AARS2

Chr 6AR

alanyl-tRNA synthetase 2, mitochondrial

Also known as: AARSL, COXPD8, LKENP, MT-ALARS, MTALARS

NCBI Gene: 57505ENSG00000124608UniProt: Q5JTZ9

The protein encoded by this gene belongs to the class-II aminoacyl-tRNA synthetase family. Aminoacyl-tRNA synthetases play critical roles in mRNA translation by charging tRNAs with their cognate amino acids. The encoded protein is a mitochondrial enzyme that specifically aminoacylates alanyl-tRNA. Mutations in this gene are a cause of combined oxidative phosphorylation deficiency 8. [provided by RefSeq, Dec 2011]

Primary Disease Associations & Inheritance

Combined oxidative phosphorylation deficiency 8MIM #614096
AR
Leukoencephalopathy, progressive, with ovarian failureMIM #615889
AR
516
ClinVar variants
65
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— AARS2
🧬
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
65 Pathogenic / Likely Pathogenic· 236 VUS of 516 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.
0.83LOEUF
pLI 0.000
Z-score 2.56
OE 0.63 (0.48–0.83)
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.
0.07Z-score
OE missense 0.99 (0.93–1.06)
567 obs / 571.9 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.0.63 (0.48–0.83)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.99 (0.93–1.06)
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.0.84
0≤1.21.6
LoF obs/exp: 35 / 55.6Missense obs/exp: 567 / 571.9Syn Z: 1.88

ClinVar Variant Classifications

516 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic34
Likely Pathogenic31
VUS236
Likely Benign174
Benign25
Conflicting16
34
Pathogenic
31
Likely Pathogenic
236
VUS
174
Likely Benign
25
Benign
16
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
13
7
14
0
34
Likely Pathogenic
17
7
7
0
31
VUS
1
221
11
3
236
Likely Benign
0
14
67
93
174
Benign
0
4
19
2
25
Conflicting
—16
Total3125311898516

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

View in ClinVar →

Protein Context — Lollipop Plot

AARS2 · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Combined oxidative phosphorylation deficiency 8

MIM #614096

Molecular basis of disorder known

Autosomal recessive

Leukoencephalopathy, progressive, with ovarian failure

MIM #615889

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — AARS2
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Practical approach to the diagnosis of adult-onset leukodystrophies: an updated guide in the genomic era.
Lynch DS et al.·J Neurol Neurosurg Psychiatry
2019Review
Genetic Basis of Severe Childhood-Onset Cardiomyopathies.
Vasilescu C et al.·J Am Coll Cardiol
2018
Clinical Diagnosis and Differential Diagnosis Between CSF1R- and AARS2-Related Leukoencephalopathy.
Mao C et al.·J Mol Neurosci
2025
AARS2-Related Leukodystrophy: a Case Report and Literature Review.
Zhang X et al.·Cerebellum
2023Review
Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia.
Wade C et al.·Handb Clin Neurol
2024Review
The emerging neurological spectrum of AARS2-associated disorders.
Parra SP et al.·Parkinsonism Relat Disord
2021Review
AARS2 as a novel biomarker for prognosis and its molecular characterization in pan-cancer.
Liu L et al.·Cancer Med
2023
Multi-omics analysis revealed heterogeneity of AARS1 and AARS2 in pan-cancer and identified AARS1 as a potential prognostic biomarker for urologic neoplasms.
Tang M et al.·Apoptosis
2025
Retinopathy and optic atrophy: Expanding the phenotypic spectrum of pathogenic variants in the AARS2 gene.
Peragallo JH et al.·Ophthalmic Genet
2018Case report
Four pedigrees with aminoacyl-tRNA synthetase abnormalities.
Okamoto N et al.·Neurol Sci
2022
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