RARS1

Summary

RARS1 (arginyl-tRNA synthetase 1, HGNC:9870) is a protein-coding gene on chromosome 5q34, encoding Arginine–tRNA ligase, cytoplasmic (P54136). Forms part of a macromolecular complex that catalyzes the attachment of specific amino acids to cognate tRNAs during protein synthesis. It is a selective cancer dependency (DepMap: 76.7% of cell lines).

Aminoacyl-tRNA synthetases catalyze the aminoacylation of tRNA by their cognate amino acid. Because of their central role in linking amino acids with nucleotide triplets contained in tRNAs, aminoacyl-tRNA synthetases are thought to be among the first proteins that appeared in evolution. Arginyl-tRNA synthetase belongs to the class-I aminoacyl-tRNA synthetase family.

Source: NCBI Gene 5917 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hypomyelinating leukodystrophy 9 (Definitive, ClinGen)
• GWAS associations: 2
• Clinical variants (ClinVar): 464 total — 19 pathogenic, 12 likely-pathogenic
• Phenotypes (HPO): 38
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 76.7% of screened cell lines
• MANE Select transcript: NM_002887

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9870
Approved symbol	RARS1
Name	arginyl-tRNA synthetase 1
Location	5q34
Locus type	gene with protein product
Status	Approved
Aliases	DALRD1
Ensembl gene	ENSG00000113643
Ensembl biotype	protein_coding
OMIM	107820
Entrez	5917

Gene structure

Transcript identifiers

Ensembl transcripts: 27 — 19 protein_coding, 4 retained_intron, 3 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000231572, ENST00000518757, ENST00000519346, ENST00000520013, ENST00000520421, ENST00000521329, ENST00000521939, ENST00000522834, ENST00000524082, ENST00000626454, ENST00000852517, ENST00000852518, ENST00000852519, ENST00000852520, ENST00000852521, ENST00000922754, ENST00000922755, ENST00000922756, ENST00000922757, ENST00000922758, ENST00000922759, ENST00000953512, ENST00000953513, ENST00000953514, ENST00000953515, ENST00000953516, ENST00000953517

RefSeq mRNA: 1 — MANE Select: NM_002887 NM_002887

CCDS: CCDS4367

Canonical transcript exons

ENST00000231572 — 15 exons

Exon	Start	End
ENSE00001148323	168486471	168486543
ENSE00002089704	168519081	168519301
ENSE00003469613	168488602	168488736
ENSE00003469905	168510581	168510686
ENSE00003538528	168497228	168497348
ENSE00003572200	168495315	168495436
ENSE00003576536	168493894	168494002
ENSE00003616899	168506021	168506199
ENSE00003617563	168502001	168502105
ENSE00003626617	168494550	168494650
ENSE00003626743	168517815	168518062
ENSE00003633663	168492659	168492847
ENSE00003641153	168506722	168506831
ENSE00003649357	168516778	168516950
ENSE00003673173	168500591	168500720

Expression profiles

Bgee: expression breadth ubiquitous, 236 present calls, max score 98.17.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 67.9774 / max 2127.3404, expressed in 1817 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
60078	67.9774	1817

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	98.17	gold quality
jejunal mucosa	UBERON:0000399	96.92	silver quality
esophagus squamous epithelium	UBERON:0006920	96.71	silver quality
rectum	UBERON:0001052	95.98	gold quality
adrenal tissue	UBERON:0018303	95.94	gold quality
islet of Langerhans	UBERON:0000006	95.59	gold quality
duodenum	UBERON:0002114	95.52	gold quality
body of pancreas	UBERON:0001150	95.35	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	95.29	gold quality
stromal cell of endometrium	CL:0002255	94.91	gold quality
skin of leg	UBERON:0001511	94.84	gold quality
skin of abdomen	UBERON:0001416	94.83	gold quality
epithelium of esophagus	UBERON:0001976	94.83	silver quality
mucosa of stomach	UBERON:0001199	94.81	gold quality
pancreas	UBERON:0001264	94.81	gold quality
monocyte	CL:0000576	94.80	gold quality
tibia	UBERON:0000979	94.73	silver quality
small intestine Peyer’s patch	UBERON:0003454	94.62	gold quality
mononuclear cell	CL:0000842	94.35	gold quality
esophagus mucosa	UBERON:0002469	94.30	gold quality
small intestine	UBERON:0002108	94.09	gold quality
leukocyte	CL:0000738	94.08	gold quality
mucosa of transverse colon	UBERON:0004991	94.04	gold quality
colonic epithelium	UBERON:0000397	93.87	gold quality
minor salivary gland	UBERON:0001830	93.87	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	93.85	gold quality
zone of skin	UBERON:0000014	93.82	gold quality
parotid gland	UBERON:0001831	93.61	silver quality
ectocervix	UBERON:0012249	93.42	gold quality
transverse colon	UBERON:0001157	93.37	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.49

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FOXO1

miRNA regulators (miRDB)

13 targeting RARS1, 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-9-5P	100.00	72.28	2361
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-219A-5P	99.91	73.36	735
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-4782-3P	99.88	73.31	735
HSA-MIR-6766-3P	99.88	73.38	732
HSA-MIR-508-3P	98.66	69.62	887
HSA-MIR-124-5P	98.11	67.65	1095
HSA-MIR-4445-5P	97.21	66.16	832
HSA-MIR-4701-5P	96.45	68.41	1121
HSA-MIR-588	96.45	68.36	1127
HSA-MIR-563	96.26	66.13	450
HSA-MIR-380-5P	95.68	67.32	512

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 76.7% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 13)

• leucyl-tRNA synthetase requires its C-terminal domain for its interaction with arginyl-tRNA synthetase in the multi-tRNA synthetase complex (PMID:16055448)
• RARS over-expression impairs aminoacyl t-RNA synthetase interacting multifunctional protein (AIMP1) secretion by both HeLa and MCF7 cells. (PMID:17443684)
• Hemin binds to human cytoplasmic arginyl-tRNA synthetase and inhibits its catalytic activity (PMID:20923763)
• report describe 4 patients with hypomyelination and mutations in RARS (PMID:24777941)
• The crystal structures of the L-arginine-complexed, and L-canavanine-complexed forms of arginyl-tRNA synthetase from Homo sapiens. (PMID:24859084)
• The mRNA of human cytoplasmic arginyl-tRNA synthetase recruits prokaryotic ribosomes independently. (PMID:24898251)
• interactions between the N-terminal domains of ArgRS and AIMP1 are important for the catalytic and noncatalytic activities of ArgRS and for the assembly of the higher-order MSC protein complex with ArgRS-GlnRS-AIMP1 (PMID:25288775)
• Data indicate that the N terminus of Pro-EMAP II binds to its C terminus, arginyl-tRNA synthetase, and the neurofilament light subunit. (PMID:25724651)
• Missense variant Ser456Leu and a de novo deletion Tyr616Leufs*6 cause disorder akin to Pelizaeus-Merzbacher disease. (PMID:28905880)
• we demonstrated the presence of the recurrent RARS-MAD1L1 gene fusion in NPC. Furthermore, we provided the first evidence showing that the RARS-MAD1L1 fusion gene enhances tumorigenicity, CSC-like properties, and therapeutic resistance (PMID:29133573)
• 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)
• RARS1-related hypomyelinating leukodystrophy: Expanding the spectrum. (PMID:31814314)
• Distinct pathogenic mechanisms of various RARS1 mutations in Pelizaeus-Merzbacher-like disease. (PMID:33515434)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	rars1	ENSDARG00000054530
mus_musculus	Rars1	ENSMUSG00000018848
rattus_norvegicus	Rars1	ENSRNOG00000007739
drosophila_melanogaster	ArgRS	FBGN0027093
caenorhabditis_elegans		WBGENE00004679

Paralogs (1): RARS2 (ENSG00000146282)

Protein

Protein identifiers

Arginine–tRNA ligase, cytoplasmic — P54136 (reviewed: P54136)

Alternative names: Arginyl-tRNA synthetase

All UniProt accessions (4): E5RH09, E5RI24, E5RJM9, P54136

UniProt curated annotations — full annotation on UniProt →

Function. Forms part of a macromolecular complex that catalyzes the attachment of specific amino acids to cognate tRNAs during protein synthesis. Modulates the secretion of AIMP1 and may be involved in generation of the inflammatory cytokine EMAP2 from AIMP1.

Subunit / interactions. Interacts (via N-terminus) with AIMP1 (via N-terminus); this stimulates its catalytic activity. Interacts (via N-terminus) with LARS2 (via C-terminus). Monomer. 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. Interacts with QARS1. Part of a complex composed of RARS1, QARS1 and AIMP1.

Subcellular location. Cytoplasm. Cytosol.

Disease relevance. Leukodystrophy, hypomyelinating, 9 (HLD9) [MIM:616140] An autosomal recessive neurodegenerative disorder characterized by delayed psychomotor development, severe spasticity, nystagmus, and ataxia associated with diffuse hypomyelination apparent on brain MRI. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The alpha-helical N-terminus (residues 1-72) mediates interaction with AIMP1 and thereby contributes to the assembly of the multisynthetase complex.

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

Isoforms (2)

UniProt ID	Names	Canonical?
P54136-1	Complexed	yes
P54136-2	Monomeric

RefSeq proteins (1): NP_002878* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001278	Arg-tRNA-ligase	Family
IPR001412	aa-tRNA-synth_I_CS	Conserved_site
IPR005148	Arg-tRNA-synth_N	Domain
IPR008909	DALR_anticod-bd	Domain
IPR009080	tRNAsynth_Ia_anticodon-bd	Homologous_superfamily
IPR014729	Rossmann-like_a/b/a_fold	Homologous_superfamily
IPR035684	ArgRS_core	Domain
IPR036695	Arg-tRNA-synth_N_sf	Homologous_superfamily

Pfam: PF00750, PF03485, PF05746

Enzyme classification (BRENDA):

• EC 6.1.1.19 — arginine-tRNA ligase (BRENDA: 22 organisms, 42 substrates, 30 inhibitors, 138 Km, 42 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
TRNAARG	0.0001–0.53	41
ATP	0.186–4.3	27
L-ARGININE	0.0007–0.0196	22
ARG	0.0006–0.7	13
TRNAARG(ACG)	0.0003–0.0041	6
TUBERCIDIN 5’-TRIPHOSPHATE	0.2–0.4	4
L-CANAVANINE	0.0453–1.32	3
2-CHLOROADENOSINE 5’-TRIPHOSPHATE	1.3–2.5	2
8-AZAADENOSINE 5’-TRIPHOSPHATE	3–3.3	2
TRNAARG ACG	0.0009–0.0018	2
2’-DEOXYADENOSINE 5’-TRIPHOSPHATE	1.5	1
3’-DEOXYADENOSINE 5’-TRIPHOSPHATE	0.5	1
3’-METHOXYADENOSINE 5’-TRIPHOSPHATE	0.1	1
DIPHOSPHATE	0.05	1
TRNAARGIII	0.0003	1

Catalyzed reactions (Rhea), 1 shown:

• tRNA(Arg) + L-arginine + ATP = L-arginyl-tRNA(Arg) + AMP + diphosphate (RHEA:20301)

UniProt features (81 total): helix 25, strand 20, sequence conflict 14, sequence variant 5, turn 5, binding site 5, region of interest 2, modified residue 2, chain 1, splice variant 1, short sequence motif 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
4ZAJ	X-RAY DIFFRACTION	2.22
4Q2T	X-RAY DIFFRACTION	2.4
4Q2X	X-RAY DIFFRACTION	2.8
4Q2Y	X-RAY DIFFRACTION	2.8
4R3Z	X-RAY DIFFRACTION	4.03

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P54136-F1	92.31	0.78

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): 200–202; 211; 384; 388; 412

