AARS1

Chr 16

alanyl-tRNA synthetase 1

Also known as: AARS, CMT2N, DEE29, EIEE29, HDLS2, TTD8

NCBI Gene: 16 ENSG00000090861 UniProt: P49588

Alanyl-tRNA synthetase catalyzes the attachment of alanine to tRNA(Ala) and edits incorrectly charged tRNA molecules, playing an essential role in protein synthesis. Mutations cause autosomal dominant or recessive disorders including Charcot-Marie-Tooth disease type 2N, developmental and epileptic encephalopathy with early onset, leukoencephalopathy with spheroids, and nonphotosensitive trichothiodystrophy. This gene is highly constrained against loss-of-function variants (LOEUF 0.617), reflecting its critical cellular function.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt

The human alanyl-tRNA synthetase (AARS) belongs to a family of tRNA synthases, of the class II enzymes. Class II tRNA synthases evolved early in evolution and are highly conserved. This is reflected by the fact that 498 of the 968-residue polypeptide human AARS shares 41% identity witht the E.coli protein. tRNA synthases are the enzymes that interpret the RNA code and attach specific aminoacids to the tRNAs that contain the cognate trinucleotide anticodons. They consist of a catalytic domain which interacts with the amino acid acceptor-T psi C helix of the tRNA, and a second domain which interacts with the rest of the tRNA structure. [provided by RefSeq, Jul 2008]

GeneReviews ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtCharcot-Marie-Tooth disease, axonal, type 2N

UniProtDevelopmental and epileptic encephalopathy 29

UniProtLeukoencephalopathy, hereditary diffuse, with spheroids 2

UniProtTrichothiodystrophy 8, non-photosensitive

Clinical highlights

Gene–disease validity (ClinGen)

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.62

LOEUF

LOF

Mechanism· G2P

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GeneReview available — AARS1

Authoritative clinical overview · Recommended first read

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Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.62LOEUF

pLI 0.000

Z-score 3.75

OE 0.43 (0.31–0.62)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.05Z-score

OE missense 0.99 (0.93–1.07)

538 obs / 541.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.43 (0.31–0.62)

0≤0.351.4

Missense OE?0.99 (0.93–1.07)

0≤0.61.4

Synonymous OE?1.08

0≤1.21.6

LoF obs/exp: 22 / 50.9Missense obs/exp: 538 / 541.4Syn Z: -0.96

Background carrier burden — how many people carry a rare variant somewhere in AARS1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 59

1,378 rare PASS variants

Rare truncating (LoF)

1 in 670

183 rare PASS variants

Rare synonymous (reference)

1 in 82

528 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for AARS1. 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 70	1 in 930
South Asian	~43k	1 in 43	1 in 330
Remaining (unassigned)	~30k	1 in 57	1 in 240
European (Finnish)	~27k	1 in 140	1 in 3,800
Admixed American	~22k	1 in 51	1 in 420
African / African American	~21k	1 in 43	1 in 1,800
East Asian	~20k	1 in 55	1 in 740
Ashkenazi Jewish	~13k	1 in 140	none seen
Middle Eastern	~2,884	1 in 58	1 in 300

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 20 coding exons well covered in gnomAD exomes and genomes.? see exons ↓