DARS1

Summary

DARS1 (aspartyl-tRNA synthetase 1, HGNC:2678) is a protein-coding gene on chromosome 2q21.3, encoding Aspartate–tRNA ligase, cytoplasmic (P14868). Catalyzes the specific attachment of an amino acid to its cognate tRNA in a 2 step reaction: the amino acid (AA) is first activated by ATP to form AA-AMP and then transferred to the acceptor end of the tRNA. It is a common-essential gene (DepMap: required in 99.6% of cancer cell lines).

This gene encodes a member of a multienzyme complex that functions in mediating the attachment of amino acids to their cognate tRNAs. The encoded protein ligates L-aspartate to tRNA(Asp). Mutations in this gene have been found in patients showing hypomyelination with brainstem and spinal cord involvement and leg spasticity. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 1615 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hypomyelination with brain stem and spinal cord involvement and leg spasticity (Definitive, GenCC)
• GWAS associations: 14
• Clinical variants (ClinVar): 261 total — 6 pathogenic, 5 likely-pathogenic
• Phenotypes (HPO): 23
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 99.6% of screened cell lines (common-essential)
• MANE Select transcript: NM_001349

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2678
Approved symbol	DARS1
Name	aspartyl-tRNA synthetase 1
Location	2q21.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000115866
Ensembl biotype	protein_coding
OMIM	603084
Entrez	1615

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 13 protein_coding, 5 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000264161, ENST00000422708, ENST00000435076, ENST00000441323, ENST00000449218, ENST00000456565, ENST00000463008, ENST00000474184, ENST00000478212, ENST00000489964, ENST00000491481, ENST00000888460, ENST00000888461, ENST00000888462, ENST00000939648, ENST00000952144, ENST00000952145, ENST00000952146, ENST00000952147

RefSeq mRNA: 2 — MANE Select: NM_001349 NM_001293312, NM_001349

CCDS: CCDS2180

Canonical transcript exons

ENST00000264161 — 16 exons

Exon	Start	End
ENSE00000777145	135914469	135914511
ENSE00000777146	135916226	135916372
ENSE00000777147	135920453	135920600
ENSE00000777148	135922784	135922918
ENSE00000777149	135924387	135924498
ENSE00000777151	135932783	135932842
ENSE00000777152	135933910	135933990
ENSE00001008785	135905881	135907407
ENSE00001071619	135943378	135943480
ENSE00001071624	135985403	135985626
ENSE00003478507	135983397	135983454
ENSE00003491991	135911382	135911493
ENSE00003542841	135979274	135979366
ENSE00003585368	135912486	135912566
ENSE00003627588	135911139	135911210
ENSE00003691233	135961396	135961498

Expression profiles

Bgee: expression breadth ubiquitous, 300 present calls, max score 98.93.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 46.7066 / max 587.6716, expressed in 1823 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
30781	20.0181	1808
30779	15.1265	1797
30778	6.9564	1680
30780	3.5301	1488
30782	0.4523	188
30775	0.3594	127
30783	0.2638	103

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
oocyte	CL:0000023	98.93	gold quality
pericardium	UBERON:0002407	98.72	gold quality
cartilage tissue	UBERON:0002418	98.59	gold quality
ventricular zone	UBERON:0003053	98.42	gold quality
secondary oocyte	CL:0000655	98.26	gold quality
parotid gland	UBERON:0001831	98.13	gold quality
type B pancreatic cell	CL:0000169	97.99	gold quality
nipple	UBERON:0002030	97.97	gold quality
vena cava	UBERON:0004087	97.96	gold quality
seminal vesicle	UBERON:0000998	97.87	gold quality
mammary duct	UBERON:0001765	97.84	gold quality
inferior olivary complex	UBERON:0002127	97.78	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	97.76	gold quality
embryo	UBERON:0000922	97.64	gold quality
lateral globus pallidus	UBERON:0002476	97.53	gold quality
epithelium of mammary gland	UBERON:0003244	97.50	gold quality
penis	UBERON:0000989	97.30	gold quality
pigmented layer of retina	UBERON:0001782	97.30	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	97.30	gold quality
pharyngeal mucosa	UBERON:0000355	97.29	gold quality
retina	UBERON:0000966	97.27	gold quality
superior surface of tongue	UBERON:0007371	97.26	gold quality
ganglionic eminence	UBERON:0004023	97.20	gold quality
adrenal tissue	UBERON:0018303	97.19	gold quality
calcaneal tendon	UBERON:0003701	97.14	gold quality
body of tongue	UBERON:0011876	97.03	gold quality
renal medulla	UBERON:0000362	97.01	gold quality
saphenous vein	UBERON:0007318	96.92	gold quality
tongue	UBERON:0001723	96.87	gold quality
medulla oblongata	UBERON:0001896	96.71	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

93 targeting DARS1, 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-4262	100.00	73.26	3931
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-520G-5P	99.99	66.76	658
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-3658	99.96	73.87	4379
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-552-5P	99.93	68.56	1583
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-329-3P	99.91	66.56	1234
HSA-MIR-362-3P	99.91	66.38	1267

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 99.6% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 8)

• the N-terminus shows a less-ordered structure with flexible beta-turn, suggesting that when tRNA is stretched, the dissociation rate of Asp-tRNA from aspartyl-tRNA synthetase is reduced, giving time for elongation factor 1alpha to interact with Asp-tRNA. (PMID:12824064)
• Report on the crystal structure of human cytosolic aspartyl-tRNA synthetase (DRS) at a resolution of 2.25 A. (PMID:23609930)
• Mutations in DARS cause hypomyelination with brain stem and spinal cord involvement and leg spasticity. (PMID:23643384)
• Genetic variants of the DARS gene may influence individual susceptibility to isolated VSD in Chinese Han population. Risk of VSD was significantly associated with rs2164331 [G/A; odds ratio (OR) = 0.78, 95% confidence interval (CI) = 0.69-0.91; P = 3.17 x 10(-3)], rs6738266 [G/A; OR = 1.17, 95% CI = 1.05-1.29, P = 1.83 x 10(-3)], and rs309143 [G/A; OR = 1.09, 95% CI = 1.01-1.17; P = 3.12 x 10(-2)]. (PMID:27871331)
• This study demonstrates that human mitochondrial AspRS, ArgRS, and LysRS, each have a specific sub-mitochondrial distribution, with ArgRS being exclusively localized in the membrane, LysRS exclusively in the soluble fraction, and AspRS being present in both. (PMID:30006346)
• Developmental delay and late onset HBSL pathology in hypomorphic Dars1(M256L) mice. (PMID:35357600)
• Functional genomics screening identifies aspartyl-tRNA synthetase as a novel prognostic marker and a therapeutic target for gastric cancers. (PMID:35696251)
• DARS expression in BCR/ABL1-negative myeloproliferative neoplasms and its association with the immune microenvironment. (PMID:39030308)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	dars1	ENSDARG00000070043
mus_musculus	Dars1	ENSMUSG00000026356
drosophila_melanogaster	AspRS	FBGN0002069
caenorhabditis_elegans		WBGENE00001094

Paralogs (4): KARS1 (ENSG00000065427), DARS2 (ENSG00000117593), NARS1 (ENSG00000134440), NARS2 (ENSG00000137513)

Protein

Protein identifiers

Aspartate–tRNA ligase, cytoplasmic — P14868 (reviewed: P14868)

Alternative names: Aspartyl-tRNA synthetase, Cell proliferation-inducing gene 40 protein

All UniProt accessions (6): A0A140VJW5, C9J7S3, P14868, C9JLC1, C9JQM9, H7BZ35

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the specific attachment of an amino acid to its cognate tRNA in a 2 step reaction: the amino acid (AA) is first activated by ATP to form AA-AMP and then transferred to the acceptor end of the tRNA.

Subunit / interactions. Homodimer. Part of a multisubunit complex that groups tRNA ligases for Arg (RARS1), Asp (DARS1), Gln (QARS1), Ile (IARS1), Leu (LARS1), Lys (KARS1), Met (MARS1) the bifunctional ligase for Glu and Pro (EPRS1) and the auxiliary subunits AIMP1/p43, AIMP2/p38 and EEF1E1/p18.

Subcellular location. Cytoplasm. Cytosol.

Tissue specificity. Expression in the developing and adult brain shows similar patterns. Highly expressed in the ventricular and subventricular zones, including hippocampal subfields, the midlateral temporal cortex and the frontal polar cortex. The cerebellum, cerebral cortex, hippocampus, and lateral ventricle show preferential neuronal expression. Expression in the peripheral neurons is evident in the colon.

Disease relevance. Hypomyelination with brainstem and spinal cord involvement and leg spasticity (HBSL) [MIM:615281] An autosomal recessive leukoencephalopathy characterized by onset in the first year of life of severe spasticity, mainly affecting the lower limbs and resulting in an inability to achieve independent ambulation. Affected individuals show delayed motor development and nystagmus; some may have mild intellectual disability. Brain MRI shows hypomyelination and white matter lesions in the cerebrum, brainstem, cerebellum, and spinal cord. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the class-II aminoacyl-tRNA synthetase family. Type 2 subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
P14868-1	1	yes
P14868-2	2

RefSeq proteins (2): NP_001280241, NP_001340* (*=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
IPR004523	Asp-tRNA_synthase_2	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 6.1.1.12 — 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 (69 total): helix 19, strand 15, sequence variant 9, binding site 8, sequence conflict 7, modified residue 5, region of interest 2, turn 2, chain 1, splice variant 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
4J15	X-RAY DIFFRACTION	2.24
5Y6L	X-RAY DIFFRACTION	2.9
6IY6	X-RAY DIFFRACTION	3.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P14868-F1	93.69	0.89

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 (8): 472–475; 229; 273–275; 273; 281–283; 424; 427; 431

Post-translational modifications (5): 52, 74, 249, 374, 500

Function

Pathways and Gene Ontology

Reactome pathways

10 pathways

ID	Pathway
R-HSA-2408522	Selenoamino acid metabolism
R-HSA-379716	Cytosolic tRNA aminoacylation
R-HSA-9856649	Transcriptional and post-translational regulation of MITF-M expression and activity
R-HSA-1266738	Developmental Biology
R-HSA-1430728	Metabolism
R-HSA-379724	tRNA Aminoacylation
R-HSA-392499	Metabolism of proteins
R-HSA-71291	Metabolism of amino acids and derivatives
R-HSA-72766	Translation
R-HSA-9730414	MITF-M-regulated melanocyte development

MSigDB gene sets: 0 (showing top):

GO Biological Process (4): translation (GO:0006412), aspartyl-tRNA aminoacylation (GO:0006422), protein-containing complex assembly (GO:0065003), tRNA aminoacylation for protein translation (GO:0006418)

GO Molecular Function (9): RNA binding (GO:0003723), aminoacylase activity (GO:0004046), aspartate-tRNA ligase activity (GO:0004815), ATP binding (GO:0005524), 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): cytoplasm (GO:0005737), cytosol (GO:0005829), membrane (GO:0016020), aminoacyl-tRNA synthetase multienzyme complex (GO:0017101), synapse (GO:0045202), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
Metabolism of amino acids and derivatives	1
tRNA Aminoacylation	1
MITF-M-regulated melanocyte development	1
Translation	1
Metabolism	1
Metabolism of proteins	1
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
binding	2
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
cellular component assembly	1
protein-containing complex organization	1
translation	1
tRNA aminoacylation	1
nucleic acid binding	1
hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds, in linear amides	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
intracellular anatomical structure	1
cytoplasm	1
intracellular protein-containing complex	1
catalytic complex	1
cell junction	1
extracellular vesicle	1

Protein interactions and networks

STRING

2256 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DARS1	QARS1	P47897	899
DARS1	EPRS1	P07814	877
DARS1	MARS1	P56192	766
DARS1	IARS1	P41252	704
DARS1	LARS1	Q9P2J5	670
DARS1	KARS1	Q15046	636
DARS1	AIMP2	Q13155	584
DARS1	EEF1E1	O43324	576
DARS1	RARS1	P54136	563
DARS1	SUMF1	Q8NBK3	533
DARS1	ARRB1	P49407	489
DARS1	DARS2	Q6PI48	476
DARS1	AARS1	P49588	459
DARS1	FARSA	Q9Y285	458
DARS1	FARS2	O95363	457
DARS1	IARS2	Q9NSE4	457

IntAct

173 interactions, top by confidence:

A	B	Type	Score
DARS1	AIMP2	psi-mi:“MI:0915”(physical association)	0.830
AIMP2	DARS1	psi-mi:“MI:0915”(physical association)	0.830
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
GRB2	DARS1	psi-mi:“MI:0915”(physical association)	0.560
gag	EEF1E1	psi-mi:“MI:0914”(association)	0.560
COMTD1	IFRD1	psi-mi:“MI:0914”(association)	0.530
QARS1	EEF1E1	psi-mi:“MI:0914”(association)	0.530
SDCBP	TARS3	psi-mi:“MI:0914”(association)	0.530
EBNA-LP	HAX1	psi-mi:“MI:0914”(association)	0.530
DARS1	FOXM1	psi-mi:“MI:0915”(physical association)	0.500
FOXM1	PES1	psi-mi:“MI:0914”(association)	0.500
CFTR	PLEKHG3	psi-mi:“MI:0914”(association)	0.480

BioGRID (457): AIMP2 (Two-hybrid), DARS (Affinity Capture-MS), DARS (Affinity Capture-MS), DARS (Reconstituted Complex), DARS (Affinity Capture-MS), DARS (Affinity Capture-MS), AIMP2 (Two-hybrid), DARS (Affinity Capture-MS), AIMP1 (Co-fractionation), AIMP2 (Co-fractionation), CAD (Co-fractionation), CANX (Co-fractionation), DARS (Co-fractionation), DARS (Co-fractionation), DARS (Co-fractionation)

ESM2 similar proteins: A0A120HYZ1, A5UCQ0, A5UIX4, A6L0U5, A6LIA1, A6LPI6, A7GTK8, A7MXL2, A9NE58, C4V8R9, O74407, O94567, P04801, P04802, P14868, P15178, P15180, P37879, P38707, P43825, Q03577, Q15046, Q22099, Q3IGU4, Q3SYZ4, Q43776, Q481G3, Q4QL88, Q554D9, Q5L8W2, Q5R9I5, Q5XIM7, Q633N6, Q6BU46, Q6F0Y5, Q6F2U9, Q6HCW9, Q72ZI3, Q75JQ1, Q7MNP6

Diamond homologs: A0AK01, A2SPG1, A3CXH4, A4G0V5, A4IQ54, A4J412, A5D2C2, A5ISY4, A5UPW5, A6QH05, A6U1S3, A6UQQ8, A6USZ9, A6VHK5, A7NHQ4, A7X2E9, A7Z5Y7, A8Z434, A9A945, A9AYM5, A9WA97, B8GBG7, B9LCU8, C5A4R8, O07683, O24822, O26328, O29342, O57980, O58776, O74407, P04802, P14868, P15178, P39772, P54263, P58695, P67571, P67572, Q03577

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
DARS1	“form complex”	“Multiaminoacyl-tRNA synthetase”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 159 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
Constitutive Signaling by EGFRvIII	6	40.8×	7e-07
Signaling by ERBB2 ECD mutants	6	38.4×	7e-07
Signaling by FLT3 ITD and TKD mutants	5	36.2×	8e-06
Cytosolic tRNA aminoacylation	8	33.5×	4e-08
Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants	6	32.6×	2e-06
Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants	6	29.7×	3e-06
Tie2 Signaling	5	28.6×	3e-05
Signaling by FLT3 fusion proteins	5	27.2×	3e-05

GO biological processes:

GO term	Partners	Fold	FDR
intrinsic apoptotic signaling pathway	7	18.9×	9e-05
cytoplasmic translation	8	11.1×	3e-04
Ras protein signal transduction	6	9.3×	8e-03
G1/S transition of mitotic cell cycle	6	9.1×	8e-03
negative regulation of translation	6	8.8×	8e-03
translation	9	7.0×	2e-03
negative regulation of neuron apoptotic process	8	6.7×	6e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	5
Uncertain significance	110
Likely benign	87
Benign	20

Top pathogenic / likely-pathogenic (11)

Variant ID	HGVS	Classification
143190	NM_001349.4(DARS1):c.839A>T (p.His280Leu)	Pathogenic
2988443	NM_001349.4(DARS1):c.821C>G (p.Ala274Gly)	Pathogenic
50986	NM_001349.4(DARS1):c.1099G>T (p.Asp367Tyr)	Pathogenic
50987	NM_001349.4(DARS1):c.821C>T (p.Ala274Val)	Pathogenic
50988	NM_001349.4(DARS1):c.766A>C (p.Met256Leu)	Pathogenic
50990	NM_001349.4(DARS1):c.1379G>A (p.Arg460His)	Pathogenic
372877	NM_001349.4(DARS1):c.1129G>C (p.Gly377Arg)	Likely pathogenic
3765823	NM_001349.4(DARS1):c.735C>G (p.Tyr245Ter)	Likely pathogenic
402207	NM_001349.4(DARS1):c.389G>C (p.Cys130Ser)	Likely pathogenic
50991	NM_001349.4(DARS1):c.1480C>G (p.Arg494Gly)	Likely pathogenic
522693	NM_001349.4(DARS1):c.1481G>A (p.Arg494His)	Likely pathogenic

SpliceAI

2313 predictions. Top by Δscore:

