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…

MultiplemechanismAR/ADLOEUF 0.782 OMIM phenotypes

Clinical Summary— NARS1

🧬

Gene-Disease Validity (ClinGen)

neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities · ADModerate

Moderate evidence — consider for supplementary testing

2 total gene-disease associations curated

⚡

Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

📋

ClinVar Variants

23 unique Pathogenic / Likely Pathogenic· 165 VUS of 236 total submissions

Explore recent and relevant literature in Research Assistant →

📖

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

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongNARS1-related neurodevelopmental disorderGOFAD

definitiveNARS1-related neurodevelopmental disorderLOFAR

This gene — mechanism propensity

0.6745th %ile

GOF

0.6248th %ile

LOF

0.2969th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOF1 literature citation

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.

Literature Evidence

GOFDe Novo and Bi-allelic Pathogenic Variants in NARS1 Cause Neurodevelopmental Delay Due to Toxic Gain-of-Function and Partial Loss-of-Function Effects1

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

References

1.PMID 32738225 ↗

ClinVar Variant Classifications

236 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4

Likely Pathogenic19

VUS165

Likely Benign22

Benign2

Conflicting3

Pathogenic

Likely Pathogenic

165

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	4	0	0	0	4
Likely Pathogenic	9	10	0	0	19
VUS	14	148	3	0	165
Likely Benign	0	7	0	15	22
Benign	0	0	1	1	2
Conflicting	—				3
Total	27	165	4	16	215

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

View in ClinVar →

68 pathogenic / likely-pathogenic (of 79) ClinVar copy-number / structural variants overlap NARS1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →