WARS2

Chr 1AR

tryptophanyl tRNA synthetase 2, mitochondrial

Also known as: NEMMLAS, PKDYS3, TrpRS, mtTrpRS

NCBI Gene: 10352ENSG00000116874UniProt: Q9UGM6OMIM: 604733

The mitochondrial tryptophanyl-tRNA synthetase catalyzes the attachment of tryptophan to tRNA(Trp) within mitochondria, essential for mitochondrial protein synthesis. Autosomal recessive mutations cause childhood-onset neurodevelopmental disorders with abnormal movements, lactic acidosis, seizures, and parkinsonism-dystonia. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.666), reflecting its critical role in mitochondrial function.

GeneReviewsOMIMResearchSummary from RefSeq, OMIM, UniProt
DNmechanismARLOEUF 0.672 OMIM phenotypes
Clinical Summary— WARS2
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Gene-Disease Validity (ClinGen)
mitochondrial disease · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.32) despite low pLI — interpret in context.
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ClinVar Variants
29 unique Pathogenic / Likely Pathogenic· 97 VUS of 202 total submissions
Explore recent and relevant literature in Research Assistant →
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GeneReview available — WARS2
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
0.67LOEUF
pLI 0.051
Z-score 2.52
OE 0.32 (0.17–0.67)
Tolerant

Typical tolerance to LoF variation

Missense Constraint
0.90Z-score
OE missense 0.83 (0.73–0.94)
174 obs / 210.9 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.32 (0.17–0.67)
0≤0.351.4
Missense OE0.83 (0.73–0.94)
0≤0.61.4
Synonymous OE0.91
0≤1.21.6
LoF obs/exp: 5 / 15.8Missense obs/exp: 174 / 210.9Syn Z: 0.69
DN
0.74top 25%
GOF
0.5955th %ile
LOF
0.2970th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

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.

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

ClinVar Variant Classifications

202 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic18
Likely Pathogenic11
VUS97
Likely Benign48
Benign13
Conflicting10
18
Pathogenic
11
Likely Pathogenic
97
VUS
48
Likely Benign
13
Benign
10
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
5
2
11
0
18
Likely Pathogenic
2
9
0
0
11
VUS
9
75
13
0
97
Likely Benign
2
6
8
32
48
Benign
0
3
6
4
13
Conflicting
—10
Total18953836197

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

View in ClinVar →

Protein Context — Lollipop Plot

WARS2 · protein map & ClinVar variants

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

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

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