NARS2

Chr 11AR

asparaginyl-tRNA synthetase 2, mitochondrial

Also known as: DFNB94, SLM5, asnRS

NCBI Gene: 79731 ENSG00000137513 UniProt: Q96I59 OMIM: 612803

The protein catalyzes the ligation of asparagine to tRNA molecules in the mitochondrial matrix, which is essential for mitochondrial protein biosynthesis. Mutations cause combined oxidative phosphorylation deficiency 24 and autosomal recessive deafness through an autosomal recessive inheritance pattern. The pathogenic mechanism appears to be dominant negative, where mutant proteins interfere with normal mitochondrial protein synthesis.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.862 OMIM phenotypes

Clinical Summary— NARS2

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Gene-Disease Validity (ClinGen)

Leigh syndrome · ARLimited

Limited evidence — not for standalone diagnostic reporting

3 total gene-disease associations curated

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Population Constraint (gnomAD)

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

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ClinVar Variants

37 unique Pathogenic / Likely Pathogenic· 156 VUS of 429 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — NARS2

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?

0.86LOEUF

pLI 0.000

Z-score 2.12

OE 0.57 (0.38–0.86)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.76Z-score

OE missense 1.13 (1.03–1.25)

292 obs / 257.7 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.57 (0.38–0.86)

0≤0.351.4

Missense OE?1.13 (1.03–1.25)

0≤0.61.4

Synonymous OE?1.14

0≤1.21.6

LoF obs/exp: 16 / 28.2Missense obs/exp: 292 / 257.7Syn Z: -1.04

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveNARS2-related oxidative phosphorylation deficiencyLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.76top 25%

GOF

0.5759th %ile

LOF

0.2483th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

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

ClinVar Variant Classifications

429 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic21

Likely Pathogenic16

VUS156

Likely Benign149

Benign51

Conflicting23

Pathogenic

Likely Pathogenic

156

VUS

149

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	13	4	4	0	21
Likely Pathogenic	9	6	1	0	16
VUS	6	140	9	1	156
Likely Benign	0	4	88	57	149
Benign	0	4	43	4	51
Conflicting	—				23
Total	28	158	145	62	416

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

View in ClinVar →

10 pathogenic / likely-pathogenic (of 12) ClinVar copy-number / structural variants overlap NARS2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →