM:119800, MIM:621485

GenCC curated gene-disease

Disease	Classification	Inheritance
leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome	Definitive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
mitochondrial disease	Definitive	AR

Mondo (7): leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome (MONDO:0012622), spastic ataxia (MONDO:0017845), mitochondrial disease (MONDO:0044970), hypertensive disorder (MONDO:0005044), gout (MONDO:0005393), clubfoot (MONDO:0007342), Charcot-Marie-Tooth disease, axonal, type 2LL (MONDO:0980969)

Orphanet (4): Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome (Orphanet:137898), Spastic ataxia (Orphanet:316226), Mitochondrial disease (Orphanet:68380), Familial clubfoot with or without associated lower limb anomalies (Orphanet:199315)

HPO phenotypes

90 total (30 of 90 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000365	Hearing impairment
HP:0000508	Ptosis
HP:0000514	Slow saccadic eye movements
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000651	Diplopia
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001265	Hyporeflexia
HP:0001268	Mental deterioration
HP:0001270	Motor delay
HP:0001271	Polyneuropathy
HP:0001272	Cerebellar atrophy
HP:0001276	Hypertonia
HP:0001284	Areflexia
HP:0001288	Gait disturbance
HP:0001315	Reduced tendon reflexes
HP:0001317	Abnormal cerebellum morphology
HP:0001324	Muscle weakness
HP:0001328	Specific learning disability
HP:0001336	Myoclonus
HP:0001337	Tremor
HP:0001344	Absent speech
HP:0001347	Hyperreflexia

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST007487_34	Waist-to-hip ratio adjusted for BMI (additive genetic model)	1.000000e-07
GCST007494_17	Waist-to-hip ratio adjusted for BMI (additive genetic model)	2.000000e-07
GCST90002383_341	Hematocrit	2.000000e-09
GCST90002384_17	Hemoglobin	5.000000e-09

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0004348	hematocrit
EFO:0004509	hemoglobin measurement

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D003025	Clubfoot	C05.330.488.655.063; C05.330.495.681.063; C05.660.585.512.380.813.063; C16.131.621.585.512.500.681.063
D006073	Gout	C05.550.114.423; C05.550.354.500; C05.799.414; C16.320.565.798.368; C18.452.648.798.368
D006973	Hypertension	C14.907.489
C567009	Leukoencephalopathy with Brainstem and Spinal Cord Involvement and Lactate Elevation (supp.)
C564815	Spastic Ataxia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Acetaminophen	decreases expression, affects expression, affects cotreatment	3
Valproic Acid	affects expression, decreases expression, increases expression	3
bisphenol A	increases abundance, increases expression, decreases reaction	2
cobaltous chloride	decreases expression	2
perfluorooctanoic acid	increases expression, affects cotreatment, decreases expression	2
Cadmium Chloride	decreases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	decreases expression	1
FR900359	decreases phosphorylation	1
ginger extract	decreases reaction, increases abundance, increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, affects expression, increases abundance	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	decreases expression	1
butyraldehyde	decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
methacrylaldehyde	increases abundance, affects cotreatment, affects expression	1
beta-methylcholine	affects expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
2,3,5-(triglutathion-S-yl)hydroquinone	increases ADP-ribosylation	1
CGP 52608	increases reaction, affects binding	1
K 7174	decreases expression	1
bisphenol B	increases expression	1
abrine	decreases expression	1
bisphenol S	increases expression	1
Sunitinib	decreases expression	1
Acrolein	affects cotreatment, affects expression, increases abundance	1
Air Pollutants	increases abundance, affects cotreatment, affects expression	1
Air Pollutants, Occupational	decreases expression	1

Cellosaurus cell lines

1 cell lines: 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_C1T4	FHUSTCi002-A	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

