DARS2

Chr 1AR

aspartyl-tRNA synthetase 2, mitochondrial

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

NCBI Gene: 55157ENSG00000117593UniProt: Q6PI48

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]

Primary Disease Associations & Inheritance

Charcot-Marie-Tooth disease, axonal, type 2LLMIM #621485
AR
Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevationMIM #611105
AR
490
ClinVar variants
94
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— DARS2
🧬
Gene-Disease Validity (ClinGen)
mitochondrial disease · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
94 Pathogenic / Likely Pathogenic· 184 VUS of 490 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.
0.92LOEUF
pLI 0.000
Z-score 1.97
OE 0.66 (0.48–0.92)
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.
1.19Z-score
OE missense 0.82 (0.74–0.90)
285 obs / 347.7 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.0.66 (0.48–0.92)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.82 (0.74–0.90)
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.0.89
0≤1.21.6
LoF obs/exp: 25 / 38.2Missense obs/exp: 285 / 347.7Syn Z: 0.96

ClinVar Variant Classifications

490 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic50
Likely Pathogenic44
VUS184
Likely Benign143
Benign43
Conflicting26
50
Pathogenic
44
Likely Pathogenic
184
VUS
143
Likely Benign
43
Benign
26
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
15
3
32
0
50
Likely Pathogenic
17
10
16
1
44
VUS
2
155
25
2
184
Likely Benign
0
5
90
48
143
Benign
0
0
43
0
43
Conflicting
—26
Total3417320651490

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

View in ClinVar →

Protein Context — Lollipop Plot

DARS2 · protein map & ClinVar variants

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

Gene2Phenotype Curations

DARS2-related leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation

strong
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

Charcot-Marie-Tooth disease, axonal, type 2LL

MIM #621485

Molecular basis of disorder known

Autosomal recessive

Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation

MIM #611105

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — DARS2
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Variants in mitochondrial disease genes are common causes of inherited peripheral neuropathies.
Ferreira T et al.·J Neurol
2024
[Expression of DARS2 in colorectal cancer and its clinical significance].
Ma L et al.·Zhonghua Bing Li Xue Za Zhi
2024
Prognostic biomarker DARS2 correlated with immune infiltrates in bladder tumor.
Yang H et al.·Front Immunol
2024
AAV9-DARS2 Gene Therapy Rescues Phenotype in Leukoencephalopathy with Brainstem and Spinal Cord Involvement and Lactate Elevation Patient Cells and Neuronal Dars2 Deficient Mice.
Garofolo I et al.·Ann Neurol
2026
Mitochondrial syndromes with leukoencephalopathies.
Wong LJ·Semin Neurol
2012Review
Diagnosis of hereditary ataxias: a real-world single center experience.
Meli A et al.·J Neurol
2025
CLPP deficiency ameliorates neurodegeneration caused by impaired mitochondrial protein synthesis.
Rumyantseva A et al.·Brain
2022
Mitochondrial aminoacyl-tRNA synthetase disorders: an emerging group of developmental disorders of myelination.
Fine AS et al.·J Neurodev Disord
2019Review
Functional analysis of missense DARS2 variants in siblings with leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation.
Wongkittichote P et al.·Mol Genet Metab
2022Functional
Amino acid supplementation in patients affected by leukoencephalopathies associated with mitochondrial aminoacyl tRNA synthetase pathogenic variants: Pilot clinical trial in adults and review of literature.
Catania A et al.·Mol Genet Metab
2025Clinical trial
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