HARS2

Chr 5AR

histidyl-tRNA synthetase 2, mitochondrial

Also known as: HARSL, HARSR, HO3, HisRS, PRLTS2

NCBI Gene: 23438ENSG00000112855UniProt: Q8TEA8OMIM: 600783

Histidyl-tRNA synthetase 2 charges histidine tRNAs in mitochondria, playing an essential role in mitochondrial protein synthesis. Mutations cause Perrault syndrome 2, characterized by sensorineural hearing loss and ovarian dysgenesis in females, inherited in an autosomal recessive pattern. The gene shows low constraint against loss-of-function variants (pLI 0.000028), which is consistent with the recessive inheritance pattern.

OMIMResearchSummary from RefSeq, OMIM, UniProt
DNmechanismARLOEUF 0.741 OMIM phenotype
Clinical Summary— HARS2
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Gene-Disease Validity (ClinGen)
Perrault syndrome 2 · ARLimited

Limited evidence — not for standalone diagnostic reporting

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Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint
0.74LOEUF
pLI 0.000
Z-score 2.60
OE 0.45 (0.29–0.74)
Tolerant

Typical tolerance to LoF variation

Missense Constraint
0.04Z-score
OE missense 0.99 (0.90–1.10)
265 obs / 267.0 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.45 (0.29–0.74)
0≤0.351.4
Missense OE0.99 (0.90–1.10)
0≤0.61.4
Synonymous OE1.05
0≤1.21.6
LoF obs/exp: 12 / 26.4Missense obs/exp: 265 / 267.0Syn Z: -0.39
DN
0.76top 25%
GOF
0.5071th %ile
LOF
0.2775th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

0 submitted variants in ClinVar

ClinVar

Protein Context — Lollipop Plot

HARS2 · 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.

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Clinical Literature
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Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
[Analysis of perrault syndrome caused by pathogenic variants in LARS2 and HARS2 genes].
Lei YB et al.·Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi
2023
CLPP Depletion Causes Diplotene Arrest; Underlying Testis Mitochondrial Dysfunction Occurs with Accumulation of Perrault Proteins ERAL1, PEO1, and HARS2.
Key J et al.·Cells
2022Open Access
Disruption of Hars2 in Cochlear Hair Cells Causes Progressive Mitochondrial Dysfunction and Hearing Loss in Mice.
Xu P et al.·Front Cell Neurosci
2021Open Access
Expanding the Clinical and Molecular Spectrum of HARS2-Perrault Syndrome: Identification of a Novel Homozygous Missense Variant in the HARS2 gene.
Souissi A et al.·Genet Test Mol Biomarkers
2021
Two novel likely pathogenic variants of HARS2 identified in a Chinese family with sensorineural hearing loss.
Yu J et al.·Hereditas
2020Open Access
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