AARS2

Chr 6AR

alanyl-tRNA synthetase 2, mitochondrial

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

NCBI Gene: 57505 ENSG00000124608 UniProt: Q5JTZ9 OMIM: 612035

The encoded protein is a mitochondrial aminoacyl-tRNA synthetase that charges tRNAs with alanine during mitochondrial protein synthesis. Mutations cause combined oxidative phosphorylation deficiency 8 and progressive leukoencephalopathy with ovarian failure through autosomal recessive inheritance. The pathogenic mechanism involves impaired mitochondrial translation leading to defective oxidative phosphorylation.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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]

OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 0.832 OMIM phenotypes

Clinical Summary— AARS2

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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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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.83LOEUF

pLI 0.000

Z-score 2.56

OE 0.63 (0.48–0.83)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.07Z-score

OE missense 0.99 (0.93–1.06)

567 obs / 571.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.63 (0.48–0.83)

0≤0.351.4

Missense OE?0.99 (0.93–1.06)

0≤0.61.4

Synonymous OE?0.84

0≤1.21.6

LoF obs/exp: 35 / 55.6Missense obs/exp: 567 / 571.9Syn Z: 1.88

This gene — mechanism propensity

0.6841th %ile

GOF

0.6443th %ile

LOF

0.2679th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

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