Variant	Effect	Δscore
2:135911137:A:AC	donor_gain	1.0000
2:135911138:C:CC	donor_gain	1.0000
2:135911206:CAAAT:C	acceptor_gain	1.0000
2:135911207:AAAT:A	acceptor_gain	1.0000
2:135911208:AAT:A	acceptor_gain	1.0000
2:135911209:AT:A	acceptor_gain	1.0000
2:135911210:TCTGC:T	acceptor_loss	1.0000
2:135911211:C:CA	acceptor_loss	1.0000
2:135911211:C:CC	acceptor_gain	1.0000
2:135911212:T:A	acceptor_loss	1.0000
2:135911357:C:A	donor_gain	1.0000
2:135911489:TGTTT:T	acceptor_gain	1.0000
2:135912484:A:AC	donor_gain	1.0000
2:135912485:C:CC	donor_gain	1.0000
2:135912562:TCATA:T	acceptor_gain	1.0000
2:135912563:CATA:C	acceptor_gain	1.0000
2:135912563:CATAC:C	acceptor_gain	1.0000
2:135912564:ATA:A	acceptor_gain	1.0000
2:135912565:TA:T	acceptor_gain	1.0000
2:135912567:C:CC	acceptor_gain	1.0000
2:135914465:CTACC:C	donor_loss	1.0000
2:135914466:TA:T	donor_loss	1.0000
2:135914467:ACCT:A	donor_loss	1.0000
2:135914468:C:CT	donor_loss	1.0000
2:135914508:TGTGC:T	acceptor_loss	1.0000
2:135914509:GTGC:G	acceptor_loss	1.0000
2:135914510:TGCT:T	acceptor_loss	1.0000
2:135914511:GCTG:G	acceptor_loss	1.0000
2:135914512:C:CC	acceptor_gain	1.0000
2:135914512:CTGAA:C	acceptor_loss	1.0000

AlphaMissense

3315 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:135907329:C:G	R498P	1.000
2:135920554:A:C	F286L	1.000
2:135920554:A:T	F286L	1.000
2:135920556:A:G	F286L	1.000
2:135920566:A:C	H282Q	1.000
2:135920566:A:T	H282Q	1.000
2:135920568:G:C	H282D	1.000
2:135920569:T:A	R281S	1.000
2:135920569:T:G	R281S	1.000
2:135920570:C:G	R281T	1.000
2:135920593:T:A	R273S	1.000
2:135920593:T:G	R273S	1.000
2:135920594:C:G	R273T	1.000
2:135922833:C:A	K254N	1.000
2:135922833:C:G	K254N	1.000
2:135922851:C:A	Q248H	1.000
2:135922851:C:G	Q248H	1.000
2:135922890:A:C	F235L	1.000
2:135922890:A:T	F235L	1.000
2:135922891:A:G	F235S	1.000
2:135922892:A:G	F235L	1.000
2:135922911:A:C	S228R	1.000
2:135922911:A:T	S228R	1.000
2:135922913:T:G	S228R	1.000
2:135961485:G:C	F77L	1.000
2:135961485:G:T	F77L	1.000
2:135961487:A:G	F77L	1.000
2:135907341:C:G	R494P	0.999
2:135907363:G:T	R487S	0.999
2:135907365:A:T	V486D	0.999

dbSNP variants (sampled 300 via entrez): RS1000012604 (2:135947025 A>C), RS1000020560 (2:135985617 C>G,T), RS1000042202 (2:135911944 A>AT), RS1000043257 (2:135914625 C>T), RS1000085669 (2:135954324 C>A), RS1000129821 (2:135934263 C>T), RS1000138199 (2:135979086 T>G), RS1000207613 (2:135949774 A>C), RS1000254170 (2:135943069 C>A,T), RS1000262094 (2:135960790 T>C), RS1000267039 (2:135953536 G>A), RS1000337725 (2:135957537 T>C), RS1000387193 (2:135953900 ATTTT>A), RS1000445794 (2:135950956 T>C), RS1000451298 (2:135921531 T>A)

Disease associations

OMIM: gene MIM:603084 | disease phenotypes: MIM:615281

GenCC curated gene-disease

Disease	Classification	Inheritance
hypomyelination with brain stem and spinal cord involvement and leg spasticity	Definitive	Autosomal recessive

Mondo (1): hypomyelination with brain stem and spinal cord involvement and leg spasticity (MONDO:0014115)

Orphanet (1): Hypomyelination with brain stem and spinal cord involvement and leg spasticity (Orphanet:363412)

HPO phenotypes

23 total (23 of 23 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000543	Optic disc pallor
HP:0000639	Nystagmus
HP:0000737	Irritability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001256	Mild intellectual disability
HP:0001260	Dysarthria
HP:0001264	Spastic diplegia
HP:0001270	Motor delay
HP:0001348	Brisk reflexes
HP:0002061	Lower limb spasticity
HP:0002079	Hypoplasia of the corpus callosum
HP:0002144	Tethered cord
HP:0002352	Leukoencephalopathy
HP:0003298	Spina bifida occulta
HP:0003429	CNS hypomyelination
HP:0003487	Babinski sign
HP:0003593	Infantile onset
HP:0003676	Progressive
HP:0008936	Axial hypotonia
HP:0010729	Cherry red spot of the macula
HP:0011463	Childhood onset

GWAS associations

14 associations (top):

Study	Trait	p-value
GCST004765_20	Total cholesterol change in response to fenofibrate in statin-treated type 2 diabetes	8.000000e-07
GCST004863_11	Mosquito bite size	4.000000e-11
GCST005752_151	Systemic lupus erythematosus	4.000000e-07
GCST005951_44	Body mass index	1.000000e-09
GCST005973_7	White blood cell count	7.000000e-30
GCST005974_7	Neutrophil count	7.000000e-28
GCST005977_27	Monocyte count	9.000000e-10
GCST008664_10	Lung function (low FEV1 vs high FEV1)	4.000000e-09
GCST010243_72	Apolipoprotein B levels	4.000000e-08
GCST010245_49	LDL cholesterol levels	3.000000e-08
GCST011956_68	Systemic lupus erythematosus	2.000000e-13
GCST012020_272	Serum metabolite levels	4.000000e-17
GCST012020_596	Serum metabolite levels	2.000000e-12
GCST012021_44	Serum metabolite levels	2.000000e-12

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0007806	total cholesterol change measurement
EFO:0008378	mosquito bite reaction size measurement
EFO:0004340	body mass index
EFO:0004833	neutrophil count
EFO:0005091	monocyte count
EFO:0004314	forced expiratory volume
EFO:0004615	apolipoprotein B measurement
EFO:0004611	low density lipoprotein cholesterol measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066385 (SINGLE PROTEIN)

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

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.25	Kd	56.37	nM	CHEMBL3752910
7.25	ED50	56.37	nM	CHEMBL3752910
5.17	Kd	6723	nM	CHEMBL5653589
5.17	ED50	6723	nM	CHEMBL5653589

PubChem BioAssay actives

2 with measured affinity, of 4 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148193: Binding affinity to human DARS incubated for 45 mins by Kinobead based pull down assay	kd	0.0564	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148193: Binding affinity to human DARS incubated for 45 mins by Kinobead based pull down assay	kd	6.7232	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	2
Arsenic Trioxide	affects binding, decreases reaction, increases expression	2
Acetaminophen	decreases expression	2
Air Pollutants	affects cotreatment, increases abundance, increases oxidation, decreases expression	2
Cadmium Chloride	decreases expression, increases expression	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
bisphenol F	increases expression	1
dicrotophos	decreases expression	1
methylmercuric chloride	decreases expression	1
alpha-pinene	increases abundance, affects cotreatment, increases oxidation	1
pyrogallol 1,3-dimethyl ether	affects localization, decreases expression, affects cotreatment	1
perfluorooctanoic acid	decreases expression	1
4-aminophenylarsenoxide	affects binding, decreases reaction	1
methacrylaldehyde	increases abundance, affects cotreatment, increases oxidation	1
chloropicrin	increases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
tanespimycin	affects cotreatment, increases expression	1
K 7174	decreases expression	1
perfluorohexanesulfonic acid	decreases expression	1
bisphenol B	increases expression	1
VER 155008	affects cotreatment, increases expression	1
bisphenol AF	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	increases expression	1
Acrolein	affects cotreatment, increases oxidation, increases abundance	1
Benzo(a)pyrene	increases methylation	1
Carbamazepine	affects expression	1
Dichlorodiphenyl Dichloroethylene	increases expression	1
Doxorubicin	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651235	Binding	Binding affinity to human DARS incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02699190	Not specified	COMPLETED	LeukoSEQ: Whole Genome Sequencing as a First-Line Diagnostic Tool for Leukodystrophies
NCT03047369	Not specified	RECRUITING	The Myelin Disorders Biorepository Project