GeneBe

RARS1

protein-coding

arginyl-tRNA synthetase 1, the group of Aminoacyl tRNA synthetases, Class I

Gene summary

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. [provided by RefSeq, Jul 2008]

Previous symbols:
  • RARS

MANE transcript

NM_002887.4

Inheritance

AR, AD

ClinVar variants

P:42U:180B:61

Top phenotype

Leukodystrophy, hypomyelinating 9

gnomAD constraint

pLI —, LoF o/e 0.52

Max pathogenic AF

—

Genomic locus

chr5:168,486,451-168,519,301

External References & Databases

Ensembl (ENSG00000113643)NCBI Gene (5917)OMIM (107820)HGNC:9870GenCCUniProt (P54136)AlphaFoldClinVar (RARS1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~32.9 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

leukodystrophy, hypomyelinating, 9STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014506

Submitter: PanelApp Australia

leukodystrophy, hypomyelinating, 9STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014506

Submitter: Labcorp Genetics (formerly Invitae)

leukodystrophy, hypomyelinating, 9MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014506

Submitter: Ambry Genetics

leukodystrophy, hypomyelinating, 9DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014506

Submitter: ClinGen

RARS1 was first reported in relation to autosomal recessive hypomyelinating leukodystrophy 9 in 2014 (Wolf et al, 2014 PMID:24777941). Reported phenotypes include spasticity, nystagmus, delayed development, intellectual disability (mild to severe), hypertonicity, ataxia, dysmetria, dysarthria, tremoring, and hypomyelination on brain MRI (Wolf et al, 2014 PMID:24777941). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanisms or inheritance pattern. Therefore, there is one disease entity, hypomyelinating leukodystrophy 9 (OMIM: 616140). 29 variants (12 putative null (4 start codon, 4 fs, 4 splice), 16 missense, 1 in-frame deletion) that have been reported in 40 patients in 11 publications (PMID:24777941, 30791064, 28905880, 31814314, 40594583, 33190326, 38618971, 30500859, 39762984, 37186453, 29451896). 9 probands and 5 publications are included in the genetic evidence of this curation. More evidence is available in the literature, and a maximum score of 12 for genetic evidence has been reached (max 12). The mechanism of pathogenicity is reported to be loss of function (Li 2021, PMID33515434). This gene-disease relationship is also supported by a knockout zebrafish model (Kim 2025 PMID: 39762984). In summary, there is definitive evidence supporting the relationship between RARS1 and autosomal recessive hypomyelinating leukodystrophy 9, also known as RARS1-related hypomyelinating leukodystrophy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Leukodystrophy and Leukoencephalopathy GCEP on the meeting date December 22, 2025 (SOP Version 11). Curation scoring was updated to reflect SOP Version 12 changes.

leukodystrophy, hypomyelinating, 9LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0014506

Submitter: Labcorp Genetics (formerly Invitae)

leukodystrophy, hypomyelinating, 9DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014506

Submitter: G2P

leukodystrophy, hypomyelinating, 9SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014506

Submitter: Orphanet

leukodystrophy, hypomyelinating, 9MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014506

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

Clinical Genomic Database (CGD)

Leukodystrophy, hypomyelinating 9AD

Manifestation: Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 24777941Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to RARS1 variants in ClinVar

8 Conditions Cataloged
not providedTotal: 291
Inborn genetic diseasesTotal: 97
not specifiedTotal: 94
Leukodystrophy, hypomyelinating, 9Total: 35
RARS1-related disorderTotal: 12
RARS-related disordersTotal: 6
LeukodystrophyTotal: 1
Hypomyelinating leukodystrophyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002887.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
2
clinvar
49
clinvar
 51
missense
1
clinvar
6
clinvar
173
clinvar
11
clinvar
1
clinvar
 192
nonsense
5
clinvar
6
clinvar
 11
start loss
4
clinvar
1
clinvar
 5
frameshift
7
clinvar
7
clinvar
3
clinvar
 17
splice donor/acceptor (+/-2bp)
1
clinvar
4
clinvar
2
clinvar
 7
Total1824180601283

Highest pathogenic variant AF is 0.000028225068

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 50 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_002887.4RefSeqNP_002878.215MANE Select
ENST00000231572.8EnsemblENSP00000231572.315MANE Select
ENST00000520013.5EnsemblENSP00000429030.14Standard
ENST00000521329.5EnsemblENSP00000428494.13Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Aminoacyl-tRNA biosynthesis - Homo sapiens (human)
  • miR-targeted genes in epithelium - TarBase
  • miR-targeted genes in lymphocytes - TarBase
  • miR-targeted genes in muscle cell - TarBase
  • miR-targeted genes in squamous cell - TarBase

Biological Process

  • tRNA aminoacylation for protein translation
  • arginyl-tRNA aminoacylation

Molecular Function

  • tRNA binding
  • arginine-tRNA ligase activity
  • protein binding
  • ATP binding
  • arginine binding

Cellular Component

  • nucleus
  • nucleoplasm
  • cytoplasm
  • cytosol
  • membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000231572
Coding exons
15
Length
32855
Individuals with no LoFs
125671
Homozygous LoFs
0
Heterozygous LoFs
77
Defined
125748
p
0.000306
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.5443193480.9180.00001754343
Missense (PolyPhen)138154.640.89241891
Synonymous0.1921161190.9780.000005471210
Loss of Function2.641834.80.5170.00000188437

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000440.00043rare
Latino/Admixed American0.000410.00038rare
Ashkenazi Jewish00.0absent
East Asian0.000440.00044rare
Finnish0.000370.00037rare
European (Non-Finnish)0.000320.00030rare
South Asian0.000200.00020rare
Other0.000160.00016rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Forms part of a macromolecular complex that catalyzes the attachment of specific amino acids to cognate tRNAs during protein synthesis (PubMed:25288775). Modulates the secretion of AIMP1 and may be involved in generation of the inflammatory cytokine EMAP2 from AIMP1 (PubMed:17443684). {ECO:0000269|PubMed:17443684, ECO:0000269|PubMed:25288775}.;
Disease
DISEASE: 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. {ECO:0000269|PubMed:24777941}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.412

Intolerance Scores

LoFtool
0.872
RVIS EVS
-0.42
RVIS percentile EVS
25.64

Essentials

Essential (CRISPR)
E
Essential (CRISPR2)
E
Essential (gene trap)
E
Indispensability pred.
E
Indispensability score
0.993

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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