RARS1

Chr 5AR

arginyl-tRNA synthetase 1

Also known as: ArgRS, DALRD1, HLD9, RARS

NCBI Gene: 5917 ENSG00000113643 UniProt: P54136 OMIM: 107820

Arginyl-tRNA synthetase catalyzes the aminoacylation of tRNA by arginine, a critical step in protein synthesis that links amino acids with their corresponding nucleotide triplets. Mutations in RARS1 cause hypomyelinating leukodystrophy 9, an autosomal recessive disorder. The pathogenic mechanism appears to be dominant negative, where mutant proteins interfere with normal cellular function.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.771 OMIM phenotype

Clinical Summary— RARS1

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Gene-Disease Validity (ClinGen)

hypomyelinating leukodystrophy 9 · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

35 unique Pathogenic / Likely Pathogenic· 169 VUS of 463 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.77LOEUF

pLI 0.000

Z-score 2.64

OE 0.52 (0.36–0.77)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.54Z-score

OE missense 0.92 (0.84–1.01)

319 obs / 347.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.52 (0.36–0.77)

0≤0.351.4

Missense OE?0.92 (0.84–1.01)

0≤0.61.4

Synonymous OE?0.98

0≤1.21.6

LoF obs/exp: 18 / 34.8Missense obs/exp: 319 / 347.5Syn Z: 0.19

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveRARS1 related hypomyelinating leukodystrophyLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6744th %ile

GOF

0.6345th %ile

LOF

0.3358th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

463 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic19

Likely Pathogenic16

VUS169

Likely Benign139

Benign89

Conflicting13

Pathogenic

Likely Pathogenic

169

VUS

139

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	14	5	0	0	19
Likely Pathogenic	10	6	0	0	16
VUS	2	156	10	1	169
Likely Benign	0	4	90	45	139
Benign	0	3	78	8	89
Conflicting	—				13
Total	26	174	178	54	445

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

View in ClinVar →

17 pathogenic / likely-pathogenic (of 24) ClinVar copy-number / structural variants overlap RARS1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →