NARS2

Chr 11AR

asparaginyl-tRNA synthetase 2, mitochondrial

Also known as: DFNB94, SLM5, asnRS

NCBI Gene: 79731ENSG00000137513UniProt: Q96I59

This gene encodes a putative member of the class II family of aminoacyl-tRNA synthetases. These enzymes play a critical role in protein biosynthesis by charging tRNAs with their cognate amino acids. This protein is encoded by the nuclear genome but is likely to be imported to the mitochondrion where it is thought to catalyze the ligation of asparagine to tRNA molecules. Mutations in this gene have been associated with combined oxidative phosphorylation deficiency 24 (COXPD24). [provided by RefSeq, Mar 2015]

Primary Disease Associations & Inheritance

?Deafness, autosomal recessive 94MIM #618434
AR
Combined oxidative phosphorylation deficiency 24MIM #616239
AR
424
ClinVar variants
46
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— NARS2
🧬
Gene-Disease Validity (ClinGen)
Leigh syndrome · ARLimited

Limited evidence — not for standalone diagnostic reporting

3 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
46 Pathogenic / Likely Pathogenic· 155 VUS of 424 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.
0.86LOEUF
pLI 0.000
Z-score 2.12
OE 0.57 (0.38–0.86)
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.
-0.76Z-score
OE missense 1.13 (1.03–1.25)
292 obs / 257.7 exp
Tolerant

Tolerant to missense variation

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.0.57 (0.38–0.86)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.13 (1.03–1.25)
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.1.14
0≤1.21.6
LoF obs/exp: 16 / 28.2Missense obs/exp: 292 / 257.7Syn Z: -1.04

ClinVar Variant Classifications

424 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic30
Likely Pathogenic16
VUS155
Likely Benign149
Benign51
Conflicting23
30
Pathogenic
16
Likely Pathogenic
155
VUS
149
Likely Benign
51
Benign
23
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
9
4
17
0
30
Likely Pathogenic
6
6
4
0
16
VUS
4
136
14
1
155
Likely Benign
0
4
88
57
149
Benign
0
4
43
4
51
Conflicting
—23
Total1915416662424

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

View in ClinVar →

Protein Context — Lollipop Plot

NARS2 · protein map & ClinVar variants

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

Gene2Phenotype Curations

NARS2-related oxidative phosphorylation deficiency

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

?Deafness, autosomal recessive 94

MIM #618434

Molecular basis of disorder known

Autosomal recessive

Combined oxidative phosphorylation deficiency 24

MIM #616239

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — NARS2
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Novel NARS2 variants in a patient with early-onset status epilepticus: case study and literature review.
Yang N et al.·BMC Pediatr
2024Review
Alzheimer's Disease Risk Variant rs2373115 Regulates GAB2 and NARS2 Expression in Human Brain Tissues.
Liu G et al.·J Mol Neurosci
2018
[Clinical characteristics and pathogenic variant analysis in a pedigree with syndromic hearing loss caused by likely pathogenic variants in the NARS2 gene].
Wang YN et al.·Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi
2024
Expanding phenotype heterogeneity of NARS2 by presenting subdural hematoma and parenchymal hemorrhage.
Khodaeian M et al.·J Clin Lab Anal
2023Case report
Investigation in yeast of novel variants in mitochondrial aminoacyl-tRNA synthetases WARS2, NARS2, and RARS2 genes associated with mitochondrial diseases.
Figuccia S et al.·Hum Mol Genet
2024
A new entity in the NARS2 variant: the first reported case of type 1 diabetes mellitus associated with the phenotype.
Cokyaman T et al.·J Trop Pediatr
2022Case report
Two siblings with homozygous pathogenic splice-site variant in mitochondrial asparaginyl-tRNA synthetase (NARS2).
Vanlander AV et al.·Hum Mutat
2015
PARS2 and NARS2 mutations in infantile-onset neurodegenerative disorder.
Mizuguchi T et al.·J Hum Genet
2017
Novel variants in the NARS2 gene as a cause of infantile-onset severe epilepsy leading to fatal refractory status epilepticus: case study and literature review.
Štěrbová K et al.·Neurogenetics
2021Review
Novel Cases of Non-Syndromic Hearing Impairment Caused by Pathogenic Variants in Genes Encoding Mitochondrial Aminoacyl-tRNA Synthetases.
Domínguez-Ruiz M et al.·Genes (Basel)
2024Cohort
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