HARS2

Chr 5AR

histidyl-tRNA synthetase 2, mitochondrial

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

NCBI Gene: 23438ENSG00000112855UniProt: Q8TEA8

Aminoacyl-tRNA synthetases are a class of enzymes that charge tRNAs with their cognate amino acids. The protein encoded by this gene is an enzyme belonging to the class II family of aminoacyl-tRNA synthetases. Functioning in the synthesis of histidyl-transfer RNA, the enzyme plays an accessory role in the regulation of protein biosynthesis. The gene is located in a head-to-head orientation with HARS on chromosome five, where the homologous genes likely share a bidirectional promoter. Mutations in this gene are associated with the pathogenesis of Perrault syndrome, which involves ovarian dysgenesis and sensorineural hearing loss. Alternative splicing results in multiple transcript variants of this gene. [provided by RefSeq, Jul 2013]

Primary Disease Associations & Inheritance

Perrault syndrome 2MIM #614926
AR
307
ClinVar variants
40
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— HARS2
🧬
Gene-Disease Validity (ClinGen)
Perrault syndrome 2 · ARLimited

Limited evidence — not for standalone diagnostic reporting

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
40 Pathogenic / Likely Pathogenic· 150 VUS of 307 total submissions

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.
0.74LOEUF
pLI 0.000
Z-score 2.60
OE 0.45 (0.29–0.74)
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.
0.04Z-score
OE missense 0.99 (0.90–1.10)
265 obs / 267.0 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.0.45 (0.29–0.74)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.99 (0.90–1.10)
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.1.05
0≤1.21.6
LoF obs/exp: 12 / 26.4Missense obs/exp: 265 / 267.0Syn Z: -0.39

ClinVar Variant Classifications

307 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic18
Likely Pathogenic22
VUS150
Likely Benign89
Benign11
Conflicting17
18
Pathogenic
22
Likely Pathogenic
150
VUS
89
Likely Benign
11
Benign
17
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
3
1
14
0
18
Likely Pathogenic
8
10
4
0
22
VUS
1
127
20
2
150
Likely Benign
0
5
43
41
89
Benign
0
0
10
1
11
Conflicting
—17
Total121439144307

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

View in 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.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Perrault syndrome 2

MIM #614926

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — HARS2
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Novel Cases of Non-Syndromic Hearing Impairment Caused by Pathogenic Variants in Genes Encoding Mitochondrial Aminoacyl-tRNA Synthetases.
Domínguez-Ruiz M et al.·Genes (Basel)
2024Cohort
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
2021Case report
[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
2023Case report
A recurrent missense variant in HARS2 results in variable sensorineural hearing loss in three unrelated families.
Demain LAM et al.·J Hum Genet
2020
Two novel likely pathogenic variants of HARS2 identified in a Chinese family with sensorineural hearing loss.
Yu J et al.·Hereditas
2020
CLPP Depletion Causes Diplotene Arrest; Underlying Testis Mitochondrial Dysfunction Occurs with Accumulation of Perrault Proteins ERAL1, PEO1, and HARS2.
Key J et al.·Cells
2022
New insights into Perrault syndrome, a clinically and genetically heterogeneous disorder.
Faridi R et al.·Hum Genet
2022Review
Novel HARS2 missense variants identified in individuals with sensorineural hearing impairment and Perrault syndrome.
Karstensen HG et al.·Eur J Med Genet
2020Case report
Expanding the genotypic spectrum of Perrault syndrome.
Demain LA et al.·Clin Genet
2017
An Application of NGS for Molecular Investigations in Perrault Syndrome: Study of 14 Families and Review of the Literature.
Lerat J et al.·Hum Mutat
2016Review
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