293 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
NCT00000521	PHASE4	COMPLETED	Sodium-Potassium Blood Pressure Trial in Children
NCT00018759	PHASE4	COMPLETED	Treatment Effects on Platelet Calcium in Hypertensive and Depressed Patients
NCT00034840	PHASE4	COMPLETED	Telmisartan vs. Valsartan in Patients With Mild to Moderate Hypertension Following a Missed Dose
NCT00044265	PHASE4	COMPLETED	Treatment of Pediatric Hypertension With Altace Trial
NCT00060918	PHASE4	COMPLETED	Glycemic Control Of Carvedilol Versus Metoprolol In Patients With Type II Diabetes Mellitus And Hypertension
NCT00060931	PHASE4	COMPLETED	Effect Of Carvedilol Versus Metoprolol On Glycemic Control In Patients With Type II Diabetes And Hypertension
NCT00110422	PHASE4	COMPLETED	Irbesartan in the Treatment of Hypertensive Patients With Metabolic Syndrome
NCT00115726	PHASE4	COMPLETED	Trial Assessing the Effect of Preoperative Furosemide on Intraoperative Blood Pressure
NCT00120380	PHASE4	TERMINATED	Combination Therapy of Bosentan and Aerosolized Iloprost in Idiopathic Pulmonary Arterial Hypertension (IPAH)
NCT00122811	PHASE4	UNKNOWN	The Hypertension in the Very Elderly Trial (HYVET)
NCT00123045	PHASE4	COMPLETED	Patient-Physician Partnership to Improve High Blood Pressure Adherence
NCT00123604	PHASE4	COMPLETED	Vascular Effects of Carvedilol Versus Metoprolol in Hypertensive Patients With Type 2 Diabetes
NCT00126516	PHASE4	COMPLETED	Angiotensin II Receptor Blockers (ARB) and ACE Inhibitors (ACEI) on Silent Brain Infarction and Cognitive Decline
NCT00127348	PHASE4	COMPLETED	Effect of Continuous Positive Airway Pressure (CPAP) on Hypertension and Cardiovascular Morbidity-Mortality in Patients With Sleep Apnea and no Daytime Sleepiness
NCT00128518	PHASE4	COMPLETED	IDEAL Study: Identification of the Determinants of the Efficacy of Arterial Blood Pressure Lowering Drugs
NCT00129233	PHASE4	COMPLETED	Comparison of Valsartan With Amlodipine in Hypertensive Patients With Glucose Intolerance
NCT00129909	PHASE4	COMPLETED	STITCH (Simplified Therapeutic Intervention To Control Hypertension)
NCT00130156	PHASE4	COMPLETED	Effects of Combination Therapy With Alpha-1 Blocker (Bunazosin or Doxazosin) in the Treatment of Patients With Mild to Moderate Essential Hypertension
NCT00131846	PHASE4	COMPLETED	Diuretics In the Management of Essential Hypertension (DIME) Study
NCT00133068	PHASE4	COMPLETED	Collaboration to Reduce Disparities in Hypertension
NCT00133328	PHASE4	UNKNOWN	A Morbidity-Mortality and Remodeling Study With Valsartan
NCT00133692	PHASE4	COMPLETED	INVEST: INternational VErapamil SR Trandolapril STudy
NCT00134160	PHASE4	COMPLETED	OlmeSartan and Calcium Antagonists Randomized (OSCAR) Study
NCT00136851	PHASE4	COMPLETED	Study Comparing the Efficacy of Amlodipine Besylate/Benazepril Versus Amlodipine in the Treatment of Severe Hypertension
NCT00139386	PHASE4	COMPLETED	Candesartan for Prevention of Cardiovascular Events After Cypher or Taxus Coronary Stenting (4C) Trial
NCT00139555	PHASE4	COMPLETED	Effects of Amlodipine/Benazepril in Reducing Left Ventricular Hypertrophy in Patients With High Risk Hypertension
NCT00139984	PHASE4	COMPLETED	Ambulatory Blood Pressure Monitoring for Antihypertensive Treatment Guidance
NCT00140790	PHASE4	TERMINATED	Valsartan in Cardiovascular Disease With Renal Dysfunction (The V-CARD) Study
NCT00140907	PHASE4	COMPLETED	ALLOGRAFT, A Study to Evaluate the Renal Protective Effects of Losartan (0954-222)(COMPLETED)
NCT00140959	PHASE4	COMPLETED	Losartan and HCTZ and Amlodipine vs Atenolol and Amlodipine (0954A-309)(COMPLETED)
NCT00144144	PHASE4	UNKNOWN	A Study on Ca Blocker Versus AII Antagonists in Hypertension With Type 2 Diabetes
NCT00144937	PHASE4	UNKNOWN	Multifactorial Intervention on Cardiovascular Risk Factors in Subjects With Peripheral Arterial Disease
NCT00147251	PHASE4	COMPLETED	Stop Atherosclerosis in Native Diabetics Study
NCT00147524	PHASE4	COMPLETED	Non-Comparative Study To Evaluate Changes In FMD After Quinapril Therapy In Hypertensive Women
NCT00147563	PHASE4	COMPLETED	Compare Effectiveness of Eplerenone vs Atenolol in Reversing the Remodelling Resistance Arteries in Subjects With HT
NCT00149227	PHASE4	COMPLETED	Add-on Effects of Valsartan on Morbi- Mortality (KYOTO HEART Study)
NCT00150358	PHASE4	COMPLETED	To Yield Further Information On The Efficacy And Safety Of Viagra Among Subjects With Arterial Hypertension .
NCT00150384	PHASE4	COMPLETED	Clinical Utility of Caduet in Achieving Blood Pressure and Lipid Endpoints in a Specific Patient Population
NCT00153023	PHASE4	COMPLETED	1 Year Trial Telmisartan 80 mg Versus Valsartan 160 mg in Hypertensive Type 2 Diabetic Patients With Overt Nephropathy