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.

GeneReviews 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]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Combined oxidative phosphorylation deficiency 8MIM #614096

Leukoencephalopathy, progressive, with ovarian failureMIM #615889

Clinical highlights

Gene–disease validity (ClinGen · GenCC)

Definitive · mitochondrial disease · AR · ClinGen 2022
Definitive · leukoencephalopathy, progressive, with ovarian failure · AR · Laboratory for Molecular Medicine
Strong · combined oxidative phosphorylation defect type 8 · AR · Labcorp Genetics (formerly Invitae)
Supportive · ovarioleukodystrophy · AR · Orphanet

+1 more curated pair

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.83

LOEUF

Multiple*

Mechanism· predicted

📖

GeneReview available — AARS2

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?

0.83LOEUF

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

Background carrier burden — how many people carry a rare variant somewhere in AARS2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 38

1,238 rare PASS variants

Rare truncating (LoF)

1 in 700

201 rare PASS variants

Rare synonymous (reference)

1 in 100

534 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for AARS2. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 52	1 in 710
South Asian	~43k	1 in 46	1 in 960
Remaining (unassigned)	~30k	1 in 32	1 in 740
European (Finnish)	~27k	1 in 120	1 in 1,600
Admixed American	~22k	1 in 39	1 in 970
African / African American	~21k	1 in 35	1 in 520
East Asian	~20k	1 in 52	1 in 580
Ashkenazi Jewish	~13k	1 in 130	1 in 2,200
Middle Eastern	~2,884	1 in 31	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 22 coding exons well covered in gnomAD exomes and genomes.? see exons ↓