WARS2

Chr 1

tryptophanyl tRNA synthetase 2, mitochondrial

ENSG00000116874UniProt: Q9UGM6

Catalyzes the attachment of tryptophan to tRNA(Trp) in a two-step reaction: tryptophan is first activated by ATP to form Trp-AMP and then transferred to the acceptor end of tRNA(Trp)

Primary Disease Associations & Inheritance

UniProtNeurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures
UniProtParkinsonism-dystonia 3, childhood-onset
0
ClinVar variants
0
Pathogenic / LP
0.05
pLI score
0
Active trials
Clinical Summary— WARS2
🧬
Gene-Disease Validity (ClinGen)
mitochondrial disease · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.32) despite low pLI — interpret in context.
Some data sources returned errors (2)

ncbi: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

omim: Error: OMIM fetch failed: 429

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.
0.67LOEUF
pLI 0.051
Z-score 2.52
OE 0.32 (0.17–0.67)
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.
0.90Z-score
OE missense 0.83 (0.73–0.94)
174 obs / 210.9 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.0.32 (0.17–0.67)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.83 (0.73–0.94)
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.0.91
0≤1.21.6
LoF obs/exp: 5 / 15.8Missense obs/exp: 174 / 210.9Syn Z: 0.69

ClinVar Variant Classifications

0 submitted variants in ClinVar

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.

OMIM — Genotype-Phenotype

OMIM

No OMIM entries found.

Clinical Literature
Landmark / reviewRecent case evidence
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Cancer-associated fibroblast-induced lncRNA WARS2-IT1 confers radioresistance of colorectal cancer via enhancing HIF-1α stability.
Li Y et al.·Cell Death Dis
2025🔓 Open Access
WARS2 -Associated Neuropsychiatric Phenotype in Childhood: A Case-Based Review.
Kalita S et al.·Ann Indian Acad Neurol
2025🔓 Open AccessReview
Mechanism of lncRNA WARS2-IT1 promoting angiogenesis of glioma through miR-299-3P/VEGFA axis and activating PI3K/AKT signaling pathway.
Hu M et al.·Cytotechnology
2025Functional
Investigation in yeast of novel variants in mitochondrial aminoacyl-tRNA synthetases WARS2, NARS2, and RARS2 genes associated with mitochondrial diseases.
Figuccia S et al.·Hum Mol Genet
2024
Compound Heterozygous WARS2 Variants Including a Hypomorphic Allele Cause a Milder Phenotype of Complex Dopa Responsive Dystonia: Case Report and Review of the Literature.
Schneider V et al.·Cerebellum
2024Review
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

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External Resources

Links to major genomics databases and tools