AARS1

Chr 16ADAR

alanyl-tRNA synthetase 1

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

NCBI Gene: 16ENSG00000090861UniProt: P49588

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]

Primary Disease Associations & Inheritance

?Leukoencephalopathy, hereditary diffuse, with spheroids 2MIM #619661
AD
Charcot-Marie-Tooth disease, axonal, type 2NMIM #613287
AD
Developmental and epileptic encephalopathy 29MIM #616339
AR
Trichothiodystrophy 8, nonphotosensitiveMIM #619691
AR
578
ClinVar variants
44
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— AARS1
🧬
Gene-Disease Validity (ClinGen)
Charcot-Marie-Tooth disease axonal type 2N · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

3 total gene-disease associations curated

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
44 Pathogenic / Likely Pathogenic· 320 VUS of 578 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.
0.62LOEUF
pLI 0.000
Z-score 3.75
OE 0.43 (0.31–0.62)
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.
0.05Z-score
OE missense 0.99 (0.93–1.07)
538 obs / 541.4 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.0.43 (0.31–0.62)
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 (0.93–1.07)
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.1.08
0≤1.21.6
LoF obs/exp: 22 / 50.9Missense obs/exp: 538 / 541.4Syn Z: -0.96

ClinVar Variant Classifications

578 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic30
Likely Pathogenic14
VUS320
Likely Benign173
Benign21
Conflicting20
30
Pathogenic
14
Likely Pathogenic
320
VUS
173
Likely Benign
21
Benign
20
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
14
0
16
0
30
Likely Pathogenic
8
3
3
0
14
VUS
5
275
36
4
320
Likely Benign
1
5
62
105
173
Benign
0
0
20
1
21
Conflicting
—20
Total28283137110578

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

View in ClinVar →

Protein Context — Lollipop Plot

AARS1 · protein map & ClinVar variants

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

Gene2Phenotype Curations

AARS1-related early-onset epileptic encephalopathy with persistent myelination defect

strong
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

?Leukoencephalopathy, hereditary diffuse, with spheroids 2

MIM #619661

Molecular basis of disorder known

Autosomal dominant

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

MIM #613287

Molecular basis of disorder known

Autosomal dominant

Developmental and epileptic encephalopathy 29

MIM #616339

Molecular basis of disorder known

Autosomal recessive

Trichothiodystrophy 8, nonphotosensitive

MIM #619691

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — AARS1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
High-glucose-associated YTHDC1 lactylation reduces the sensitivity of bladder cancer to enfortumab vedotin therapy.
Xing Z et al.·Cell Rep
2025
An AARS1 variant identified to cause adult-onset leukoencephalopathy with neuroaxonal spheroids and pigmented glia.
Wu J et al.·Transl Neurodegener
2023
Recessive, pathogenic AARS1 variants display variable loss-of-function and dominant-negative effects.
Kuo ME et al.·Dis Model Mech
2025
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
Clinical characteristics and proteome modifications in two Charcot-Marie-Tooth families with the AARS1 Arg326Trp mutation.
Høyer H et al.·BMC Neurol
2022
A humanized yeast model reveals dominant-negative properties of neuropathy-associated alanyl-tRNA synthetase mutations.
Meyer-Schuman R et al.·Hum Mol Genet
2023Functional
AARS1-mediated AKR1B10 lactylation stabilizes an aerobic glycolysis-positive feedback loop to drive lenvatinib resistance in hepatocellular carcinoma.
Liu Z et al.·Clin Transl Med
2026
ASH2L-K312-Lac Stimulates Angiogenesis in Tumors to Expedite the Malignant Progression of Hepatocellular Carcinoma.
Han H et al.·Adv Sci (Weinh)
2025
Expanded phenotype of AARS1-related white matter disease.
Helman G et al.·Genet Med
2021
Lactylation in cancer: Metabolic-epigenetic nexus and therapeutic frontiers.
Zhang C et al.·Crit Rev Oncol Hematol
2026Review
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