DARS2

Chr 1AR

aspartyl-tRNA synthetase 2, mitochondrial

Also known as: ASPRS, CMT2LL, LBSL, MT-ASPRS, mtAspRS

NCBI Gene: 55157 ENSG00000117593 OMIM: 610956

The protein is a mitochondrial aminoacyl-tRNA synthetase that specifically charges aspartyl-tRNA, essential for mitochondrial protein synthesis. Autosomal recessive mutations cause leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) and axonal Charcot-Marie-Tooth disease type 2LL through impaired mitochondrial translation. Disease mechanisms likely involve loss of enzyme function leading to defective mitochondrial protein synthesis and subsequent energy metabolism defects.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

The protein encoded by this gene belongs to the class-II aminoacyl-tRNA synthetase family. It is a mitochondrial enzyme that specifically aminoacylates aspartyl-tRNA. Mutations in this gene are associated with leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL). [provided by RefSeq, Nov 2009]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.922 OMIM phenotypes

Clinical Summary— DARS2

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Gene-Disease Validity (ClinGen)

mitochondrial disease · 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

79 unique Pathogenic / Likely Pathogenic· 190 VUS of 512 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — DARS2

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.92LOEUF

pLI 0.000

Z-score 1.97

OE 0.66 (0.48–0.92)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.19Z-score

OE missense 0.82 (0.74–0.90)

285 obs / 347.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.66 (0.48–0.92)

0≤0.351.4

Missense OE?0.82 (0.74–0.90)

0≤0.61.4

Synonymous OE?0.89

0≤1.21.6

LoF obs/exp: 25 / 38.2Missense obs/exp: 285 / 347.7Syn Z: 0.96

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongDARS2-related leukoencephalopathy with brainstem and spinal cord involvement and lactate elevationLOFAR

This gene — mechanism propensity

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

0.6939th %ile

GOF

0.5660th %ile

LOF

0.3164th %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

512 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic32

Likely Pathogenic47

VUS190

Likely Benign148

Benign51

Conflicting34

Pathogenic

Likely Pathogenic

190

VUS

148

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	23	5	4	0	32
Likely Pathogenic	26	13	7	1	47
VUS	3	163	21	3	190
Likely Benign	0	6	94	48	148
Benign	0	2	49	0	51
Conflicting	—				34
Total	52	189	175	52	502

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

View in ClinVar →

38 pathogenic / likely-pathogenic (of 47) ClinVar copy-number / structural variants overlap DARS2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →