NARS1

Chr 18ARAD

asparaginyl-tRNA synthetase 1

Also known as: ASNRS, NARS, NEDMILEG, NEDMILG

NCBI Gene: 4677ENSG00000134440UniProt: O43776

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]

Primary Disease Associations & Inheritance

Neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities, autosomal recessiveMIM #619091
AR
Neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities, autosomal dominantMIM #619092
AD
282
ClinVar variants
85
Pathogenic / LP
0.00
pLI score
0
Active trials
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
85 Pathogenic / Likely Pathogenic· 170 VUS of 282 total submissions

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.
0.78LOEUF
pLI 0.000
Z-score 2.62
OE 0.54 (0.38–0.78)
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.
0.83Z-score
OE missense 0.87 (0.78–0.96)
268 obs / 308.9 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.0.54 (0.38–0.78)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.87 (0.78–0.96)
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.1.04
0≤1.21.6
LoF obs/exp: 20 / 37.2Missense obs/exp: 268 / 308.9Syn Z: -0.34

ClinVar Variant Classifications

282 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic67
Likely Pathogenic18
VUS170
Likely Benign22
Benign2
Conflicting3
67
Pathogenic
18
Likely Pathogenic
170
VUS
22
Likely Benign
2
Benign
3
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
3
0
64
0
67
Likely Pathogenic
2
11
5
0
18
VUS
12
143
15
0
170
Likely Benign
0
7
0
15
22
Benign
0
0
1
1
2
Conflicting
—3
Total171618516282

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

View in ClinVar →

Protein Context — Lollipop Plot

NARS1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

NARS1-related neurodevelopmental disorder

strong
ADGain Of FunctionAltered Gene Product Structure
Dev. Disorders
G2P ↗

NARS1-related neurodevelopmental disorder

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities, autosomal recessive

MIM #619091

Molecular basis of disorder known

Autosomal recessive

Neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities, autosomal dominant

MIM #619092

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — NARS1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
De Novo and Bi-allelic Pathogenic Variants in NARS1 Cause Neurodevelopmental Delay Due to Toxic Gain-of-Function and Partial Loss-of-Function Effects.
Manole A et al.·Am J Hum Genet
2020
Asparaginyl-tRNA synthetase (NARS1) variants implicated in dominant neurological phenotypes display dominant-negative properties.
Peeples SM et al.·HGG Adv
2026
A previously unreported NARS1 variant causes dominant distal hereditary motor neuropathy in a French family.
Theuriet J et al.·J Peripher Nerv Syst
2024Case report
Expanding the genetic spectrum of hereditary motor sensory neuropathies in Pakistan.
Ahmed AN et al.·BMC Neurol
2024
Genomic analysis of multiplex consanguineous families reveals causes of neurodevelopmental disorders with epilepsy.
Shafique A et al.·Gene
2023
Whole exome-based variant profiling and functional network characterization in neural tube defects.
Akcali N et al.·Childs Nerv Syst
2025Functional
Potential prognostic biomarkers of hepatocellular carcinoma based on 4D label-free quantitative proteomics analysis pilot investigation.
Suo L et al.·Int J Biol Markers
2024
A novel pathogenic DICER1 gene variant is associated with hereditary multinodular goiter in an Argentine family as evidenced by clinical, biochemical and molecular genetic analysis.
Targovnik HM et al.·Endocrine
2025Case report
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools