AARS1

Chr 16ADAR

alanyl-tRNA synthetase 1

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

NCBI Gene: 16 ENSG00000090861 UniProt: P49588 OMIM: 601065

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 OMIM 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 OMIM ResearchGenerating clinical summary…

LOFmechanismAD/ARLOEUF 0.624 OMIM phenotypes

Clinical Summary— AARS1

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Gene-Disease Validity (ClinGen)

Charcot-Marie-Tooth disease axonal type 2N · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

3 total gene-disease associations curated

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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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ClinVar Variants

93 unique Pathogenic / Likely Pathogenic· 840 VUS of 1700 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — AARS1

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?

0.62LOEUF

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

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongAARS1-related early-onset epileptic encephalopathy with persistent myelination defectLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6649th %ile

GOF

0.6248th %ile

LOF

0.3358th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Literature Evidence

DNThis suggests that neuropathy-associated AARS1 variants exert a dominant-negative effect, which supports a common, loss-of-function mechanism for ARS-mediated dominant peripheral neuropathy.1

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

References

1.PMID 37010095 ↗

ClinVar Variant Classifications

1700 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic58

Likely Pathogenic35

VUS840

Likely Benign620

Benign44

Conflicting81

Pathogenic

Likely Pathogenic

840

VUS

620

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	45	4	9	0	58
Likely Pathogenic	22	11	2	0	35
VUS	16	752	63	9	840
Likely Benign	1	21	275	323	620
Benign	0	2	39	3	44
Conflicting	—				81
Total	84	790	388	335	1,678

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

View in ClinVar →

25 pathogenic / likely-pathogenic (of 52) ClinVar copy-number / structural variants overlap AARS1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →