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…

Primary Disease Associations & Inheritance

?Deafness, autosomal recessive 94MIM #618434

Combined oxidative phosphorylation deficiency 24MIM #616239

Clinical highlights

Gene–disease validity (ClinGen · GenCC)

Definitive · mitochondrial disease · AR · ClinGen 2024
Definitive · combined oxidative phosphorylation defect type 24 · AR · G2P
Limited · nonsyndromic genetic hearing loss · AR · ClinGen 2021 — not for standalone diagnostic reporting
Limited · Leigh syndrome · AR · ClinGen 2019 — not for standalone diagnostic reporting
Limited · hearing loss, autosomal recessive 94 · AR · Labcorp Genetics (formerly Invitae) — not for standalone diagnostic reporting

+1 more curated pair

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.86

LOEUF

LOF

Mechanism· G2P

📖

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

Background carrier burden — how many people carry a rare variant somewhere in NARS2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 92

660 rare PASS variants

Rare truncating (LoF)

1 in 1,400

115 rare PASS variants

Rare synonymous (reference)

1 in 170

212 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for NARS2. 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 150	1 in 1,400
South Asian	~43k	1 in 84	1 in 2,200
Remaining (unassigned)	~30k	1 in 83	1 in 2,900
European (Finnish)	~27k	1 in 170	1 in 2,900
Admixed American	~22k	1 in 72	1 in 1,500
African / African American	~21k	1 in 82	1 in 1,100
East Asian	~20k	1 in 110	1 in 3,300
Ashkenazi Jewish	~13k	1 in 250	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 73	≈ 1 in 1,400

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 9 poorly covered. Genomes: all 14.? see exons ↓