WARS1

Chr 14ARAD

tryptophanyl-tRNA synthetase 1

Also known as: GAMMA-2, HMN9, HMND9, IFI53, IFP53, NEDMSBA, WARS

NCBI Gene: 7453ENSG00000140105UniProt: P23381

Aminoacyl-tRNA synthetases catalyze the aminoacylation of tRNA by their cognate amino acid. Because of their central role in linking amino acids with nucleotide triplets contained in tRNAs, aminoacyl-tRNA synthetases are thought to be among the first proteins that appeared in evolution. Two forms of tryptophanyl-tRNA synthetase exist, a cytoplasmic form, named WARS, and a mitochondrial form, named WARS2. Tryptophanyl-tRNA synthetase (WARS) catalyzes the aminoacylation of tRNA(trp) with tryptophan and is induced by interferon. Tryptophanyl-tRNA synthetase belongs to the class I tRNA synthetase family. Four transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Neurodevelopmental disorder with microcephaly and speech delay, with or without brain abnormalitiesMIM #620317
AR
Neuronopathy, distal hereditary motor, autosomal dominant 9MIM #617721
AD
82
ClinVar variants
7
Pathogenic / LP
0.30
pLI score
2
Active trials
Clinical Summary— WARS1
🧬
Gene-Disease Validity (ClinGen)
distal hereditary motor neuropathy · ADLimited

Limited evidence — not for standalone diagnostic reporting

⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.23) despite low pLI — interpret in context.
📋
ClinVar Variants
7 Pathogenic / Likely Pathogenic· 59 VUS of 82 total submissions
💊
Clinical Trials
2 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
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.
0.49LOEUF
pLI 0.303
Z-score 3.28
OE 0.23 (0.12–0.49)
Moderately constrained

More LoF-intolerant than ~75% of genes

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.
1.99Z-score
OE missense 0.67 (0.59–0.75)
188 obs / 282.2 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.0.23 (0.12–0.49)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.67 (0.59–0.75)
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.0.88
0≤1.21.6
LoF obs/exp: 5 / 21.4Missense obs/exp: 188 / 282.2Syn Z: 1.01

ClinVar Variant Classifications

82 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic5
Likely Pathogenic2
VUS59
Likely Benign13
Benign1
Conflicting2
5
Pathogenic
2
Likely Pathogenic
59
VUS
13
Likely Benign
1
Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
5
0
5
Likely Pathogenic
0
1
1
0
2
VUS
1
54
4
0
59
Likely Benign
0
5
3
5
13
Benign
0
1
0
0
1
Conflicting
—2
Total16113582

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

View in ClinVar →

Protein Context — Lollipop Plot

WARS1 · protein map & ClinVar variants

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

Gene2Phenotype Curations

WARS1-related distal hereditary motor neuropathy

definitive
ADUndeterminedDecreased Gene Product Level
Dev. Disorders
G2P ↗

WARS1-related neurodevelopmental syndrome

limited
ARUndeterminedAbsent Gene Product, Altered Gene Product Structure, Decreased Gene Product Level
Dev. Disorders
G2P ↗
start lostmissense variant

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Neurodevelopmental disorder with microcephaly and speech delay, with or without brain abnormalities

MIM #620317

Molecular basis of disorder known

Autosomal recessive

Neuronopathy, distal hereditary motor, autosomal dominant 9

MIM #617721

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Highly secreted tryptophanyl tRNA synthetase 1 as a potential theranostic target for hypercytokinemic severe sepsis.
Kim YT et al.·EMBO Mol Med
2024
Pinpointing Novel Plasma and Brain Proteins for Common Ocular Diseases: A Comprehensive Cross-Omics Integration Analysis.
Mo Q et al.·Int J Mol Sci
2024
WARS1 and SARS1: Two tRNA synthetases implicated in autosomal recessive microcephaly.
Bögershausen N et al.·Hum Mutat
2022
Biallelic variants in WARS1 cause a highly variable neurodevelopmental syndrome and implicate a critical exon for normal auditory function.
Lin SJ et al.·Hum Mutat
2022
Clinical Significance of Tryptophanyl-tRNA Synthetase 1 Gene Expression in Patients With Locally Advanced Gastric Cancer.
Oshima T et al.·Anticancer Res
2024Cohort
Four pedigrees with aminoacyl-tRNA synthetase abnormalities.
Okamoto N et al.·Neurol Sci
2022
Variants of aminoacyl-tRNA synthetase genes in Charcot-Marie-Tooth disease: A Korean cohort study.
Nam DE et al.·J Peripher Nerv Syst
2022Cohort
Knocking Down WARS1 in Colorectal Cancer: Implications for Apoptosis and Cell Cycle Arrest via the p53 Signaling Pathway.
Hu M et al.·Discov Med
2025
A missense, loss-of-function YARS1 variant in a patient with proximal-predominant motor neuropathy.
Forrest ME et al.·Cold Spring Harb Mol Case Stud
2022Case report
Clinical characteristics and proteome modifications in two Charcot-Marie-Tooth families with the AARS1 Arg326Trp mutation.
Høyer H et al.·BMC Neurol
2022
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
Single Cell Sequencing TechnologyGene Expression ProfilingGene Expression

Host Response to Infection by Direct Analysis of Leukocyte Single Cell-type Gene Expression/transcript Abundance, Direct LS-TA. a Prospective Study Will Evaluate the Performance of Direct LS-TA in Triage Febrile Patients Into Major Categories of Infections: Viral, Bacterial or Active Tuberculosis.

NOT YET RECRUITING
NCT06846645Chinese University of Hong KongStarted 2025-02
No intervention
Gene ExpressionGene Expression ProfilingInfection

Host Response to Infection by Direct Analysis of Leukocyte Single Cell-type Gene Expression/transcript Abundance, Direct LS-TA

ACTIVE NOT RECRUITING
NCT06838780Chinese University of Hong KongStarted 2018-01-01
No intervention

External Resources

Links to major genomics databases and tools