LARS2

Chr 3AR

leucyl-tRNA synthetase 2, mitochondrial

ENSG00000011376UniProt: Q15031

Catalyzes the attachment of leucine to its cognate tRNA

Primary Disease Associations & Inheritance

Hydrops, lactic acidosis, and sideroblastic anemiaMIM #617021
AR
Perrault syndrome 4MIM #615300
AR
643
ClinVar variants
38
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— LARS2
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
38 Pathogenic / Likely Pathogenic· 130 VUS of 643 total submissions
Some data sources returned errors (1)

ncbi: 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
Tolerant — LoF & missense variants common in population
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.
0.86LOEUF
pLI 0.000
Z-score 2.40
OE 0.64 (0.49–0.86)
Tolerant

Typical tolerance to LoF variation

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.
1.33Z-score
OE missense 0.83 (0.77–0.90)
427 obs / 511.7 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.0.64 (0.49–0.86)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.83 (0.77–0.90)
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.0.96
0≤1.21.6
LoF obs/exp: 34 / 52.8Missense obs/exp: 427 / 511.7Syn Z: 0.48

ClinVar Variant Classifications

643 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic19
Likely Pathogenic19
VUS130
Likely Benign127
Benign17
Conflicting10
19
Pathogenic
19
Likely Pathogenic
130
VUS
127
Likely Benign
17
Benign
10
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
10
2
7
0
19
Likely Pathogenic
7
7
5
0
19
VUS
1
124
4
1
130
Likely Benign
0
1
56
70
127
Benign
0
3
4
10
17
Conflicting
—10
Total181377681322

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

View in ClinVar →

Protein Context — Lollipop Plot

LARS2 · protein map & ClinVar variants

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

Gene2Phenotype Curations

LARS2-related Perrault syndrome

strong
ARUndeterminedAltered Gene Product Structure
Dev. DisordersEar
G2P ↗
missense variantinframe deletioninframe insertion

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Hydrops, lactic acidosis, and sideroblastic anemia

MIM #617021

Molecular basis of disorder known

Autosomal recessive

Perrault syndrome 4

MIM #615300

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Leucine-tRNA-synthase-2-expressing B cells contribute to colorectal cancer immunoevasion.
Wang Z et al.·Immunity
2022
Aging-induced tRNA(Glu)-derived fragment impairs glutamate biosynthesis by targeting mitochondrial translation-dependent cristae organization.
Li D et al.·Cell Metab
2024
Genetics of ovarian insufficiency and defects of folliculogenesis.
França MM et al.·Best Pract Res Clin Endocrinol Metab
2022Review
Regulating Lars2 in mitochondria: A potential Alzheimer's therapy by inhibiting tau phosphorylation.
Qian W et al.·Neurotherapeutics
2024
YAP enhances mitochondrial OXPHOS in tumor-infiltrating Treg through upregulating Lars2 on stiff matrix.
Bai J et al.·J Immunother Cancer
2024
Mechanism of Piezo1 regulating chondrocyte mitochondrial function and promoting fracture healing through β-catenin/LARS2 signaling pathway.
Zhang T et al.·Bone Res
2025Functional
Perrault Syndrome Overview.
Adam MP et al.
2025Review
Heterogeneity of immune cells and their communications unveiled by transcriptome profiling in acute inflammatory lung injury.
Kang ZY et al.·Front Immunol
2024
Single-Cell RNA Sequencing Unveils Unique Transcriptomic Signatures of Organ-Specific Endothelial Cells.
Paik DT et al.·Circulation
2020
Lars2 Deficiency-Induced Mitochondrial Dysfunction Drives the Emergence of a Pro-Inflammatory Stroke-Specific Microglial Subpopulation.
Zou Q et al.·Aging Dis
2025
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

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools