IARS2

Chr 1AR

isoleucyl-tRNA synthetase 2, mitochondrial

Also known as: CAGSSS, ILERS

NCBI Gene: 55699 ENSG00000067704 UniProt: Q9NSE4 OMIM: 612801

The protein catalyzes the aminoacylation of tRNA with isoleucine in the mitochondrial matrix, serving as the mitochondrial isoleucine-tRNA synthetase essential for mitochondrial protein synthesis. Biallelic mutations cause an autosomal recessive multisystem disorder characterized by cataracts, growth hormone deficiency, sensory neuropathy, sensorineural hearing loss, and skeletal dysplasia. The pathogenicity likely results from impaired mitochondrial protein synthesis due to defective aminoacylation of mitochondrial tRNAs.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

Aminoacyl-tRNA synthetases catalyze the aminoacylation of tRNA by their cognate amino acid. Because of their central role in linking amino acids with nucleotide triplets contained in tRNAS, aminoacyl-tRNA synthetases are thought to be among the first proteins that appeared in evolution. Two forms of isoleucine-tRNA synthetase exist, a cytoplasmic form and a mitochondrial form. This gene encodes the mitochondrial isoleucine-tRNA synthetase which belongs to the class-I aminoacyl-tRNA synthetase family. [provided by RefSeq, Dec 2014]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.391 OMIM phenotype

Clinical Summary— IARS2

🧬

Gene-Disease Validity (ClinGen)

Leigh syndrome · ARLimited

Limited evidence — not for standalone diagnostic reporting

2 total gene-disease associations curated

⚡

Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.25) despite low pLI — interpret in context.

📋

ClinVar Variants

30 unique Pathogenic / Likely Pathogenic· 270 VUS of 645 total submissions

💊

Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

📖

GeneReview available — IARS2

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.39LOEUF

pLI 0.081

Z-score 5.26

OE 0.25 (0.16–0.39)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.17Z-score

OE missense 0.86 (0.80–0.93)

479 obs / 556.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.25 (0.16–0.39)

0≤0.351.4

Missense OE?0.86 (0.80–0.93)

0≤0.61.4

Synonymous OE?0.94

0≤1.21.6

LoF obs/exp: 14 / 56.8Missense obs/exp: 479 / 556.9Syn Z: 0.68

ClinVar Variant Classifications

645 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic15

Likely Pathogenic15

VUS270

Likely Benign253

Benign61

Conflicting14

Pathogenic

Likely Pathogenic

270

VUS

253

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	10	3	2	0	15
Likely Pathogenic	12	3	0	0	15
VUS	8	241	18	3	270
Likely Benign	0	11	125	117	253
Benign	0	4	52	5	61
Conflicting	—				14
Total	30	262	197	125	628

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

View in ClinVar →

30 pathogenic / likely-pathogenic (of 40) ClinVar copy-number / structural variants overlap IARS2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →