HARS1

Chr 5ADAR

histidyl-tRNA synthetase 1

Also known as: CMT2W, HARS, HRS, USH3B

NCBI Gene: 3035ENSG00000170445UniProt: P12081

Aminoacyl-tRNA synthetases are a class of enzymes that charge tRNAs with their cognate amino acids. The protein encoded by this gene is a cytoplasmic enzyme which belongs to the class II family of aminoacyl-tRNA synthetases. The enzyme is responsible for the synthesis of histidyl-transfer RNA, which is essential for the incorporation of histidine into proteins. The gene is located in a head-to-head orientation with HARSL on chromosome five, where the homologous genes share a bidirectional promoter. The gene product is a frequent target of autoantibodies in the human autoimmune disease polymyositis/dermatomyositis. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

Primary Disease Associations & Inheritance

Charcot-Marie-Tooth disease, axonal, type 2WMIM #616625
AD
Usher syndrome type 3BMIM #614504
AR
UniProtUsher syndrome 3B
495
ClinVar variants
8
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— HARS1
🧬
Gene-Disease Validity (ClinGen)
Usher syndrome type 3 · ARRefuted

Refuted — evidence has disproved this relationship

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
8 Pathogenic / Likely Pathogenic· 314 VUS of 495 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.
0.76LOEUF
pLI 0.000
Z-score 2.54
OE 0.49 (0.32–0.76)
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.
1.26Z-score
OE missense 0.80 (0.71–0.89)
239 obs / 300.5 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.0.49 (0.32–0.76)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.80 (0.71–0.89)
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.0.85
0≤1.21.6
LoF obs/exp: 14 / 28.7Missense obs/exp: 239 / 300.5Syn Z: 1.23

ClinVar Variant Classifications

495 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic7
Likely Pathogenic1
VUS314
Likely Benign151
Benign2
Conflicting20
7
Pathogenic
1
Likely Pathogenic
314
VUS
151
Likely Benign
2
Benign
20
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
1
6
0
7
Likely Pathogenic
1
0
0
0
1
VUS
23
241
45
5
314
Likely Benign
0
4
77
70
151
Benign
0
0
1
1
2
Conflicting
—20
Total2424612976495

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

View in ClinVar →

Protein Context — Lollipop Plot

HARS1 · protein map & ClinVar variants

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

Gene2Phenotype Curations

HARS1-related Usher syndrome

limited
ARUndeterminedAltered Gene Product Structure
Dev. DisordersEye
G2P ↗
missense variantinframe deletioninframe insertion

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Charcot-Marie-Tooth disease, axonal, type 2W

MIM #616625

Molecular basis of disorder known

Autosomal dominant

Usher syndrome type 3B

MIM #614504

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — HARS1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Genetic overlap between ALS and other neurodegenerative or neuromuscular disorders.
Olsen CG et al.·Amyotroph Lateral Scler Frontotemporal Degener
2024
Bi-allelic mutations in HARS1 severely impair histidyl-tRNA synthetase expression and enzymatic activity causing a novel multisystem ataxic syndrome.
Galatolo D et al.·Hum Mutat
2020
Variants of aminoacyl-tRNA synthetase genes in Charcot-Marie-Tooth disease: A Korean cohort study.
Nam DE et al.·J Peripher Nerv Syst
2022Cohort
Neuropathy-associated histidyl-tRNA synthetase variants attenuate protein synthesis in vitro and disrupt axon outgrowth in developing zebrafish.
Mullen P et al.·FEBS J
2021Functional
Clinical characteristics and proteome modifications in two Charcot-Marie-Tooth families with the AARS1 Arg326Trp mutation.
Høyer H et al.·BMC Neurol
2022
A patient with demyelinating CMT carrying the p.Y347C heterozygous variant of the MME gene and the p.L131F heterozygous variant of the HARS1 gene.
Parisi M et al.·Neurol Sci
2023
Diagnostic yield of targeted sequential and massive panel approaches for inherited neuropathies.
Padilha JPD et al.·Clin Genet
2020
A missense, loss-of-function YARS1 variant in a patient with proximal-predominant motor neuropathy.
Forrest ME et al.·Cold Spring Harb Mol Case Stud
2022Case 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

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools