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…

Primary Disease Associations & Inheritance

Neurodevelopmental disorder with microcephaly and speech delay, with or without brain abnormalitiesMIM #620317

Neuronopathy, distal hereditary motor, autosomal dominant 9MIM #617721

Clinical highlights

Gene–disease validity (ClinGen)

Limited · distal hereditary motor neuropathy · AD · ClinGen 2026

not for standalone diagnostic reporting

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.49

LOEUF

Mechanism· predicted

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

Background carrier burden — how many people carry a rare variant somewhere in WARS1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 77

559 rare PASS variants

Rare truncating (LoF)

1 in 900

60 rare PASS variants

Rare synonymous (reference)

1 in 99

268 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for WARS1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 150	1 in 2,900
South Asian	~43k	1 in 88	1 in 410
Remaining (unassigned)	~30k	1 in 53	1 in 1,800
European (Finnish)	~27k	1 in 180	1 in 940
Admixed American	~22k	1 in 74	1 in 820
African / African American	~21k	1 in 85	1 in 2,500
East Asian	~20k	1 in 91	1 in 750
Ashkenazi Jewish	~13k	1 in 500	1 in 590
Middle Eastern	~2,884	1 in 89	≈ 1 in 2,600

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 9 of 10 coding exons well covered in gnomAD exomes; exon 2 marginal. Genomes: all 10.? see exons ↓