WARS2

Chr 1AR

tryptophanyl tRNA synthetase 2, mitochondrial

Also known as: NEMMLAS, PKDYS3, TrpRS, mtTrpRS

NCBI Gene: 10352 ENSG00000116874 UniProt: Q9UGM6 OMIM: 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.

GeneReviews 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. This gene encodes the mitochondrial tryptophanyl-tRNA synthetase. Two alternative transcripts encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

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

19 unique Pathogenic / Likely Pathogenic· 89 VUS of 182 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 OE?0.32 (0.17–0.67)

0≤0.351.4

Missense OE?0.83 (0.73–0.94)

0≤0.61.4

Synonymous OE?0.91

0≤1.21.6

LoF obs/exp: 5 / 15.8Missense obs/exp: 174 / 210.9Syn Z: 0.69

This gene — mechanism propensity

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

182 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic8

Likely Pathogenic11

VUS89

Likely Benign46

Benign13

Conflicting10

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	5	2	1	0	8
Likely Pathogenic	2	9	0	0	11
VUS	9	77	3	0	89
Likely Benign	2	5	7	32	46
Benign	0	3	6	4	13
Conflicting	—				10
Total	18	96	17	36	177

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

View in ClinVar →

10 pathogenic / likely-pathogenic (of 22) ClinVar copy-number / structural variants overlap WARS2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →