IARS2

Chr 1AR

isoleucyl-tRNA synthetase 2, mitochondrial

Also known as: CAGSSS, ILERS

NCBI Gene: 55699ENSG00000067704UniProt: Q9NSE4

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]

Primary Disease Associations & Inheritance

Cataracts, growth hormone deficiency, sensory neuropathy, sensorineural hearing loss, and skeletal dysplasiaMIM #616007
AR
483
ClinVar variants
31
Pathogenic / LP
0.08
pLI score
1
Active trials
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
31 Pathogenic / Likely Pathogenic· 228 VUS of 483 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available
Some data sources returned errors (1)

clinvar: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
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.
0.39LOEUF
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?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.
1.17Z-score
OE missense 0.86 (0.80–0.93)
479 obs / 556.9 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.0.25 (0.16–0.39)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.86 (0.80–0.93)
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.0.94
0≤1.21.6
LoF obs/exp: 14 / 56.8Missense obs/exp: 479 / 556.9Syn Z: 0.68

ClinVar Variant Classifications

483 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic25
Likely Pathogenic6
VUS228
Likely Benign180
Benign36
Conflicting8
25
Pathogenic
6
Likely Pathogenic
228
VUS
180
Likely Benign
36
Benign
8
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
6
0
19
0
25
Likely Pathogenic
5
1
0
0
6
VUS
2
198
26
2
228
Likely Benign
0
11
87
82
180
Benign
0
0
34
2
36
Conflicting
—8
Total1321016686483

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

View in ClinVar →

Protein Context — Lollipop Plot

IARS2 · protein map & ClinVar variants

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

Gene2Phenotype Curations

IARS2-related cataracts, growth hormone deficiency, sensory neuropathy, sensorineural hearing loss, and skeletal dysplasia

limited
ARLoss Of FunctionAbsent Gene Product
Dev. DisordersEyeSkeletal
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Cataracts, growth hormone deficiency, sensory neuropathy, sensorineural hearing loss, and skeletal dysplasia

MIM #616007

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — IARS2
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
IARS2 mutations lead to Leigh syndrome with a combined oxidative phosphorylation deficiency.
Dong Q et al.·Orphanet J Rare Dis
2024
Expanding the clinical phenotype of IARS2-related mitochondrial disease.
Vona B et al.·BMC Med Genet
2018Case report
Mechanisms and Future Research Perspectives on Mitochondrial Diseases Associated with Isoleucyl-tRNA Synthetase Gene Mutations.
Watanabe M et al.·Genes (Basel)
2024Review
Identification of mutations associated with congenital cataracts in nineteen Chinese families.
Sun HS et al.·BMC Ophthalmol
2025
Mutation in the nuclear-encoded mitochondrial isoleucyl-tRNA synthetase IARS2 in patients with cataracts, growth hormone deficiency with short stature, partial sensorineural deafness, and peripheral neuropathy or with Leigh syndrome.
Schwartzentruber J et al.·Hum Mutat
2014Case report
Identification of a novel lactylation-related gene signature predicts the prognosis of multiple myeloma and experiment verification.
Sun C et al.·Sci Rep
2024
Clinical and genetic characteristics of Chinese patients with familial or sporadic pediatric cataract.
Li J et al.·Orphanet J Rare Dis
2018Cohort
Genetic heterogeneity in Leigh syndrome: Highlighting treatable and novel genetic causes.
Lee JS et al.·Clin Genet
2020
Phenotypic diversity of brain MRI patterns in mitochondrial aminoacyl-tRNA synthetase mutations.
Roux CJ et al.·Mol Genet Metab
2021
Confirmation of CAGSSS syndrome as a distinct entity in a Danish patient with a novel homozygous mutation in IARS2.
Moosa S et al.·Am J Med Genet A
2017Case 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
AnemiaGeneticsErythropoiesis

Genomic of CONgenital Sideroblastic Anemias

RECRUITING
NCT07459816Phase NACentre Hospitalier Universitaire, AmiensStarted 2025-10-28
blood redrawal

External Resources

Links to major genomics databases and tools