HARS1

Summary

HARS1 (histidyl-tRNA synthetase 1, HGNC:4816) is a protein-coding gene on chromosome 5q31.3, encoding Histidine–tRNA ligase, cytoplasmic (P12081). Catalyzes the ATP-dependent ligation of histidine to the 3’-end of its cognate tRNA, via the formation of an aminoacyl-adenylate intermediate (His-AMP). It is a common-essential gene (DepMap: required in 99.6% of cancer cell lines).

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.

Source: NCBI Gene 3035 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Usher syndrome type 3B (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 677 total — 6 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 50
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 99.6% of screened cell lines (common-essential)
• MANE Select transcript: NM_002109

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4816
Approved symbol	HARS1
Name	histidyl-tRNA synthetase 1
Location	5q31.3
Locus type	gene with protein product
Status	Approved
Aliases	HisRS
Ensembl gene	ENSG00000170445
Ensembl biotype	protein_coding
OMIM	142810
Entrez	3035

Gene structure

Transcript identifiers

Ensembl transcripts: 39 — 22 protein_coding, 9 retained_intron, 6 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000307633, ENST00000415192, ENST00000431330, ENST00000438307, ENST00000457527, ENST00000502888, ENST00000504156, ENST00000504366, ENST00000506579, ENST00000507746, ENST00000509087, ENST00000512396, ENST00000518126, ENST00000643686, ENST00000645491, ENST00000646229, ENST00000674523, ENST00000674721, ENST00000674819, ENST00000675094, ENST00000675204, ENST00000675355, ENST00000675366, ENST00000675698, ENST00000675763, ENST00000675827, ENST00000675851, ENST00000675898, ENST00000675967, ENST00000676327, ENST00000937415, ENST00000937416, ENST00000937417, ENST00000937418, ENST00000937419, ENST00000942725, ENST00000942726, ENST00000942727, ENST00000942728

RefSeq mRNA: 7 — MANE Select: NM_002109 NM_001258040, NM_001258041, NM_001258042, NM_001289092, NM_001289093, NM_001289094, NM_002109

CCDS: CCDS4237, CCDS58976, CCDS58977, CCDS58978, CCDS75323, CCDS75324

Canonical transcript exons

ENST00000504156 — 13 exons

Exon	Start	End
ENSE00001258123	140676654	140676896
ENSE00001820390	140691215	140691370
ENSE00002020566	140673905	140674328
ENSE00002293852	140675017	140675133
ENSE00002436527	140677908	140678015
ENSE00002503788	140677655	140677753
ENSE00003461912	140683100	140683219
ENSE00003476954	140679788	140679883
ENSE00003513945	140676989	140677116
ENSE00003545217	140679002	140679127
ENSE00003618891	140674679	140674825
ENSE00003645889	140690855	140690944
ENSE00003675678	140677327	140677420

Expression profiles

Bgee: expression breadth ubiquitous, 291 present calls, max score 97.91.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 44.9246 / max 198.2184, expressed in 1825 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
63828	44.9246	1825

Top tissues by expression

300 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
lateral nuclear group of thalamus	UBERON:0002736	97.91	gold quality
right frontal lobe	UBERON:0002810	97.02	gold quality
adenohypophysis	UBERON:0002196	96.91	gold quality
pituitary gland	UBERON:0000007	96.43	gold quality
substantia nigra pars compacta	UBERON:0001965	96.42	gold quality
substantia nigra pars reticulata	UBERON:0001966	96.39	gold quality
right hemisphere of cerebellum	UBERON:0014890	96.36	gold quality
cerebellar hemisphere	UBERON:0002245	96.30	gold quality
Brodmann (1909) area 9	UBERON:0013540	96.28	gold quality
cerebellar cortex	UBERON:0002129	96.15	gold quality
nucleus accumbens	UBERON:0001882	96.01	gold quality
putamen	UBERON:0001874	95.98	gold quality
caudate nucleus	UBERON:0001873	95.77	gold quality
middle temporal gyrus	UBERON:0002771	95.53	gold quality
cortical plate	UBERON:0005343	95.52	gold quality
skin of leg	UBERON:0001511	95.42	gold quality
amygdala	UBERON:0001876	95.37	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	95.33	gold quality
hypothalamus	UBERON:0001898	95.28	gold quality
substantia nigra	UBERON:0002038	95.23	gold quality
skin of abdomen	UBERON:0001416	95.17	gold quality
cerebellum	UBERON:0002037	95.12	gold quality
midbrain	UBERON:0001891	94.92	gold quality
prefrontal cortex	UBERON:0000451	94.90	gold quality
gingival epithelium	UBERON:0001949	94.84	gold quality
lower esophagus mucosa	UBERON:0035834	94.78	gold quality
forebrain	UBERON:0001890	94.76	gold quality
brain	UBERON:0000955	94.73	gold quality
zone of skin	UBERON:0000014	94.66	gold quality
central nervous system	UBERON:0001017	94.66	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-6379	no	758.20
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

28 targeting HARS1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-106B-5P	99.88	74.72	2795
HSA-MIR-20A-5P	99.88	74.76	2769
HSA-MIR-20B-5P	99.88	74.01	2621
HSA-MIR-519D-3P	99.88	73.97	2607
HSA-MIR-526B-3P	99.88	74.06	2587
HSA-MIR-93-5P	99.88	73.98	2606
HSA-MIR-182-5P	99.87	74.03	2589
HSA-MIR-5580-3P	99.70	69.41	2052
HSA-MIR-3059-5P	99.70	69.93	2491
HSA-MIR-519A-3P	99.67	71.67	1868
HSA-MIR-519B-3P	99.67	71.67	1868
HSA-MIR-519C-3P	99.67	71.67	1870
HSA-MIR-330-3P	99.41	69.95	2521
HSA-MIR-939-3P	98.97	65.07	2347
HSA-MIR-11399	98.71	65.69	869
HSA-MIR-26B-3P	98.71	67.49	1102
HSA-MIR-6780A-3P	98.42	67.49	1518
HSA-MIR-5585-5P	97.95	68.80	1024
HSA-MIR-4535	97.27	65.17	469
HSA-MIR-4256	96.22	67.70	669
HSA-MIR-11181-5P	96.12	67.46	665
HSA-MIR-191-5P	95.88	67.82	171
HSA-MIR-3150A-5P	90.54	58.82	91
HSA-MIR-3150B-5P	90.54	58.82	91

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 99.6% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 20)

• genomic organization of the HARS locus and mapping of transcripts originating from a bi-directional promoter controlling the differential expression of these gene (PMID:12056811)
• Demonstrating histidyl-tRNA synthetase (Jo-1)-specific T cell responses represents a key step in establishing the hypothesis that Jo-1 drives T cell-mediated autoimmunity in Jo-1+ polymyositis. (PMID:12471150)
• the TSG101 interaction with HRS is a crucial step in endocytic down-regulation of mitogenic signaling and this interaction may have a role in linking the functions of early and late endosomes (PMID:12802020)
• A proteolytically sensitive conformation of HisRS exists in the lung, the target tissue associated with this autoantibody response. (PMID:17665459)
• clinical and prognostic profiles of 45 patients displaying anti-histidyl-tRNA synthetase autoantibodies were determined (PMID:17785330)
• Study identified sequence variants in the known disease-causing genes SLC6A3 and FLVCR1, and present evidence to strongly support the pathogenicity of variants identified in TUBGCP6, BRAT1, SNIP1, CRADD, and HARS. (PMID:22279524)
• Although anti-Jo1 positive patients with antisynthetase syndrome share features of patients with anti-PL7/PL12 antibody, they exhibit many differences regarding clinical phenotype and long-term outcome. (PMID:22326685)
• Findings suggest that histidyl-tRNA synthetase (HARS) is associated with axonal peripheral neuropathy. (PMID:22930593)
• The crystal structure of a novel splice variant of a tRNA synthetase lacking the entire catalytic domain. (PMID:22958643)
• Non-Jo-1 anti-synAb positive patients have decreased survival compared with Jo-1 patients. (PMID:23422076)
• Data indicate that higher anti-Jo1 levels were associated with disease severity in antisynthetase syndrome (ASS) patients. (PMID:24286268)
• Secreted histidyl-tRNA synthetase splice variants elaborate major epitopes for autoantibodies in inflammatory myositis. (PMID:24898250)
• Data suggest that by comparing human and trypanosomatid histidyl-tRNA synthetases (HisRS) may provide opportunities for developing specific inhibitors of Trypanosoma brucei HisRS. (PMID:25151410)
• Loss of function mutations in histidyl-tRNA synthetase cause a spectrum of inherited peripheral neuropathies (PMID:26072516)
• This study suggests that the human HisRS genes, while descending from a common ancestor with dual function for both types of tRNA(His), have acquired highly specialized tRNA recognition properties through evolution. (PMID:28321488)
• Despite the similar kinetics, differential scanning fluorimetry revealed that Y454S is less thermally stable than Wild Type HARS, and cells from Y454S patients grown at elevated temperatures demonstrate diminished levels of protein synthesis compared to those of Wild Type cells. The thermal sensitivity associated with the Y454S mutation represents a biochemical basis for understanding Usher Syndrome Type IIIB. (PMID:28632987)
• the first biochemical analysis of Charcot-Marie-Tooth-associated HARS mutations and underscores how loss of the primary aminoacylation function can contribute to disease pathology. (PMID:29235198)
• Serum-circulating His-tRNA synthetase inhibits organ-targeted immune responses. (PMID:31797905)
• Serological risk factors for concomitant interstitial lung disease in patients with idiopathic inflammatory myopathy. (PMID:31982271)
• Bi-allelic mutations in HARS1 severely impair histidyl-tRNA synthetase expression and enzymatic activity causing a novel multisystem ataxic syndrome. (PMID:32333447)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	hars	ENSDARG00000003693
mus_musculus	Hars1	ENSMUSG00000001380
rattus_norvegicus	Hars1	ENSRNOG00000028105
rattus_norvegicus		ENSRNOG00000064147
drosophila_melanogaster	HisRS	FBGN0027087
caenorhabditis_elegans		WBGENE00002001

Paralogs (1): HARS2 (ENSG00000112855)

Protein

Protein identifiers

Histidine–tRNA ligase, cytoplasmic — P12081 (reviewed: P12081)

Alternative names: Histidyl-tRNA synthetase

All UniProt accessions (15): P12081, A0A2R8YCI2, A0A2R8YFR1, A0A6Q8PF07, A0A6Q8PF47, A0A6Q8PFF2, A0A6Q8PFG9, A0A6Q8PFN6, A0A6Q8PHA5, A0A6Q8PHE3, A0A6Q8PHQ0, B4DDD8, B4E1C5, D6RF05, E7ETE2

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the ATP-dependent ligation of histidine to the 3’-end of its cognate tRNA, via the formation of an aminoacyl-adenylate intermediate (His-AMP). Plays a role in axon guidance.

Subunit / interactions. Homodimer.

Subcellular location. Cytoplasm.

Tissue specificity. Brain, heart, liver and kidney.

Disease relevance. Usher syndrome 3B (USH3B) [MIM:614504] A syndrome characterized by progressive vision and hearing loss during early childhood. Some patients have the so-called ‘Charles Bonnet syndrome,’ involving decreased visual acuity and vivid visual hallucinations. USH is a genetically heterogeneous condition characterized by the association of retinitis pigmentosa with sensorineural deafness. Age at onset and differences in auditory and vestibular function distinguish Usher syndrome type 1 (USH1), Usher syndrome type 2 (USH2) and Usher syndrome type 3 (USH3). USH3 is characterized by postlingual, progressive hearing loss, variable vestibular dysfunction, and onset of retinitis pigmentosa symptoms, including nyctalopia, constriction of the visual fields, and loss of central visual acuity, usually by the second decade of life. The disease may be caused by variants affecting the gene represented in this entry. Charcot-Marie-Tooth disease, axonal, type 2W (CMT2W) [MIM:616625] An autosomal dominant, axonal form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Neuropathies of the CMT2 group are characterized by signs of axonal degeneration in the absence of obvious myelin alterations, normal or slightly reduced nerve conduction velocities, and progressive distal muscle weakness and atrophy. CMT2W patients manifest a peripheral neuropathy mainly affecting the lower limbs and resulting in gait difficulties and distal sensory impairment. Most patients also have upper limb involvement. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the class-II aminoacyl-tRNA synthetase family.

Isoforms (4)

UniProt ID	Names	Canonical?
P12081-1	1	yes
P12081-2	2
P12081-3	3
P12081-4	4

RefSeq proteins (7): NP_001244969, NP_001244970, NP_001244971, NP_001276021, NP_001276022, NP_001276023, NP_002100* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000738	WHEP-TRS_dom	Domain
IPR004154	Anticodon-bd	Domain
IPR004516	HisRS/HisZ	Family
IPR006195	aa-tRNA-synth_II	Domain
IPR009068	uS15_NS1_RNA-bd_sf	Homologous_superfamily
IPR015807	His-tRNA-ligase	Family
IPR033656	HisRS_anticodon	Domain
IPR036621	Anticodon-bd_dom_sf	Homologous_superfamily
IPR041715	HisRS-like_core	Domain
IPR045864	aa-tRNA-synth_II/BPL/LPL	Homologous_superfamily

Pfam: PF00458, PF03129, PF13393

Enzyme classification (BRENDA):

• EC 6.1.1.21 — histidine-tRNA ligase (BRENDA: 37 organisms, 53 substrates, 38 inhibitors, 81 Km, 64 kcat entries)

Substrate kinetics (BRENDA)

13 substrates with measured Km, best-characterized 13. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
TRNAHIS	—	19
ATP	0.0442–1.763	17
HIS	0.0006–0.08	15
L-HISTIDINE	0.008–0.6872	7
SYNTHETIC TRNAHIS A-1	0.001–0.0063	4
SYNTHETIC TRNAHIS G-1	0.0012–0.0178	4
WILD-TYPE FULL LENGTH TRNAHIS G-1	0.0003–0.015	4
RNA MICROHELIX	0.0038–0.124	2
TRNAHISCUA	0.0055–0.013	2
U73TRNAHISGUG	0.0003–0.0016	2
L-HIS	0.0005	1
TRNAHISII	—	1
WILD TYPE TRNAHIS	—	0

Catalyzed reactions (Rhea), 1 shown:

• tRNA(His) + L-histidine + ATP = L-histidyl-tRNA(His) + AMP + diphosphate + H(+) (RHEA:17313)

UniProt features (90 total): helix 23, strand 20, sequence variant 15, sequence conflict 14, binding site 6, turn 4, modified residue 3, splice variant 2, initiator methionine 1, chain 1, domain 1

Structure

Experimental structures (PDB)

10 structures.

PDB	Method	Resolution (Å)
8YOR	X-RAY DIFFRACTION	2.3
4G84	X-RAY DIFFRACTION	2.4
6O76	X-RAY DIFFRACTION	2.79
8YP1	X-RAY DIFFRACTION	2.79
4X5O	X-RAY DIFFRACTION	2.8
4PHC	X-RAY DIFFRACTION	2.84
4G85	X-RAY DIFFRACTION	3.11
5W6M	X-RAY DIFFRACTION	3.7
1X59	SOLUTION NMR
2LW7	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P12081-F1	92.06	0.82

Antibody-complex structures (SAbDab): 1 — 8YOR

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (6): 130–132; 157; 173; 177; 326; 330–331

Post-translational modifications (3): 66, 356, 2

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-379716	Cytosolic tRNA aminoacylation

MSigDB gene sets: 248 (showing top): GOBP_AMINO_ACID_ACTIVATION, GOBP_TRNA_METABOLIC_PROCESS, GOBP_TRANSLATION, BYSTRYKH_HEMATOPOIESIS_STEM_CELL_AND_BRAIN_QTL_CIS, WANG_TARGETS_OF_MLL_CBP_FUSION_DN, TIEN_INTESTINE_PROBIOTICS_24HR_UP, MODULE_110, KEGG_AMINOACYL_TRNA_BIOSYNTHESIS, ZHANG_BREAST_CANCER_PROGENITORS_UP, DANG_BOUND_BY_MYC, BERENJENO_TRANSFORMED_BY_RHOA_UP, chr5q31, BENPORATH_MYC_MAX_TARGETS, SCGGAAGY_ELK1_02, GOMF_PROTEIN_DIMERIZATION_ACTIVITY

GO Biological Process (3): translation (GO:0006412), tRNA aminoacylation for protein translation (GO:0006418), histidyl-tRNA aminoacylation (GO:0006427)

GO Molecular Function (8): RNA binding (GO:0003723), histidine-tRNA ligase activity (GO:0004821), ATP binding (GO:0005524), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), nucleotide binding (GO:0000166), aminoacyl-tRNA ligase activity (GO:0004812), ligase activity (GO:0016874)

GO Cellular Component (2): cytosol (GO:0005829), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
tRNA Aminoacylation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
peptidyltransferase activity	1
translational initiation	1
translational elongation	1
translational termination	1
macromolecule biosynthetic process	1
protein metabolic process	1
protein biosynthetic process	1
translation	1
tRNA aminoacylation	1
tRNA aminoacylation for protein translation	1
nucleic acid binding	1
aminoacyl-tRNA ligase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
protein binding	1
identical protein binding	1
protein dimerization activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
ligase activity, forming carbon-oxygen bonds	1
catalytic activity, acting on a tRNA	1
catalytic activity	1
cytoplasm	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

2288 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HARS1	GARS1	P41250	968
HARS1	AARS1	P49588	857
HARS1	YARS1	P54577	846
HARS1	NARS2	Q96I59	844
HARS1	TARS3	A2RTX5	828
HARS1	TARS2	Q9BW92	826
HARS1	NARS1	O43776	822
HARS1	TARS1	P26639	821
HARS1	IARS2	Q9NSE4	815
HARS1	WARS2	Q9UGM6	810
HARS1	MARS1	P56192	810
HARS1	YARS2	Q9Y2Z4	810
HARS1	KARS1	Q15046	810
HARS1	WARS1	P23381	810
HARS1	IARS1	P41252	809

IntAct

47 interactions, top by confidence:

A	B	Type	Score
PRELID3B	TRIAP1	psi-mi:“MI:0914”(association)	0.710
HARS2	HSPD1	psi-mi:“MI:0914”(association)	0.610
HARS1	HARS1	psi-mi:“MI:0407”(direct interaction)	0.560
	GNAT3	psi-mi:“MI:0915”(physical association)	0.400
KSR1	FBLL1	psi-mi:“MI:0914”(association)	0.350
DAG1	AGRN	psi-mi:“MI:0914”(association)	0.350
MAPT	MEX3A	psi-mi:“MI:0914”(association)	0.350
LRRK2		psi-mi:“MI:0914”(association)	0.350
SGCZ	ATP5F1B	psi-mi:“MI:0914”(association)	0.350
NME4	NRDC	psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
PTPDC1	HARS1	psi-mi:“MI:0914”(association)	0.350
PTPN2	GOLIM4	psi-mi:“MI:0914”(association)	0.350
ATG16L1	ESYT2	psi-mi:“MI:0914”(association)	0.350
ATG16L1		psi-mi:“MI:0914”(association)	0.350
	GTPBP1	psi-mi:“MI:0914”(association)	0.350
SGCZ	HARS1	psi-mi:“MI:0914”(association)	0.350
AFG2A	ESYT2	psi-mi:“MI:0914”(association)	0.350
AFG2B	MMP24OS	psi-mi:“MI:0914”(association)	0.350
DDX28	UBA6	psi-mi:“MI:0914”(association)	0.350
GAB2	UBA6	psi-mi:“MI:0914”(association)	0.350
MRPL49	UBA6	psi-mi:“MI:0914”(association)	0.350
NPPB	ACOT7	psi-mi:“MI:0914”(association)	0.350
PEX7	UBA6	psi-mi:“MI:0914”(association)	0.350
SMPD2	A2ML1	psi-mi:“MI:0914”(association)	0.350

BioGRID (145): HARS (Affinity Capture-RNA), HARS (Affinity Capture-RNA), HARS (Affinity Capture-MS), CKAP5 (Co-fractionation), DTD1 (Co-fractionation), GCN1L1 (Co-fractionation), HARS (Co-fractionation), HARS (Co-fractionation), HARS (Co-fractionation), HARS (Co-fractionation), HARS (Co-fractionation), HARS (Co-fractionation), HARS (Co-fractionation), HARS (Co-fractionation), HARS (Co-fractionation)

ESM2 similar proteins: A1A4Q2, A6NEY8, A6QP05, O80526, P11172, P12081, P13439, P31754, P37111, P38918, P47897, Q02053, Q16798, Q28EX9, Q2KI84, Q2KJD7, Q32LQ4, Q3MHH4, Q502H1, Q53JY8, Q5FWT7, Q5R4A0, Q5R4C4, Q5R4R2, Q5R514, Q5R8R4, Q5RGJ5, Q5U300, Q5ZJJ8, Q61035, Q641F1, Q66H61, Q6DI37, Q6DIJ1, Q6IQS6, Q6NRL0, Q7ZVX6, Q8BGR9, Q8BML9, Q8C878

Diamond homologs: A0M0E2, A1B3C5, A1UTY3, A5F9R5, A5VTT4, A6KXA6, A6LIF7, A8LKA5, A9MDU4, A9WXP3, B0S168, B0U3B6, B1L6B4, B2FPL6, B2I5Y4, B2J5J5, B2SCY7, B2SKP3, B2UUV2, B4STN3, B5Z8I6, B5ZRD0, B6JN30, B6YS23, B8DU04, B8ER30, B9J9Y1, C0RKC7, C5CCH4, E9QI36, F4IYF8, O58028, P07263, P12081, P34183, P56455, P60920, P62367, P62371, P70076

SIGNOR signaling

7 interactions.

A	Effect	B	Mechanism
HARS1	“down-regulates quantity”	tRNA(His)	“chemical modification”
HARS1	“down-regulates quantity”	histidine	“chemical modification”
HARS1	“down-regulates quantity”	ATP(4-)	“chemical modification”
HARS1	“up-regulates quantity”	diphosphate(3-)	“chemical modification”
HARS1	“up-regulates quantity”	AMP	“chemical modification”
HARS1	“up-regulates quantity”	His-tRNA(His)	“chemical modification”
HARS1	“up-regulates quantity”	alpha-aminoacyl-tRNA	“chemical modification”

Disease & clinical

Clinical variants and AI predictions

ClinVar

677 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	3
Uncertain significance	378
Likely benign	216
Benign	23

Top pathogenic / likely-pathogenic (9)

Variant ID	HGVS	Classification
217507	NM_002109.6(HARS1):c.401C>A (p.Pro134His)	Pathogenic
217508	NM_002109.6(HARS1):c.525T>G (p.Asp175Glu)	Pathogenic
217509	NM_002109.6(HARS1):c.1090G>T (p.Asp364Tyr)	Pathogenic
804285	NM_002109.6(HARS1):c.616G>T (p.Asp206Tyr)	Pathogenic
804286	NM_002109.6(HARS1):c.730delG	Pathogenic
804287	NM_002109.6(HARS1):c.910_912dup (p.Leu305dup)	Pathogenic
1683585	NM_002109.6(HARS1):c.168del (p.Thr58fs)	Likely pathogenic
3770189	NM_002109.6(HARS1):c.*331A>T	Likely pathogenic
548118	NM_002109.6(HARS1):c.397G>T (p.Val133Phe)	Likely pathogenic

SpliceAI

2215 predictions. Top by Δscore:

Variant	Effect	Δscore
5:140673292:T:TA	donor_gain	1.0000
5:140674231:T:TA	donor_gain	1.0000
5:140674236:T:A	donor_gain	1.0000
5:140674334:C:CT	acceptor_gain	1.0000
5:140674334:C:T	acceptor_gain	1.0000
5:140674335:A:T	acceptor_gain	1.0000
5:140674672:C:A	donor_gain	1.0000
5:140674673:CCTCA:C	donor_loss	1.0000
5:140674674:CTCAC:C	donor_loss	1.0000
5:140674675:TCA:T	donor_loss	1.0000
5:140674676:CA:C	donor_loss	1.0000
5:140674677:ACCT:A	donor_loss	1.0000
5:140674678:CCT:C	donor_gain	1.0000
5:140674683:T:TA	donor_gain	1.0000
5:140674684:C:A	donor_gain	1.0000
5:140674708:TGATG:T	donor_gain	1.0000
5:140674719:T:TA	donor_gain	1.0000
5:140674728:T:TA	donor_gain	1.0000
5:140674821:TCAGC:T	acceptor_gain	1.0000
5:140674822:CAGC:C	acceptor_gain	1.0000
5:140674822:CAGCC:C	acceptor_gain	1.0000
5:140674823:AGC:A	acceptor_gain	1.0000
5:140674824:GC:G	acceptor_gain	1.0000
5:140674825:CC:C	acceptor_gain	1.0000
5:140674825:CCTG:C	acceptor_loss	1.0000
5:140674826:C:CC	acceptor_gain	1.0000
5:140674826:C:CG	acceptor_loss	1.0000
5:140674827:T:A	acceptor_loss	1.0000
5:140674829:C:CT	acceptor_gain	1.0000
5:140674830:A:T	acceptor_gain	1.0000

AlphaMissense

3303 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:140679011:G:C	F171L	1.000
5:140679011:G:T	F171L	1.000
5:140679013:A:G	F171L	1.000
5:140679834:A:G	L117P	1.000
5:140676685:C:G	R388P	0.999
5:140676694:C:T	G385E	0.999
5:140676699:G:C	S383R	0.999
5:140676699:G:T	S383R	0.999
5:140676701:T:G	S383R	0.999
5:140676706:C:T	G381E	0.999
5:140676707:C:A	G381W	0.999
5:140676775:G:T	A358D	0.999
5:140676780:A:C	S356R	0.999
5:140676780:A:T	S356R	0.999
5:140676782:T:G	S356R	0.999
5:140676868:C:T	G327E	0.999
5:140676869:C:G	G327R	0.999
5:140676869:C:T	G327R	0.999
5:140679005:C:A	Q173H	0.999
5:140679005:C:G	Q173H	0.999
5:140679018:C:G	R169P	0.999
5:140679049:C:G	D159H	0.999
5:140679051:C:G	R158P	0.999
5:140679054:C:G	R157P	0.999
5:140679055:G:C	R157G	0.999
5:140679058:A:C	Y156D	0.999
5:140679114:C:G	R137P	0.999
5:140679117:G:T	A136D	0.999
5:140679126:A:T	V133D	0.999
5:140679792:A:G	L131P	0.999

dbSNP variants (sampled 300 via entrez): RS1000253074 (5:140674508 A>C), RS1000384612 (5:140681671 TAAAA>T,TAAA,TAAAAA,TAAAAAA), RS1000436938 (5:140681923 TAA>T), RS1000790608 (5:140674191 T>A,C), RS1000936811 (5:140673714 T>C,G), RS1001013603 (5:140688593 C>T), RS1001045341 (5:140692496 T>C), RS1001211465 (5:140691804 A>G), RS1001470481 (5:140678192 G>T), RS1001584317 (5:140692303 A>C,G), RS1001734155 (5:140674893 C>G,T), RS1001845053 (5:140682531 T>A), RS1001900824 (5:140680553 A>T), RS1001963662 (5:140678538 A>C,G), RS1002014913 (5:140689361 C>T)

Disease associations

OMIM: gene MIM:142810 | disease phenotypes: MIM:614504, MIM:616625, MIM:108600, MIM:118220

GenCC curated gene-disease

Disease	Classification	Inheritance
Usher syndrome type 3B	Strong	Autosomal recessive
autosomal dominant Charcot-Marie-Tooth disease type 2W	Strong	Autosomal dominant
Usher syndrome type 3	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Usher syndrome type 3	Refuted	AR

Mondo (13): Usher syndrome type 3B (MONDO:0013788), autosomal dominant Charcot-Marie-Tooth disease type 2W (MONDO:0014711), inherited retinal dystrophy (MONDO:0019118), Usher syndrome type 3 (MONDO:0016485), intellectual disability (MONDO:0001071), pathologic nystagmus (MONDO:0004843), peripheral neuropathy (MONDO:0005244), spastic ataxia (MONDO:0017845), cerebellar ataxia (MONDO:0000437), microcephaly (MONDO:0001149), flatfoot (MONDO:0005293), scoliosis (MONDO:0005392), Charcot-Marie-Tooth disease (MONDO:0015626)

Orphanet (7): Autosomal dominant Charcot-Marie-Tooth disease type 2W (Orphanet:488333), OBSOLETE: Inherited retinal disorder (Orphanet:71862), Usher syndrome type 3 (Orphanet:231183), Spastic ataxia (Orphanet:316226), Rare ataxia (Orphanet:102002), Charcot-Marie-Tooth disease/Hereditary motor and sensory neuropathy (Orphanet:166), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

50 total (30 of 50 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000365	Hearing impairment
HP:0000375	Abnormal cochlea morphology
HP:0000407	Sensorineural hearing impairment
HP:0000505	Visual impairment
HP:0000510	Rod-cone dystrophy
HP:0000512	Abnormal electroretinogram
HP:0000543	Optic disc pallor
HP:0000572	Visual loss
HP:0000575	Scotoma
HP:0000613	Photophobia
HP:0000662	Nyctalopia
HP:0000666	Horizontal nystagmus
HP:0000716	Depression
HP:0000739	Anxiety
HP:0001288	Gait disturbance
HP:0001348	Brisk reflexes
HP:0001751	Abnormal vestibular function
HP:0001756	Vestibular hyporeflexia
HP:0001760	Abnormal foot morphology
HP:0001761	Pes cavus
HP:0001765	Hammertoe
HP:0002078	Truncal ataxia
HP:0002166	Impaired vibration sensation in the lower limbs
HP:0002194	Delayed gross motor development
HP:0002460	Distal muscle weakness
HP:0002936	Distal sensory impairment
HP:0003100	Slender long bone
HP:0003376	Steppage gait

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST006803_54	Schizophrenia	8.000000e-07
GCST010146_22	Serum immune biomarker levels	7.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004872	inflammatory biomarker measurement

MeSH disease descriptors (9)

Descriptor	Name	Tree numbers
D002524	Cerebellar Ataxia	C10.228.140.252.190; C10.597.350.090.500; C23.888.592.350.090.200
D002607	Charcot-Marie-Tooth Disease	C10.500.300.200; C10.574.500.495.200; C10.668.829.800.300.200; C16.131.666.300.200; C16.320.400.375.200
D005413	Flatfoot	C05.330.488.655.250; C05.330.495.681.250; C05.660.585.512.380.813.250; C16.131.621.585.512.500.681.250
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
D009759	Nystagmus, Pathologic	C10.292.562.675; C11.590.400
D058499	Retinal Dystrophies	C11.768.585.658
D012600	Scoliosis	C05.116.900.800.875
C564815	Spastic Ataxia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4002 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

1 potent at pChembl≥5 of 3 total, top 1 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.89	IC50	130	nM	CHEMBL412891

PubChem BioAssay actives

1 with measured affinity, of 7 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl N-[(2S)-2-amino-3-(1H-imidazol-5-yl)propanoyl]sulfamate	90193: Inhibitory activity against cognate Staphylococcus aureus Histidyl-tRNA synthetase	ic50	0.1300	uM

CTD chemical–gene interactions

46 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, increases expression, increases methylation	3
Valproic Acid	increases expression, increases methylation, affects expression	3
Air Pollutants	increases abundance, affects cotreatment, decreases expression	2
aristolochic acid I	increases expression	1
bisphenol F	increases expression	1
alpha-pinene	decreases expression, increases abundance, affects cotreatment	1
pyrogallol 1,3-dimethyl ether	affects localization, increases expression, affects cotreatment, decreases expression	1
sodium arsenite	increases expression	1
pyrrolidine dithiocarbamic acid	decreases reaction, affects cotreatment, decreases expression	1
4-aminophenylarsenoxide	affects binding, decreases reaction	1
methacrylaldehyde	increases abundance, affects cotreatment, decreases expression	1
chloropicrin	increases expression	1
calfactant	affects cotreatment, increases expression	1
nutlin 3	affects cotreatment, increases secretion	1
bisphenol B	increases expression	1
bisphenol S	increases expression	1
3-(2-hydroxy-4-(2-methylnonan-2-yl)phenyl)cyclohexan-1-ol	increases expression	1
bisphenol AF	increases expression	1
Arsenic Trioxide	affects binding, decreases reaction	1
Acrolein	decreases expression, increases abundance, affects cotreatment	1
Benztropine	increases expression	1
Cadmium	increases abundance, increases expression	1
Clozapine	increases expression	1
Dactinomycin	affects cotreatment, increases secretion	1
Doxorubicin	increases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Furaldehyde	affects localization, increases expression, affects cotreatment, decreases expression	1
Haloperidol	increases expression	1
Ivermectin	decreases expression	1
Ozone	affects cotreatment, decreases expression, increases abundance	1

ChEMBL screening assays

5 unique, capped per target: 5 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4341394	Binding	Binding affinity to HARS in human A549 cells lysates grown on SILAC media at 10 uM incubated for 1 hr by LC-MS/MS analysis	Profiling withanolide A for therapeutic targets in neurodegenerative diseases. — Bioorg Med Chem

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT00380965	PHASE4	COMPLETED	Evaluation of the Efficacy of Cesamet™ for the Treatment of Pain in Patients With Chemotherapy-Induced Neuropathy
NCT00487981	PHASE4	TERMINATED	Spinal Cord Stimulation for Painful Diabetic Neuropathy
NCT00904202	PHASE4	COMPLETED	A Study Of Lidocaine Patch 5% Alone, Gabapentin Alone, And Lidocaine Patch 5% And Gabapentin In Combination For The Relief Of Pain In Patients With Diverse Peripheral Neuropathic Pain Conditions
NCT01192113	PHASE4	COMPLETED	Safety and Efficacy of Mecobalamin Injection in Peripheral Neuropathies Patients (Study JGAZSY091109)
NCT01373983	PHASE4	COMPLETED	Intrathecal Bolus Doses of Ziconotide
NCT01458015	PHASE4	TERMINATED	Tapentadol Versus Oxycodone - a Mechanism-based Treatment Approach in Neuropathic Pain
NCT02074267	PHASE4	COMPLETED	Clinical Study for Assessment of the Efficacy of Gabapentin (Carbatin and Neurontin) in Patients With Neuropathy Pain
NCT02372149	PHASE4	UNKNOWN	IVIg for Demyelination in Diabetes Mellitus
NCT02670161	PHASE4	ENROLLING_BY_INVITATION	Quality Improvement and Practice Based Research in Neurology Using the EMR
NCT07022938	PHASE4	COMPLETED	Nutritional Supplement for Treating Chemotherapy Induced Neuropathy
NCT07025005	PHASE4	RECRUITING	Fenofibrate Role in the Prophylaxis From Peripheral Neuropathy Induced by Bortezomib, Lenalidomide and Dexamethasone (VRd) Protocol in the Treatment of Patients With Multiple Myeloma (MM)
NCT04224207	PHASE3	COMPLETED	Management of Retinitis Pigmentosa by Mesenchymal Stem Cells by Wharton’s Jelly Derived Mesenchymal Stem Cells
NCT07082855	PHASE3	NOT_YET_RECRUITING	A Multicenter, Randomized, Double-Blind, Controlled Clinical Study of Minocycline for the Treatment of Retinitis Pigmentosa
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT00058071	PHASE3	COMPLETED	Amifostine in Treating Peripheral Neuropathy in Patients Who Have Received Chemotherapy for Cancer
NCT00125268	PHASE3	TERMINATED	Near Infrared Light for the Treatment of Painful Peripheral Neuropathy
NCT00195013	PHASE3	COMPLETED	Randomized Placebo-Controlled Trial of Glutamine for Breast Cancer Patients With Peripheral Neuropathy
NCT00232141	PHASE3	COMPLETED	Study of Pregabalin Versus Placebo in the Treatment of Nerve Pain Associated With HIV Neuropathy
NCT00264875	PHASE3	COMPLETED	Open Label Safety And Efficacy Study Of Pregabalin In Subjects With Nerve Pain Asociated With Human Immunodeficiency Virus (HIV) Neuropathy
NCT00369564	PHASE3	COMPLETED	Glutamic Acid in Reducing Nerve Damage Caused by Vincristine in Young Patients With Cancer
NCT00471445	PHASE3	COMPLETED	Topical Amitriptyline and Ketamine Cream in Treating Peripheral Neuropathy Caused by Chemotherapy in Cancer Patients
NCT00489411	PHASE3	COMPLETED	Duloxetine in Treating Peripheral Neuropathy Caused by Chemotherapy in Patients With Cancer
NCT00710554	PHASE3	COMPLETED	A Study of Sativex® for Pain Relief of Peripheral Neuropathic Pain, Associated With Allodynia
NCT00711880	PHASE3	COMPLETED	A Study of Sativex® for Relief of Peripheral Neuropathic Pain Associated With Allodynia.
NCT00713323	PHASE3	COMPLETED	A Study to Compare the Safety and Tolerability of Sativex® in Patients With Neuropathic Pain.
NCT00713817	PHASE3	COMPLETED	A Study to Determine the Maintenance of Effect After Long-term Treatment of Sativex® in Subjects With Neuropathic Pain
NCT00775645	PHASE3	COMPLETED	S0715: Acetyl-L-Carnitine in Preventing Neuropathy in Women With Stage I, II, or IIIA Breast Cancer Undergoing Chemo
NCT00872352	PHASE3	UNKNOWN	Evaluation of Bortezomib Induced Peripheral Neuropathy of Multiple Myeloma (MM) Patients
NCT00998738	PHASE3	TERMINATED	Calcium and Magnesium in Preventing Peripheral Neuropathy Caused by Ixabepilone in Patients With Breast Cancer
NCT01049217	PHASE3	TERMINATED	Pregabalin Versus Placebo In The Treatment Of Neuropathic Pain Associated With HIV Neuropathy
NCT01099449	PHASE3	COMPLETED	Calcium Gluconate and Magnesium Sulfate in Preventing Neurotoxicity in Patients With Colon Cancer or Rectal Cancer Receiving Oxaliplatin-Based Combination Chemotherapy
NCT01288937	PHASE3	TERMINATED	A Placebo Controlled, Randomized, Double Blind Trial of Milnacipran for the Treatment of Idiopathic Neuropathy Pain
NCT01492920	PHASE3	WITHDRAWN	Acetyl-L-Carnitine Hydrochloride in Preventing Peripheral Neuropathy in Patients With Recurrent Ovarian Epithelial Cancer, Primary Peritoneal Cavity Cancer, or Fallopian Tube Cancer Undergoing Chemotherapy
NCT01775449	PHASE3	COMPLETED	Prevention of Oxaliplatin-induced Neuropathic Pain by a Specific Diet
NCT02024191	PHASE3	UNKNOWN	The Role of Glutamine for Preventing Oxaliplatin-Induced Peripheral Neuropathy
NCT02217267	PHASE3	COMPLETED	Long Term Outcome After Serial Lidocaine Infusion in Peripheral Neuropathic Pain