Post-translational modifications (2): 1, 1

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: 284 (showing top): BORCZUK_MALIGNANT_MESOTHELIOMA_UP, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_AMINO_ACID_ACTIVATION, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, GOBP_TRNA_METABOLIC_PROCESS, GOBP_TRANSLATION, RICKMAN_TUMOR_DIFFERENTIATED_WELL_VS_POORLY_DN, GGAANCGGAANY_UNKNOWN, GROSS_HYPOXIA_VIA_ELK3_DN, GROSS_HYPOXIA_VIA_ELK3_AND_HIF1A_UP, GNF2_XRCC5, GENTILE_UV_HIGH_DOSE_DN, GARY_CD5_TARGETS_DN, BERTUCCI_MEDULLARY_VS_DUCTAL_BREAST_CANCER_UP

GO Biological Process (3): tRNA aminoacylation for protein translation (GO:0006418), arginyl-tRNA aminoacylation (GO:0006420), translation (GO:0006412)

GO Molecular Function (9): tRNA binding (GO:0000049), arginine-tRNA ligase activity (GO:0004814), ATP binding (GO:0005524), arginine binding (GO:0034618), cadherin binding (GO:0045296), nucleotide binding (GO:0000166), aminoacyl-tRNA ligase activity (GO:0004812), protein binding (GO:0005515), ligase activity (GO:0016874)

GO Cellular Component (8): nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytoplasm (GO:0005737), cytosol (GO:0005829), membrane (GO:0016020), aminoacyl-tRNA synthetase multienzyme complex (GO:0017101), 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	4
nuclear lumen	2
translation	1
tRNA aminoacylation	1
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
RNA binding	1
aminoacyl-tRNA ligase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
amino acid binding	1
carboxylic acid binding	1
cation binding	1
cell adhesion molecule binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
ligase activity, forming carbon-oxygen bonds	1
catalytic activity, acting on a tRNA	1
binding	1
catalytic activity	1
intracellular membrane-bounded organelle	1
intracellular membraneless organelle	1
intracellular anatomical structure	1
cytoplasm	1
intracellular protein-containing complex	1
catalytic complex	1
extracellular vesicle	1

Protein interactions and networks

STRING

3473 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RARS1	QARS1	P47897	996
RARS1	KARS1	Q15046	995
RARS1	LARS1	Q9P2J5	982
RARS1	LARS2	Q15031	978
RARS1	EPRS1	P07814	976
RARS1	IARS1	P41252	975
RARS1	RARG	P13631	968
RARS1	RARB	P10826	959
RARS1	IARS2	Q9NSE4	959
RARS1	RARA	P10276	942
RARS1	MARS1	P56192	942
RARS1	NCOR1	O75376	941
RARS1	MARS2	Q96GW9	933
RARS1	NCOR2	Q9Y618	904
RARS1	SARS1	P49591	903

IntAct

173 interactions, top by confidence:

A	B	Type	Score
LARS1	RARS1	psi-mi:“MI:0915”(physical association)	0.760
LARS1	RARS1	psi-mi:“MI:0914”(association)	0.760
RARS1	LARS1	psi-mi:“MI:0407”(direct interaction)	0.760
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
RARS1	VMA22	psi-mi:“MI:0915”(physical association)	0.670
EPRS1	RARS1	psi-mi:“MI:0915”(physical association)	0.660
CD68	TTI1	psi-mi:“MI:0914”(association)	0.640
AIMP1	RARS1	psi-mi:“MI:0914”(association)	0.640
CFTR	HAX1	psi-mi:“MI:0914”(association)	0.610
RARS1	AIMP1	psi-mi:“MI:0915”(physical association)	0.560
RARS1	ZNF521	psi-mi:“MI:0915”(physical association)	0.560
COMTD1	IFRD1	psi-mi:“MI:0914”(association)	0.530
QARS1	EEF1E1	psi-mi:“MI:0914”(association)	0.530
NME1	NME2P1	psi-mi:“MI:0914”(association)	0.530
SDCBP	TARS3	psi-mi:“MI:0914”(association)	0.530
CD68	TNPO2	psi-mi:“MI:0914”(association)	0.530
LAMP1	FZD7	psi-mi:“MI:0914”(association)	0.530
CD93	RARS1	psi-mi:“MI:0914”(association)	0.530
DDX21	MED19	psi-mi:“MI:2364”(proximity)	0.480
gag	SDCBP	psi-mi:“MI:0914”(association)	0.460

BioGRID (448): RARS (Affinity Capture-MS), RARS (Affinity Capture-MS), RARS (Affinity Capture-MS), RARS (Affinity Capture-MS), RARS (Affinity Capture-MS), AIMP1 (Co-fractionation), DARS (Co-fractionation), EEF1E1 (Co-fractionation), EPRS (Co-fractionation), IARS (Co-fractionation), KARS (Co-fractionation), LARS (Co-fractionation), MARS (Co-fractionation), QARS (Co-fractionation), RARS (Co-fractionation)

ESM2 similar proteins: A0Q5D7, A4IZF4, A5UJ40, A6VNB3, A7NDV6, A7YW98, B0B7L8, B0BBT3, B0UUF1, B2SDQ4, B4ETN5, B4RU34, C4K487, O23247, O84304, P37880, P40329, P43832, P54136, Q0BKP4, Q0I3B0, Q0W0H2, Q10XL4, Q14IZ0, Q15W53, Q19825, Q21I40, Q253D1, Q2A215, Q2NTK2, Q2SMY0, Q3KM60, Q487B1, Q5L5J6, Q5L6U4, Q5NHI8, Q5RA20, Q5ZM11, Q6MEP4, Q6MLI2

Diamond homologs: A0L1H3, A1RP36, A1S2P7, A1SQW6, A2C016, A2CDB7, A3D9A3, A3Q9V2, A4Y2U9, A5GP97, A5GW85, A6VNB3, A6W2V1, A6WIK3, A7MT26, A7YW98, A8FQM2, A8H953, A9BDF0, A9KYS9, B0JLI8, B0TVV1, B0UUF1, B1KK48, B1LCZ5, B1X0N5, B1XHE4, B1XPX8, B2J6I0, B3PKE3, B4RU34, B5YR22, B6EI57, B7JVP5, B7KCT7, B7L7S9, B7MBT5, B7NBM7, B7NS42, B7USQ3

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
RARS1	“form complex”	“Multiaminoacyl-tRNA synthetase”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 165 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
Cytosolic tRNA aminoacylation	7	26.3×	2e-06
tRNA Aminoacylation	7	17.1×	3e-05
Transcriptional and post-translational regulation of MITF-M expression and activity	10	15.2×	7e-07
Selenoamino acid metabolism	9	15.2×	2e-06
FCERI mediated MAPK activation	5	14.8×	2e-03
FLT3 Signaling	5	14.8×	2e-03
Signaling by FGFR1 in disease	5	12.5×	3e-03
NCAM signaling for neurite out-growth	5	11.6×	3e-03

GO biological processes:

GO term	Partners	Fold	FDR
stress granule assembly	5	21.3×	3e-03
MAPK cascade	8	8.7×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	19
Likely pathogenic	12
Uncertain significance	170
Likely benign	128
Benign	89

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1218728	NM_002887.4(RARS1):c.3G>T (p.Met1Ile)	Pathogenic
1299011	NM_002887.4(RARS1):c.445G>T (p.Glu149Ter)	Pathogenic
162080	NM_002887.4(RARS1):c.5A>G (p.Asp2Gly)	Pathogenic
162081	NM_002887.4(RARS1):c.45+1G>T	Pathogenic
162082	NM_002887.4(RARS1):c.96_97del (p.Cys32fs)	Pathogenic
162083	NM_002887.4(RARS1):c.1A>G (p.Met1Val)	Pathogenic
1909378	NM_002887.4(RARS1):c.1807G>T (p.Glu603Ter)	Pathogenic
2027507	NM_002887.4(RARS1):c.838_850del (p.Phe280fs)	Pathogenic
2036640	NM_002887.4(RARS1):c.1715G>A (p.Trp572Ter)	Pathogenic
3384892	NM_002887.4(RARS1):c.999del (p.Glu335fs)	Pathogenic
3613640	NM_002887.4(RARS1):c.160C>T (p.Arg54Ter)	Pathogenic
3656058	NM_002887.4(RARS1):c.49G>T (p.Glu17Ter)	Pathogenic
3688633	NM_002887.4(RARS1):c.748_754del (p.Ala250fs)	Pathogenic
373799	NM_002887.4(RARS1):c.1443_1446del (p.Arg482fs)	Pathogenic
419440	NM_002887.4(RARS1):c.1853_1854del (p.Val618fs)	Pathogenic
424864	NM_002887.4(RARS1):c.1846_1847del (p.Tyr616fs)	Pathogenic
4762124	NM_002887.4(RARS1):c.1581_1582del (p.Gly528fs)	Pathogenic
4798624	NM_002887.4(RARS1):c.6_7delinsGA (p.Asp2_Val3delinsGluIle)	Pathogenic
488942	NM_002887.4(RARS1):c.2T>A (p.Met1Lys)	Pathogenic
1324988	NM_002887.4(RARS1):c.614_615del (p.Lys205fs)	Likely pathogenic
1991882	NM_002887.4(RARS1):c.180+2T>C	Likely pathogenic
2632633	NM_002887.4(RARS1):c.1795del (p.Asp599fs)	Likely pathogenic
2683827	NM_002887.4(RARS1):c.1716G>A (p.Trp572Ter)	Likely pathogenic
3380996	NM_002887.4(RARS1):c.1283G>A (p.Trp428Ter)	Likely pathogenic
3380997	NM_002887.4(RARS1):c.1579dup (p.Arg527fs)	Likely pathogenic
3780529	NM_002887.4(RARS1):c.639del (p.Arg213fs)	Likely pathogenic
422330	NM_002887.4(RARS1):c.448_456del (p.Cys150_Glu152del)	Likely pathogenic
4530986	NM_002887.4(RARS1):c.579G>T (p.Lys193Asn)	Likely pathogenic
4692958	NM_002887.4(RARS1):c.369+1G>A	Likely pathogenic
809838	NM_002887.4(RARS1):c.1534C>T (p.Arg512Trp)	Likely pathogenic

SpliceAI

2352 predictions. Top by Δscore:

Variant	Effect	Δscore
5:168488598:A:AG	acceptor_gain	1.0000
5:168488599:C:G	acceptor_gain	1.0000
5:168488599:CAGG:C	acceptor_loss	1.0000
5:168488600:A:AC	acceptor_loss	1.0000
5:168488600:A:AG	acceptor_gain	1.0000
5:168488601:G:GT	acceptor_gain	1.0000
5:168488601:GGA:G	acceptor_gain	1.0000
5:168488601:GGAA:G	acceptor_gain	1.0000
5:168488732:GAAAG:G	donor_gain	1.0000
5:168488733:AAAG:A	donor_gain	1.0000
5:168488734:AAG:A	donor_gain	1.0000
5:168488735:AG:A	donor_gain	1.0000
5:168488736:GG:G	donor_gain	1.0000
5:168488737:G:GG	donor_gain	1.0000
5:168492812:GACTA:G	donor_gain	1.0000
5:168492820:GT:G	donor_gain	1.0000
5:168493888:TTGTA:T	acceptor_loss	1.0000
5:168493889:TGTAG:T	acceptor_loss	1.0000
5:168493890:GTAGA:G	acceptor_loss	1.0000
5:168493891:TAG:T	acceptor_loss	1.0000
5:168493892:A:AC	acceptor_loss	1.0000
5:168493892:A:AG	acceptor_gain	1.0000
5:168493893:G:GG	acceptor_gain	1.0000
5:168493893:G:GT	acceptor_loss	1.0000
5:168494546:TTA:T	acceptor_loss	1.0000
5:168494547:TAGGT:T	acceptor_loss	1.0000
5:168494548:AGGTT:A	acceptor_loss	1.0000
5:168494549:G:GT	acceptor_loss	1.0000
5:168494647:AAAGG:A	donor_loss	1.0000
5:168494648:AAGGT:A	donor_loss	1.0000

AlphaMissense

4372 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:168494552:T:C	F161L	0.999
5:168494554:T:A	F161L	0.999
5:168494554:T:G	F161L	0.999
5:168495341:T:A	N202K	0.999
5:168495341:T:G	N202K	0.999
5:168495349:A:T	K205I	0.999
5:168495350:A:C	K205N	0.999
5:168495350:A:T	K205N	0.999
5:168495373:G:C	R213T	0.999
5:168495373:G:T	R213M	0.999
5:168497250:G:T	G242W	0.999
5:168497263:G:A	G246D	0.999
5:168497281:T:C	L252P	0.999
5:168516848:T:C	L508P	0.999
5:168517983:T:G	C598W	0.999
5:168495346:C:A	A204D	0.998
5:168495364:G:A	G210D	0.998
5:168495370:T:C	L212P	0.998
5:168495374:G:C	R213S	0.998
5:168495374:G:T	R213S	0.998
5:168495388:G:A	G218E	0.998
5:168497244:G:C	D240H	0.998
5:168497247:T:A	W241R	0.998
5:168497247:T:C	W241R	0.998
5:168497250:G:A	G242R	0.998
5:168497250:G:C	G242R	0.998
5:168497251:G:A	G242E	0.998
5:168497269:T:C	L248P	0.998
5:168500594:T:C	S276P	0.998
5:168506806:T:C	F441L	0.998

dbSNP variants (sampled 300 via entrez): RS1000068359 (5:168505526 A>C), RS1000213716 (5:168502076 A>G), RS1000268420 (5:168495784 G>A), RS1000302337 (5:168514114 C>G,T), RS1000322659 (5:168496108 C>T), RS1000341890 (5:168507980 A>C,G), RS1000446021 (5:168507742 CAA>C), RS1000633487 (5:168500160 C>G), RS1000822239 (5:168512034 A>G,T), RS1000907583 (5:168512642 T>G), RS1001061576 (5:168518092 TTTTAG>T), RS1001074505 (5:168518433 G>A), RS1001169811 (5:168489239 G>A), RS1001182806 (5:168506555 T>A), RS1001198043 (5:168519653 C>T)

Disease associations

OMIM: gene MIM:107820 | disease phenotypes: MIM:616140, MIM:312080

GenCC curated gene-disease

Disease	Classification	Inheritance
hypomyelinating leukodystrophy 9	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
hypomyelinating leukodystrophy 9	Definitive	AR

Mondo (2): hypomyelinating leukodystrophy 9 (MONDO:0014506), leukodystrophy (MONDO:0019046)

Orphanet (2): RARS-related autosomal recessive hypomyelinating leukodystrophy (Orphanet:438114), Leukodystrophy (Orphanet:68356)

HPO phenotypes

38 total (30 of 38 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000639	Nystagmus
HP:0000817	Reduced eye contact
HP:0001251	Ataxia
HP:0001256	Mild intellectual disability
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001288	Gait disturbance
HP:0001310	Dysmetria
HP:0001332	Dystonia
HP:0001347	Hyperreflexia
HP:0001583	Rotary nystagmus
HP:0002013	Vomiting
HP:0002059	Cerebral atrophy
HP:0002061	Lower limb spasticity
HP:0002071	Abnormality of extrapyramidal motor function
HP:0002079	Hypoplasia of the corpus callosum
HP:0002080	Intention tremor
HP:0002151	Increased circulating lactate concentration
HP:0002395	Lower limb hyperreflexia
HP:0002415	Leukodystrophy
HP:0002421	Poor head control
HP:0002506	Diffuse cerebral atrophy
HP:0003487	Babinski sign
HP:0003593	Infantile onset
HP:0006808	Cerebral hypomyelination
HP:0006895	Lower limb hypertonia
HP:0007024	Pseudobulbar paralysis

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST001204_16	Response to platinum-based chemotherapy (carboplatin)	1.000000e-06
GCST007680_9	Triiodothyronine levels and thyroxine levels	4.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0008392	triiodothyronine measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2824 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,538 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1232461	MOLIBRESIB	2	1,538

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs244898	Efficacy	3	cisplatin	Urinary Bladder Neoplasms

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs244898	RARS1	3	2.25	1	cisplatin

ChEMBL bioactivities

7 potent at pChembl≥5 of 7 total, top 7 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.35	IC50	4.5	nM	CHEMBL1160244
8.12	IC50	7.5	nM	CHEMBL434782
6.35	Kd	442.9	nM	CHEMBL5653589
6.35	ED50	442.9	nM	CHEMBL5653589
6.21	IC50	610	nM	MOLIBRESIB
6.05	Kd	886.5	nM	CHEMBL3752910
6.05	ED50	886.5	nM	CHEMBL3752910

PubChem BioAssay actives

5 with measured affinity, of 14 total; 5 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
[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl N-[(2S)-2-amino-5-(diaminomethylideneamino)pentanoyl]sulfamate	38918: Inhibitory activity against cognate Staphylococcus aureus Arginyl-tRNA synthetase	ic50	0.0045	uM
[(2S)-2-amino-5-(diaminomethylideneamino)pentyl] [(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl hydrogen phosphate	38918: Inhibitory activity against cognate Staphylococcus aureus Arginyl-tRNA synthetase	ic50	0.0075	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149194: Binding affinity to human RARS incubated for 45 mins by Kinobead based pull down assay	kd	0.4429	uM
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2178536: Inhibition of RARS (unknown origin) incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	ic50	0.6100	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149194: Binding affinity to human RARS incubated for 45 mins by Kinobead based pull down assay	kd	0.8865	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects cotreatment, increases abundance, increases expression, decreases expression	2
aristolochic acid I	decreases expression	1
bisphenol F	increases expression	1
dicrotophos	decreases expression	1
pyrogallol 1,3-dimethyl ether	affects localization, affects cotreatment, decreases expression	1
arsenite	affects binding, increases reaction	1
methylparaben	increases expression	1
manganese chloride	increases abundance, increases expression, affects cotreatment	1
potassium chromate(VI)	decreases expression, affects cotreatment	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
chloropicrin	increases expression	1
nutlin 3	affects cotreatment, increases secretion	1
bisphenol B	increases expression	1
jinfukang	decreases expression	1
bisphenol AF	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Arsenic Trioxide	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	increases expression, affects cotreatment, increases abundance	1
Dactinomycin	affects cotreatment, increases secretion	1
Dichlorodiphenyl Dichloroethylene	increases expression	1
Dinitrochlorobenzene	affects binding	1
Doxorubicin	increases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Furaldehyde	decreases expression, affects localization, increases expression, affects cotreatment	1
Hydrogen Peroxide	affects expression	1
Ivermectin	decreases expression	1
Lead	affects expression	1
Manganese	affects cotreatment, increases abundance, increases expression	1
Plant Extracts	affects cotreatment, increases expression	1

ChEMBL screening assays

10 unique, capped per target: 10 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4118632	Binding	Binding affinity to RARS in human NCI-H23 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — Bioorg Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00889174	Not specified	COMPLETED	The Nosology and Etiology of Leukodystrophies of Unknown Causes
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT02699190	Not specified	COMPLETED	LeukoSEQ: Whole Genome Sequencing as a First-Line Diagnostic Tool for Leukodystrophies
NCT02843555	Not specified	COMPLETED	Natural History of the Leukodystrophies
NCT03047369	Not specified	RECRUITING	The Myelin Disorders Biorepository Project
NCT03333200	Not specified	RECRUITING	Longitudinal Study of Neurodegenerative Disorders
NCT03639285	Not specified	RECRUITING	Natural History, Diagnosis, and Outcomes for Leukodystrophies
NCT05443906	Not specified	RECRUITING	Home Exercise for Individuals with Neurodegenerative Disease