DARS1

Chr 2AR

aspartyl-tRNA synthetase 1

Also known as: DARS, HBSL, aspRS

NCBI Gene: 1615 ENSG00000115866 UniProt: P14868 OMIM: 603084

The protein ligates L-aspartate to tRNA(Asp) as part of a multienzyme complex essential for protein synthesis. Biallelic mutations cause hypomyelination with brainstem and spinal cord involvement and leg spasticity, inherited in an autosomal recessive pattern. The pathogenic mechanism involves dominant-negative effects that disrupt normal aminoacyl-tRNA synthetase function.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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. [provided by RefSeq, Jun 2014]

OMIM ResearchGenerating clinical summary…

DNmechanismARLOEUF 0.681 OMIM phenotype

Clinical Summary— DARS1

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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

11 unique Pathogenic / Likely Pathogenic· 114 VUS of 265 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?

0.68LOEUF

pLI 0.000

Z-score 2.96

OE 0.44 (0.29–0.68)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.75Z-score

OE missense 0.87 (0.78–0.97)

235 obs / 269.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.44 (0.29–0.68)

0≤0.351.4

Missense OE?0.87 (0.78–0.97)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

LoF obs/exp: 14 / 32.1Missense obs/exp: 235 / 269.5Syn Z: 0.11

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveDARS1-related hypomyelination with brain stem and spinal cord involvement and leg spasticityOTHERAR

This gene — mechanism propensity

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

0.6937th %ile

GOF

0.5856th %ile

LOF

0.3163th %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

265 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic5

Likely Pathogenic6

VUS114

Likely Benign89

Benign20

Conflicting9

Pathogenic

Likely Pathogenic

114

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	5	0	0	5
Likely Pathogenic	1	5	0	0	6
VUS	8	97	9	0	114
Likely Benign	1	3	51	34	89
Benign	0	1	18	1	20
Conflicting	—				9
Total	10	111	78	35	243

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

View in ClinVar →

12 pathogenic / likely-pathogenic (of 17) ClinVar copy-number / structural variants overlap DARS1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →