HARS1

Chr 5ADAR

histidyl-tRNA synthetase 1

Also known as: CMT2W, HARS, HRS, USH3B

NCBI Gene: 3035 ENSG00000170445 UniProt: P12081 OMIM: 142810

The protein encoded by HARS1 is a cytoplasmic aminoacyl-tRNA synthetase that synthesizes histidyl-transfer RNA, essential for incorporating histidine into proteins during translation. Mutations cause Charcot-Marie-Tooth disease axonal type 2W (autosomal dominant) and Usher syndrome type 3B (autosomal recessive). The pathogenic mechanism appears to involve dominant-negative effects for the dominant form, while the recessive form likely results from loss of enzymatic function.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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]

GeneReviews OMIM ResearchGenerating clinical summary…

DNmechanismAD/ARLOEUF 0.762 OMIM phenotypes

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

6 unique Pathogenic / Likely Pathogenic· 347 VUS of 601 total submissions

Explore recent and relevant literature in Research Assistant →

📖

GeneReview available — HARS1

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?

0.76LOEUF

pLI 0.000

Z-score 2.54

OE 0.49 (0.32–0.76)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.26Z-score

OE missense 0.80 (0.71–0.89)

239 obs / 300.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.49 (0.32–0.76)

0≤0.351.4

Missense OE?0.80 (0.71–0.89)

0≤0.61.4

Synonymous OE?0.85

0≤1.21.6

LoF obs/exp: 14 / 28.7Missense obs/exp: 239 / 300.5Syn Z: 1.23

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedHARS1-related Usher syndromeOTHERAR

This gene — mechanism propensity

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

0.7133th %ile

GOF

0.5071th %ile

LOF

0.3552th %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.

Literature Evidence

DNEvidence for a dominant-negative mechanism in HARS1-mediated peripheral neuropathy.1

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

References

1.PMID 32940403 ↗

ClinVar Variant Classifications

601 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic3

Likely Pathogenic3

VUS347

Likely Benign199

Benign17

Conflicting21

Pathogenic

Likely Pathogenic

347

VUS

199

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	2	1	0	3
Likely Pathogenic	1	1	1	0	3
VUS	35	274	33	5	347
Likely Benign	0	4	102	93	199
Benign	0	0	16	1	17
Conflicting	—				21
Total	36	281	153	99	590

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

View in ClinVar →

6 pathogenic / likely-pathogenic (of 10) ClinVar copy-number / structural variants overlap HARS1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →