NARS1

Chr 18ARAD

asparaginyl-tRNA synthetase 1

Also known as: ASNRS, NARS, NEDMILEG, NEDMILG

NCBI Gene: 4677 ENSG00000134440 UniProt: O43776 OMIM: 108410

The protein catalyzes the attachment of asparagine to tRNA(Asn) and plays an essential role in cerebral cortex development by regulating radial glial cell proliferation. Mutations cause neurodevelopmental disorders with microcephaly, impaired language, and gait abnormalities, with some patients also presenting with epilepsy. The gene shows both autosomal recessive and autosomal dominant inheritance patterns and is highly constrained against loss-of-function variants.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

Aminoacyl-tRNA synthetases are a class of enzymes that charge tRNAs with their cognate amino acids. Asparaginyl-tRNA synthetase is localized to the cytoplasm and belongs to the class II family of tRNA synthetases. The N-terminal domain represents the signature sequence for the eukaryotic asparaginyl-tRNA synthetases. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities, autosomal recessiveMIM #619091

Neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities, autosomal dominantMIM #619092

Clinical highlights

Gene–disease validity (ClinGen)

Interpreting a novel variant

The dominant disease is caused by gain-of-function changes and the recessive disease by loss of function (Gene2Phenotype). A single heterozygous truncating variant therefore fits the recessive disease and does not by itself explain a dominant presentation; a novel missense has to be read against the dominant mechanism.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.78

LOEUF

Multiple*

Mechanism· G2P

📖

GeneReview available — NARS1

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?

0.78LOEUF

pLI 0.000

Z-score 2.62

OE 0.54 (0.38–0.78)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.83Z-score

OE missense 0.87 (0.78–0.96)

268 obs / 308.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.54 (0.38–0.78)

0≤0.351.4

Missense OE?0.87 (0.78–0.96)

0≤0.61.4

Synonymous OE?1.04

0≤1.21.6

LoF obs/exp: 20 / 37.2Missense obs/exp: 268 / 308.9Syn Z: -0.34

Background carrier burden — how many people carry a rare variant somewhere in NARS1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 130

697 rare PASS variants

Rare truncating (LoF)

1 in 1,600

132 rare PASS variants

Rare synonymous (reference)

1 in 200

243 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for NARS1. 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 130	1 in 1,500
South Asian	~43k	1 in 130	1 in 1,000
Remaining (unassigned)	~30k	1 in 100	1 in 2,200
European (Finnish)	~27k	1 in 470	1 in 3,000
Admixed American	~22k	1 in 170	1 in 2,800
African / African American	~21k	1 in 77	1 in 2,000
East Asian	~20k	1 in 160	≈ 1 in 9,900
Ashkenazi Jewish	~13k	1 in 1,500	≈ 1 in 6,400
Middle Eastern	~2,884	1 in 100	≈ 1 in 2,900

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): 13 of 14 coding exons well covered in gnomAD exomes; exon 6 marginal. Genomes: all 14.? see exons ↓