WARS1

Chr 14ARAD

tryptophanyl-tRNA synthetase 1

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

NCBI Gene: 7453 ENSG00000140105 UniProt: P23381 OMIM: 191050

The protein catalyzes the aminoacylation of tRNA with tryptophan in the cytoplasm, a critical step in protein synthesis. Mutations cause neurodevelopmental disorder with microcephaly and speech delay with or without brain abnormalities (autosomal recessive) and distal hereditary motor neuronopathy type 9 (autosomal dominant). The pathogenic mechanism involves disruption of cytoplasmic protein synthesis due to impaired tryptophan incorporation into nascent proteins.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

MultiplemechanismAR/ADLOEUF 0.492 OMIM phenotypes

Clinical Summary— WARS1

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Gene-Disease Validity (ClinGen)

distal hereditary motor neuropathy · ADLimited

Limited evidence — not for standalone diagnostic reporting

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.23) despite low pLI — interpret in context.

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ClinVar Variants

5 unique Pathogenic / Likely Pathogenic· 79 VUS of 146 total submissions

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Clinical Trials

2 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

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?

1.99Z-score

OE missense 0.67 (0.59–0.75)

188 obs / 282.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.23 (0.12–0.49)

0≤0.351.4

Missense OE?0.67 (0.59–0.75)

0≤0.61.4

Synonymous OE?0.88

0≤1.21.6

LoF obs/exp: 5 / 21.4Missense obs/exp: 188 / 282.2Syn Z: 1.01

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveWARS1-related distal hereditary motor neuropathyOTHERAD

limitedWARS1-related neurodevelopmental syndromeOTHERAR

This gene — mechanism propensity

0.6258th %ile

GOF

0.5759th %ile

LOF

0.3843th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and loss-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median · 1 literature citation

LOF40% of P/LP variants are LoF · LOEUF 0.49

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNCell transfection studies demonstrated a dominant-negative effect of the p.His257Arg mutation on aminoacylation activity of TrpRS, which subsequently compromised protein synthesis and reduced cell viability.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 28369220 ↗

ClinVar Variant Classifications

146 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

Likely Pathogenic4

VUS79

Likely Benign24

Benign15

Conflicting5

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	1	0	0	1
Likely Pathogenic	2	2	0	0	4
VUS	3	75	1	0	79
Likely Benign	0	7	5	12	24
Benign	0	1	13	1	15
Conflicting	—				5
Total	5	86	19	13	128

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

View in ClinVar →

36 pathogenic / likely-pathogenic (of 42) ClinVar copy-number / structural variants overlap WARS1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →

Protein Context — Lollipop Plot

WARS1 · protein map & ClinVar variants

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

External Resources

Links to major genomics databases and tools

Franklin by Genoox

AI-powered variant curation and clinical analysis

DECIPHER

Genomic variants and phenotypes in rare disease patients

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

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

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

Clinical Literature

Open Research Assistant →

Landmark / reviewRecent case evidence

Full-Text Mentions

NLP-detected gene mentions in article bodies · via PubTator3

PubTator3

Secreted tryptophanyl-tRNA synthetase 1 is a prognostic marker in sepsis patients without monocytopenia.

Kim KS et al.·Shock

2023Cohort