IARS1

Chr 9AR

isoleucyl-tRNA synthetase 1

Also known as: GRIDHH, IARS, ILERS, ILRS, IRS, PRO0785

NCBI Gene: 3376ENSG00000196305UniProt: P41252OMIM: 600709

Isoleucine-tRNA synthetase catalyzes the ATP-dependent attachment of isoleucine to its cognate tRNA, an essential step in protein synthesis. Autosomal recessive mutations cause a multisystem disorder with growth retardation, intellectual disability, hypotonia, and hepatopathy. This gene is highly intolerant to loss-of-function variants (pLI nearly 1.0), consistent with its essential cellular function.

GeneReviewsOMIMResearchSummary from RefSeq, OMIM, UniProt
LOFmechanismARLOEUF 0.771 OMIM phenotype
Clinical Summary— IARS1
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
66 unique Pathogenic / Likely Pathogenic· 260 VUS of 571 total submissions
Explore recent and relevant literature in Research Assistant →
📖
GeneReview available — IARS1
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
0.77LOEUF
pLI 0.000
Z-score 3.24
OE 0.60 (0.47–0.77)
Tolerant

Typical tolerance to LoF variation

Missense Constraint
1.13Z-score
OE missense 0.88 (0.82–0.94)
594 obs / 676.9 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.60 (0.47–0.77)
0≤0.351.4
Missense OE0.88 (0.82–0.94)
0≤0.61.4
Synonymous OE1.07
0≤1.21.6
LoF obs/exp: 46 / 76.6Missense obs/exp: 594 / 676.9Syn Z: -0.83
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
strongIARS1-related growth retardation with prenatal onset, intellectual disability, muscular hypotonia, and infantile hepatopathyLOFAR

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

DN
0.5869th %ile
GOF
0.6443th %ile
LOF
0.2971th %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

571 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic48
Likely Pathogenic18
VUS260
Likely Benign162
Benign30
Conflicting6
48
Pathogenic
18
Likely Pathogenic
260
VUS
162
Likely Benign
30
Benign
6
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
16
6
26
0
48
Likely Pathogenic
14
1
3
0
18
VUS
1
239
20
0
260
Likely Benign
0
17
66
79
162
Benign
0
9
13
8
30
Conflicting
—6
Total3127212887524

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

View in ClinVar →

Protein Context — Lollipop Plot

IARS1 · protein map & ClinVar variants

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

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 4 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Mechanisms and Future Research Perspectives on Mitochondrial Diseases Associated with Isoleucyl-tRNA Synthetase Gene Mutations.
Watanabe M et al.·Genes (Basel)
2024Review
Compound heterozygous variations in IARS1 cause recurrent liver failure and growth retardation in a Chinese patient: a case report.
Zou TT et al.·BMC Pediatr
2022Case report
Novel IARS1 variants cause syndromic developmental disorder with epilepsy in a Chinese patient and the literature review.
Jiang J et al.·Mol Genet Genomic Med
2024Review
Pulmonary alveolar proteinosis and anemia may be associated with poor prognosis in patients with IARS1 variants.
Li SY et al.·Orphanet J Rare Dis
2025Case report
A disease-causing isoleucyl-tRNA synthetase variant leads to altered protein complex formation and cellular stress response.
Gao H et al.·J Biol Chem
2026
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients