RARS1

Chr 5AR

arginyl-tRNA synthetase 1

Also known as: ArgRS, DALRD1, HLD9, RARS

NCBI Gene: 5917ENSG00000113643UniProt: P54136

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]

Primary Disease Associations & Inheritance

Leukodystrophy, hypomyelinating, 9MIM #616140
AR
469
ClinVar variants
52
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— RARS1
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
52 Pathogenic / Likely Pathogenic· 176 VUS of 469 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.77LOEUF
pLI 0.000
Z-score 2.64
OE 0.52 (0.36–0.77)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.54Z-score
OE missense 0.92 (0.84–1.01)
319 obs / 347.5 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.52 (0.36–0.77)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.92 (0.84–1.01)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.98
0≤1.21.6
LoF obs/exp: 18 / 34.8Missense obs/exp: 319 / 347.5Syn Z: 0.19

ClinVar Variant Classifications

469 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic35
Likely Pathogenic17
VUS176
Likely Benign140
Benign89
Conflicting12
35
Pathogenic
17
Likely Pathogenic
176
VUS
140
Likely Benign
89
Benign
12
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
9
5
21
0
35
Likely Pathogenic
7
5
5
0
17
VUS
2
155
18
1
176
Likely Benign
0
4
91
45
140
Benign
0
3
78
8
89
Conflicting
—12
Total1817221354469

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

RARS1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

RARS1 related hypomyelinating leukodystrophy

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Leukodystrophy, hypomyelinating, 9

MIM #616140

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
RARS1-related developmental and epileptic encephalopathy.
Wan L et al.·Epilepsia Open
2023Review
RARS1-related hypomyelinating leukodystrophy-9 (HLD-9) in two distinct Iranian families: Case report and literature review.
Biglari S et al.·Mol Genet Genomic Med
2024Review
RARS1-related hypomyelinating leukodystrophy: Expanding the spectrum.
Mendes MI et al.·Ann Clin Transl Neurol
2020
Overview of genetic variants in a cohort of Iranian patients with leukodystrophy.
Fathi M et al.·Sci Rep
2025Review
Distinct pathogenic mechanisms of various RARS1 mutations in Pelizaeus-Merzbacher-like disease.
Li G et al.·Sci China Life Sci
2021Functional
Hypomyelinating leukodystrophies in adults: Clinical and genetic features.
Di Bella D et al.·Eur J Neurol
2021
Uncovering potential causal genes for undiagnosed congenital anomalies using an in-house pipeline for trio-based whole-genome sequencing.
Kim JM et al.·Hum Genomics
2025
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools