KARS1

Summary

KARS1 (lysyl-tRNA synthetase 1, HGNC:6215) is a protein-coding gene on chromosome 16q23.1, encoding Lysine–tRNA ligase (Q15046). Catalyzes the specific attachment of an amino acid to its cognate tRNA in a 2 step reaction: the amino acid (AA) is first activated by ATP to form AA-AMP and then transferred to the acceptor end of the tRNA. It is a common-essential gene (DepMap: required in 100.0% of cancer cell lines).

Aminoacyl-tRNA synthetases are a class of enzymes that charge tRNAs with their cognate amino acids. Lysyl-tRNA synthetase is a homodimer localized to the cytoplasm which belongs to the class II family of tRNA synthetases. It has been shown to be a target of autoantibodies in the human autoimmune diseases, polymyositis or dermatomyositis. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 3735 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autosomal recessive nonsyndromic hearing loss 89 (Strong, GenCC) — +4 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 552 total — 16 pathogenic, 12 likely-pathogenic
• Phenotypes (HPO): 78
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 100.0% of screened cell lines (common-essential)
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_005548

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6215
Approved symbol	KARS1
Name	lysyl-tRNA synthetase 1
Location	16q23.1
Locus type	gene with protein product
Status	Approved
Aliases	KARS2
Ensembl gene	ENSG00000065427
Ensembl biotype	protein_coding
OMIM	601421
Entrez	3735

Gene structure

Transcript identifiers

Ensembl transcripts: 20 — 14 protein_coding, 3 nonsense_mediated_decay, 3 retained_intron

ENST00000302445, ENST00000319410, ENST00000562875, ENST00000564578, ENST00000565738, ENST00000566249, ENST00000566560, ENST00000566772, ENST00000568378, ENST00000568682, ENST00000569298, ENST00000570215, ENST00000898534, ENST00000898535, ENST00000898536, ENST00000898537, ENST00000912463, ENST00000912464, ENST00000912465, ENST00000958942

RefSeq mRNA: 3 — MANE Select: NM_005548 NM_001130089, NM_001378148, NM_005548

CCDS: CCDS10923, CCDS45532

Canonical transcript exons

ENST00000302445 — 14 exons

Exon	Start	End
ENSE00001844980	75647578	75647665
ENSE00001900311	75627724	75627993
ENSE00003463045	75629415	75629541
ENSE00003493821	75636454	75636547
ENSE00003501800	75630423	75630508
ENSE00003570453	75641564	75641723
ENSE00003581077	75635912	75636098
ENSE00003593797	75631693	75631855
ENSE00003603121	75634173	75634292
ENSE00003603390	75631416	75631589
ENSE00003605310	75628569	75628712
ENSE00003651838	75640184	75640349
ENSE00003682520	75635680	75635805
ENSE00003682912	75631168	75631253

Expression profiles

Bgee: expression breadth ubiquitous, 299 present calls, max score 99.49.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 49.5371 / max 398.8763, expressed in 1825 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
158182	47.4609	1822
158184	2.0762	1048

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
gingival epithelium	UBERON:0001949	99.49	gold quality
parietal pleura	UBERON:0002400	99.39	gold quality
endometrium epithelium	UBERON:0004811	99.39	gold quality
pleura	UBERON:0000977	99.36	gold quality
gingiva	UBERON:0001828	99.33	gold quality
visceral pleura	UBERON:0002401	99.33	gold quality
skin of hip	UBERON:0001554	99.29	gold quality
epithelium of nasopharynx	UBERON:0001951	99.29	gold quality
parotid gland	UBERON:0001831	99.25	gold quality
endothelial cell	CL:0000115	99.24	gold quality
squamous epithelium	UBERON:0006914	99.20	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	99.16	gold quality
cervix squamous epithelium	UBERON:0006922	99.14	gold quality
tibialis anterior	UBERON:0001385	99.12	gold quality
deltoid	UBERON:0001476	99.12	gold quality
tibia	UBERON:0000979	99.11	gold quality
esophagus squamous epithelium	UBERON:0006920	99.08	gold quality
oral cavity	UBERON:0000167	99.07	gold quality
Brodmann (1909) area 23	UBERON:0013554	99.06	gold quality
upper leg skin	UBERON:0004262	99.05	gold quality
palpebral conjunctiva	UBERON:0001812	99.00	gold quality
tongue squamous epithelium	UBERON:0006919	99.00	gold quality
corpus epididymis	UBERON:0004359	98.97	gold quality
sperm	CL:0000019	98.95	gold quality
amniotic fluid	UBERON:0000173	98.95	gold quality
biceps brachii	UBERON:0001507	98.95	gold quality
gluteal muscle	UBERON:0002000	98.95	gold quality
caput epididymis	UBERON:0004358	98.91	gold quality
male germ cell	CL:0000015	98.83	gold quality
eye	UBERON:0000970	98.83	gold quality

Single-cell (SCXA)

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

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

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

16 targeting KARS1, 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-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-5002-5P	99.76	70.84	1763
HSA-MIR-1273H-3P	99.29	67.55	980
HSA-MIR-6895-3P	98.79	65.69	996
HSA-MIR-3159	97.94	66.79	1098

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 100.0% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 40)

• HIV-1 Gag interacts with human lysyl-tRNA synthetase during viral assembly (PMID:12756246)
• packaged into human immunodeficiency virus type 1 (HIV-1) via its interaction with Gag; this enzyme facilitates the selective packaging of tRNA(3)(Lys), the primer for initiating reverse transcription, into HIV-1 (PMID:15220430)
• analysis of the interaction between HIV-1 Gag and human lysyl-tRNA synthetase (PMID:16702215)
• HIV-1 Vpr fulfills an essential role in the process of packaging of mitochondrial Lysyl-tRNA synthase. (PMID:17560997)
• This work reports further characterization of the interaction between HIV-1 capsid domain of Gag and human LysRS using truncation constructs and point mutations in the putative interaction helices. (PMID:17724017)
• present a 2.3-A crystal structure of a tetrameric form of human LysRS (PMID:18272479)
• mitoKARS is the first described member of a group of mitochondrial proteins whose interaction with mutant SOD1 contributes to mitochondrial dysfunction in ALS (PMID:18715867)
• These results underscore the contribution of KARS to the emission of (one of) the principal signal(s) of immunogenic cell death, CRT exposure. (PMID:20699648)
• Loss-of-function lysyl-tRNA synthetase mutations associated with peripheral neuropathy and Charcot-Marie-Tooth disease. (PMID:20920668)
• The interaction between helix 7 of LysRS and helix 4 of the capsid C-terminal domain of HIV-1 Gag (HIV-CA-CTD) was studied using circular dichromism spectroscopy and molecular dynamics simulation. (PMID:21093454)
• The results suggest that this unique geometry, which reconfigures the LysRS tetramer from alpha(2):alpha(2) to alpha(2)beta(1):beta(1)alpha(2), is designed to control both retention and mobilization of LysRS from the multi-tRNA synthetase complex (PMID:21536907)
• LysRS associates with the Pol domain of GagPol. (PMID:21763493)
• Data are consistent with hypothesis that maturation of cytoplasmic KARS precursor is needed to reveal the potent tRNA binding properties of mitochondrial KARS. (PMID:22235746)
• The work thus unveiled a unique function of KRS in the control of cell migration and its pathological implication in metastasis. (PMID:22751010)
• Dual role for motif 1 residues of human lysyl-tRNA synthetase in dimerization and packaging into HIV-1. (PMID:23095741)
• A single conformational change triggered by phosphorylation leads to multiple effects driving an exclusive switch of LysRS function from translation to transcription. (PMID:23159739)
• C-terminal domain of HIV-1 capsid protein as surrogate for human lysyl tRNA synthetase (PMID:23208549)
• The KARS variant is identified in two families affected by DFNB89-associated autosomal-recessive nonsyndromic hearing impairment. (PMID:23768514)
• The role of preKARS2 in the tRNA mitochondrial import. (PMID:23799079)
• Lysyl-tRNA synthetase plays essential role in HIV replication, transcriptional regulation, cytokine-like signaling. [review] (PMID:23972532)
• structural characteristics of the KRS-LR interaction on the cell surface (PMID:24983501)
• tRK1 forms a complex with human enolases and interacts with tRK1 and human pre-lysyl-tRNA synthetase (preKARS2) (PMID:25918939)
• KRS at the plasma membrane plays new roles in metastatic migration as a signaling inducer, and causes intracellular signaling for cancer dissemination (PMID:26091349)
• finding show that enzymatically active Shiga toxins trigger the dissociation of lysyl-tRNA synthetase (KRS) from the multi-aminoacyl-tRNA synthetase complex in human macrophage-like differentiated THP-1 cells and its subsequent secretion. (PMID:26643967)
• Results indicate that KRS can promote cell-cell and cellextracellular matrix adhesion for migration. (PMID:26891990)
• Using the TruSight One sequencing panel we identified two novel mutations in KARS. Both mutations, never reported previously, occur in a highly conserved region of the catalytic domain and displayed a dramatic effect on KARS stability (PMID:27891585)
• Caspase-8 controls the secretion of inflammatory lysyl-tRNA synthetase in exosomes from colorectal cancer cells. (PMID:28611052)
• The studies showed that mutations in KARS lead to a newly defined subtype of leukoencephalopathy associated with sensorineural hearing impairment. The combined effect of reduced aminoacylation and release of LysRS from the multiple-synthetase complex (MSC) likely underlies the pathogenesis of the KARS mutations identified in this study. (PMID:28887846)
• This study demonstrates that human mitochondrial AspRS, ArgRS, and LysRS, each have a specific sub-mitochondrial distribution, with ArgRS being exclusively localized in the membrane, LysRS exclusively in the soluble fraction, and AspRS being present in both. (PMID:30006346)
• KRS in colon cancer cells remodels the microenvironment to promote metastasis, which can thus be therapeutically targeted at these bidirectional KRS-dependent communications of cancer spheroids with environmental cues. (PMID:30188867)
• Through whole-exome sequencing, we discovered genetic abnormalities in lysyl-tRNA synthetase (KARS). All patients harboured the variant [c.1786C>T, p.Leu596Phe] KARS isoform 1 ([c.1702C>T, p.Leu568Phe] of KARS isoform 2). These KARS pathological variants are novel, including the variant [c.1786C>T; p.Leu596Phe] (c.1702C>T; p.Leu568Phe) shared by all patients in the homozygous or compound-heterozygous state. (PMID:30715177)
• This study adds LARS2 and KARS pathogenic variants as gene defects that may underlie deafness, ovarian failure, and leukodystrophy with mitochondrial signature. (PMID:30737337)
• Hairpin RNA-induced conformational change of a eukaryotic-specific lysyl-tRNA synthetase extension and role of adjacent anticodon-binding domain. (PMID:32611767)
• Structural analyses of a human lysyl-tRNA synthetase mutant associated with autosomal recessive nonsyndromic hearing impairment. (PMID:33784510)
• Bi-allelic KARS1 pathogenic variants affecting functions of cytosolic and mitochondrial isoforms are associated with a progressive and multisystem disease. (PMID:33942428)
• Biallelic variants in KARS1 are associated with neurodevelopmental disorders and hearing loss recapitulated by the knockout zebrafish. (PMID:34172899)
• Changes in subcellular localization of Lysyl-tRNA synthetase and the 67-kDa laminin receptor in epithelial ovarian cancer metastases. (PMID:35912727)
• Antibody Deficiency in Patients with Biallelic KARS1 Mutations. (PMID:37770806)
• Human lysyl-tRNA synthetase phosphorylation promotes HIV-1 proviral DNA transcription. (PMID:37933844)
• Determinants of the interaction between the 5’-leader of HIV-1 genome and human lysyl-tRNA synthetase in reverse transcription primer release process. (PMID:38878758)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	kars1	ENSDARG00000103799
mus_musculus	Kars1	ENSMUSG00000031948
rattus_norvegicus	Kars1	ENSRNOG00000019456
drosophila_melanogaster	LysRS	FBGN0027084
caenorhabditis_elegans		WBGENE00002238

Paralogs (4): DARS1 (ENSG00000115866), DARS2 (ENSG00000117593), NARS1 (ENSG00000134440), NARS2 (ENSG00000137513)

Protein

Protein identifiers

Lysine–tRNA ligase — Q15046 (reviewed: Q15046)

Alternative names: Lysyl-tRNA synthetase

All UniProt accessions (8): Q15046, H3BMR9, H3BPV7, H3BQK5, H3BRC9, H3BSN6, H3BVA8, J3KRL2

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the specific attachment of an amino acid to its cognate tRNA in a 2 step reaction: the amino acid (AA) is first activated by ATP to form AA-AMP and then transferred to the acceptor end of the tRNA. When secreted, acts as a signaling molecule that induces immune response through the activation of monocyte/macrophages. Catalyzes the synthesis of the signaling molecule diadenosine tetraphosphate (Ap4A), and thereby mediates disruption of the complex between HINT1 and MITF and the concomitant activation of MITF transcriptional activity. (Microbial infection) Interacts with HIV-1 virus GAG protein, facilitating the selective packaging of tRNA(3)(Lys), the primer for reverse transcription initiation.

Subunit / interactions. Homodimer and tetradimer. Part of the multisynthetase complex (MSC), a multisubunit complex that groups tRNA ligases for Arg (RARS), Asp (DARS), Gln (QARS), Ile (IARS), Leu (LARS), Lys (KARS), Met (MARS) the bifunctional ligase for Glu and Pro (EPRS) and the auxiliary subunits AIMP1/p43, AIMP2/p38 and EEF1E1/p18. Interacts with AIMP2 (via N-terminus) and MITF. Interacts with TARSL2. (Microbial infection) Interacts directly with HIV-1 virus GAG protein.

Subcellular location. Cytoplasm. Cytosol. Nucleus. Cell membrane. Secreted Mitochondrion.

Post-translational modifications. Phosphorylated on a serine residue after mast cell stimulation with immunoglobulin E (IgE).

Disease relevance. Charcot-Marie-Tooth disease, recessive intermediate B (CMTRIB) [MIM:613641] A 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. Recessive intermediate forms of Charcot-Marie-Tooth disease are characterized by clinical and pathologic features intermediate between demyelinating and axonal peripheral neuropathies, and motor median nerve conduction velocities ranging from 25 to 45 m/sec. The disease is caused by variants affecting the gene represented in this entry. Deafness, autosomal recessive, 89 (DFNB89) [MIM:613916] A form of non-syndromic deafness characterized by bilateral, prelingual, moderate to severe hearing loss affecting all frequencies. The disease is caused by variants affecting the gene represented in this entry. Deafness, congenital, and adult-onset progressive leukoencephalopathy (DEAPLE) [MIM:619196] An autosomal recessive, complex neurodegenerative disorder characterized by congenital sensorineural deafness, and progressive motor and cognitive decline apparent in young adulthood. Brain imaging shows diffuse white matter abnormalities affecting various brain regions, consistent with a progressive leukoencephalopathy. More variable additional features may include visual impairment and axonal peripheral neuropathy. Premature death may occurr in some patients. The disease is caused by variants affecting the gene represented in this entry. Leukoencephalopathy, progressive, infantile-onset, with or without deafness (LEPID) [MIM:619147] An autosomal recessive, complex neurodegenerative disorder apparent from infancy. LEPID is characterized by early-onset progressive leukoencephalopathy with brainstem and spinal cord calcifications, sensorineural deafness in most patients, global developmental delay with cognitive impairment and poor or absent speech, developmental regression, and neurologic deterioration. Additional more variable features may include poor overall growth with microcephaly, seizures, visual loss, microcytic anemia, and hepatic enlargement or abnormal liver enzymes. Premature death is common. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Up-regulated by DARS and EEF1A1, but not by AIMP2.

Domain organisation. The N-terminal domain (1-65) of the cytoplasmic isoform is a functional tRNA-binding domain, is required for nuclear localization, is involved in the interaction with DARS, but has a repulsive role in the binding to EEF1A1. A central domain (208-259) is involved in homodimerization and is required for interaction with HIV-1 GAG and incorporation into virions. The C-terminal domain (452-597) is not required for interaction with AIMP2.

Miscellaneous. Shares a bidirectional promoter with TERF2IP/RAP1. Mitochondrial precursor. Contains a mitochondrial transit peptide at positions 1-16.

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

Isoforms (2)

UniProt ID	Names	Canonical?
Q15046-1	Cytoplasmic	yes
Q15046-2	Mitochondrial

RefSeq proteins (3): NP_001123561, NP_001365077, NP_005539* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002313	Lys-tRNA-ligase_II	Family
IPR004364	Aa-tRNA-synt_II	Domain
IPR004365	NA-bd_OB_tRNA	Domain
IPR006195	aa-tRNA-synth_II	Domain
IPR012340	NA-bd_OB-fold	Homologous_superfamily
IPR018149	Lys-tRNA-synth_II_C	Domain
IPR034762	Lys-tRNA-ligase_II_bac/euk	Family
IPR044136	Lys-tRNA-ligase_II_N	Domain
IPR045864	aa-tRNA-synth_II/BPL/LPL	Homologous_superfamily

Pfam: PF00152, PF01336

Enzyme classification (BRENDA):

• EC 6.1.1.6 — lysine-tRNA ligase (BRENDA: 55 organisms, 146 substrates, 83 inhibitors, 145 Km, 133 kcat entries)

Substrate kinetics (BRENDA)

36 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
L-LYSINE	0.0013–8.1	43
ATP	0.0001–9.5	38
TRNALYSUUU	0.0004–5.1	13
TRNALYS	—	9
L-LYS	0.0025–0.0236	7
LYS	0.0024–0.0047	4
TRNALYSCUU	0.0006–1.4	3
BORELLIA BURGDORFERI TRNALYS	0.002–0.0043	2
ESCHERICHIA COLI G2.U71 TRNA	0.0039–0.0063	2
ESCHERICHIA COLI WILD TYPE TRNA	0.0015–0.0019	2
HUMAN TRNALYS3	0.003–0.0117	2
TRNALYSGUU	0.0003–1.5	2
YEAST TRNALYS	0.002–0.0028	2
2-CHLOROADENOSINE 5’-TRIPHOSPHATE	0.1	1
AMP	1.5	1

Catalyzed reactions (Rhea), 1 shown:

• tRNA(Lys) + L-lysine + ATP = L-lysyl-tRNA(Lys) + AMP + diphosphate (RHEA:20792)

UniProt features (93 total): strand 22, helix 19, sequence variant 18, binding site 10, mutagenesis site 8, modified residue 7, compositionally biased region 2, turn 2, initiator methionine 1, chain 1, region of interest 1, splice variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

14 structures.

PDB	Method	Resolution (Å)
6ILD	X-RAY DIFFRACTION	1.88
4YCU	X-RAY DIFFRACTION	2.1
8XP4	X-RAY DIFFRACTION	2.26
3BJU	X-RAY DIFFRACTION	2.31
6CHD	X-RAY DIFFRACTION	2.5
7EA9	X-RAY DIFFRACTION	2.5
6ILH	X-RAY DIFFRACTION	2.5
8HYR	X-RAY DIFFRACTION	2.55
9DPL	ELECTRON MICROSCOPY	2.8
4DPG	X-RAY DIFFRACTION	2.84
4YCW	X-RAY DIFFRACTION	2.9
9DPB	ELECTRON MICROSCOPY	2.9
9DPA	ELECTRON MICROSCOPY	3
9DOW	ELECTRON MICROSCOPY	3.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q15046-F1	91.23	0.83

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 (10): 341; 494–495; 497; 501; 550–553; 277; 301; 323–325; 331–332; 339

Post-translational modifications (7): 2, 88, 141, 207, 590, 591, 596

Mutagenesis-validated functional residues (8):

Position	Phenotype
1–65	loss of nuclear localization, but no effect on packaging into hiv-1.
101	disrupts interaction with aimp2 and the multisynthase complex.
207	strongly reduced production of diadenosine tetraphosphate (ap4a). reduced protein phosphorylation.
207	phosphomimetic mutant that strongly enhances translocation into the nucleus and production of diadenosine tetraphosphate
207	strongly decreased trna ligase activity.
207	almost complete loss of trna ligase activity.
346	induces protein aggregation. releases from the subunit complex.
540	disrupts interaction with aimp2 and the multisynthase complex. increases production of diadenosine tetraphosphate (ap4a)

Function

Pathways and Gene Ontology

Reactome pathways

11 pathways

ID	Pathway
R-HSA-2408522	Selenoamino acid metabolism
R-HSA-379716	Cytosolic tRNA aminoacylation
R-HSA-379726	Mitochondrial tRNA aminoacylation
R-HSA-9856649	Transcriptional and post-translational regulation of MITF-M expression and activity
R-HSA-1266738	Developmental Biology
R-HSA-1430728	Metabolism
R-HSA-379724	tRNA Aminoacylation
R-HSA-392499	Metabolism of proteins
R-HSA-71291	Metabolism of amino acids and derivatives
R-HSA-72766	Translation
R-HSA-9730414	MITF-M-regulated melanocyte development

MSigDB gene sets: 413 (showing top): MORF_MTA1, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_RESPONSE_TO_IONIZING_RADIATION, GOBP_AMINO_ACID_ACTIVATION, GOBP_REGULATION_OF_INFLAMMATORY_RESPONSE_TO_ANTIGENIC_STIMULUS, MORF_MBD4, GOBP_POSITIVE_REGULATION_OF_MACROPHAGE_ACTIVATION, GOBP_INFLAMMATORY_RESPONSE, MORF_UBE2I, GOBP_TRNA_METABOLIC_PROCESS, MORF_HDAC1, MORF_RAD21, GOBP_REGULATION_OF_MACROPHAGE_ACTIVATION, HSIAO_HOUSEKEEPING_GENES, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS

GO Biological Process (11): basophil activation involved in immune response (GO:0002276), positive regulation of inflammatory response to antigenic stimulus (GO:0002863), lysyl-tRNA aminoacylation (GO:0006430), tRNA processing (GO:0008033), response to X-ray (GO:0010165), diadenosine tetraphosphate biosynthetic process (GO:0015966), positive regulation of macrophage activation (GO:0043032), positive regulation of DNA-templated transcription (GO:0045893), ERK1 and ERK2 cascade (GO:0070371), translation (GO:0006412), tRNA aminoacylation for protein translation (GO:0006418)

GO Molecular Function (13): tRNA binding (GO:0000049), ATP:ADP adenylyltransferase activity (GO:0003877), lysine-tRNA ligase activity (GO:0004824), ATP binding (GO:0005524), amino acid binding (GO:0016597), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), nucleotide binding (GO:0000166), nucleic acid binding (GO:0003676), aminoacyl-tRNA ligase activity (GO:0004812), protein binding (GO:0005515), transferase activity (GO:0016740), ligase activity (GO:0016874)

GO Cellular Component (11): obsolete extracellular space (GO:0005615), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), cytosol (GO:0005829), plasma membrane (GO:0005886), aminoacyl-tRNA synthetase multienzyme complex (GO:0017101), extracellular region (GO:0005576), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
tRNA Aminoacylation	2
Metabolism of amino acids and derivatives	1
MITF-M-regulated melanocyte development	1
Translation	1
Metabolism	1
Metabolism of proteins	1
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
binding	3
catalytic activity	2
intracellular membrane-bounded organelle	2
cytoplasm	2
myeloid cell activation involved in immune response	1
leukocyte activation involved in immune response	1
immune response	1
basophil activation	1
inflammatory response to antigenic stimulus	1
regulation of inflammatory response to antigenic stimulus	1
positive regulation of inflammatory response	1
positive regulation of immune response	1
tRNA aminoacylation for protein translation	1
RNA processing	1
tRNA metabolic process	1
response to ionizing radiation	1
diadenosine polyphosphate biosynthetic process	1
positive regulation of leukocyte activation	1
macrophage activation	1
regulation of macrophage activation	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
MAPK cascade	1
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
RNA binding	1
adenylyltransferase activity	1
aminoacyl-tRNA ligase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
protein binding	1

Protein interactions and networks

STRING

3857 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KARS1	QARS1	P47897	998
KARS1	RARS2	Q5T160	998
KARS1	RARS1	P54136	995
KARS1	IARS1	P41252	995
KARS1	LARS2	Q15031	995
KARS1	LARS1	Q9P2J5	995
KARS1	EPRS1	P07814	992
KARS1	MARS1	P56192	991
KARS1	AARS1	P49588	990
KARS1	MARS2	Q96GW9	987
KARS1	IARS2	Q9NSE4	987
KARS1	YARS1	P54577	971
KARS1	AIMP2	Q13155	934
KARS1	PARS2	Q7L3T8	928
KARS1	ADAT1	Q9BUB4	920

IntAct

302 interactions, top by confidence:

A	B	Type	Score
KARS1	AIMP2	psi-mi:“MI:0915”(physical association)	0.970
AIMP2	KARS1	psi-mi:“MI:0915”(physical association)	0.970
KARS1	AIMP2	psi-mi:“MI:0407”(direct interaction)	0.970
AIMP2	KARS1	psi-mi:“MI:2364”(proximity)	0.970
MED4	MED19	psi-mi:“MI:0914”(association)	0.900
KARS1	KARS1	psi-mi:“MI:0407”(direct interaction)	0.810
RPSA	KARS1	psi-mi:“MI:0915”(physical association)	0.760
KARS1	RPSA	psi-mi:“MI:0915”(physical association)	0.760
RPSA	KARS1	psi-mi:“MI:0407”(direct interaction)	0.760
EPRS1	KARS1	psi-mi:“MI:0915”(physical association)	0.720
KARS1	EPRS1	psi-mi:“MI:0915”(physical association)	0.720
EPRS1	SYNCRIP	psi-mi:“MI:0914”(association)	0.640

BioGRID (522): AIMP2 (Two-hybrid), KARS (Affinity Capture-MS), KARS (Reconstituted Complex), AIMP2 (Two-hybrid), AIMP1 (Co-fractionation), AIMP2 (Co-fractionation), DARS (Co-fractionation), DARS2 (Co-fractionation), EEF1E1 (Co-fractionation), EPRS (Co-fractionation), IARS (Co-fractionation), KARS (Co-fractionation), KARS (Co-fractionation), KARS (Co-fractionation), KARS (Co-fractionation)

ESM2 similar proteins: A0A120HYZ1, A3M3D6, A6L8C6, A7MXL2, A8FRH9, A9CS74, A9NE58, B0TTP2, B0V9L5, B0VSE0, B7GXW0, C4V8R9, O74407, O74858, O94567, P04802, P10723, P13642, P15180, P37879, P38707, Q0HM10, Q15046, Q19722, Q22099, Q43776, Q43990, Q47WT5, Q4R4U9, Q554D9, Q5L545, Q5R9K9, Q5XIM7, Q6BU46, Q6DRC0, Q6F2U9, Q75JQ1, Q7MNP6, Q821U6, Q87SB1

Diamond homologs: A0A120HYZ1, A0AF28, A0KNK7, A0M5H8, A0PXN4, A0R8E9, A2C629, A5D5Q4, A5FRN5, A5GI38, A5GQ58, A5ILE6, A6L7P5, A6L8C6, A7GJY9, A7WYS8, A8F4K1, A8G7C4, A9BD62, A9CS74, A9VN90, B0K5C0, B0KCE4, B1HSY5, B1LAX6, B2J384, B7HJ16, B7HPY8, B7ID87, B7ISY7, B7JK84, C4V8R9, P15180, P37477, P37879, P67609, P67610, P73443, Q0B0N3, Q0IDW9

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
MAPK3	up-regulates	KARS1	phosphorylation
KARS1	“form complex”	“Multiaminoacyl-tRNA synthetase”	binding
SOD1	“down-regulates quantity by destabilization”	KARS1	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 180 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Cytosolic tRNA aminoacylation	6	21.6×	1e-04
Long-term potentiation	5	19.5×	7e-04
tRNA Aminoacylation	6	14.0×	7e-04
Selenoamino acid metabolism	8	12.9×	1e-04
Dengue Virus Attachment and Entry	5	10.6×	5e-03
Assembly and cell surface presentation of NMDA receptors	5	10.4×	5e-03
Transcriptional and post-translational regulation of MITF-M expression and activity	7	10.2×	7e-04
MITF-M-regulated melanocyte development	8	7.5×	1e-03

GO biological processes:

GO term	Partners	Fold	FDR
receptor clustering	6	23.1×	8e-05
establishment or maintenance of epithelial cell apical/basal polarity	6	21.5×	1e-04
regulation of postsynaptic membrane neurotransmitter receptor levels	6	18.4×	2e-04
peptidyl-tyrosine phosphorylation	6	15.6×	4e-04
cell surface receptor protein tyrosine kinase signaling pathway	10	10.7×	4e-05
substrate adhesion-dependent cell spreading	5	10.6×	1e-02
protein autophosphorylation	10	9.0×	8e-05
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	12	5.8×	2e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	16
Likely pathogenic	12
Uncertain significance	244
Likely benign	172
Benign	41

Top pathogenic / likely-pathogenic (28)

Variant ID	HGVS	Classification
1675188	NM_005548.3(KARS1):c.1696-2A>C	Pathogenic
1682436	NM_005548.3(KARS1):c.773_774insTTTTTTTTTTTTTTTTTTTTNNNNNNNNNNAGGGAGAGGGAGACCGAGAGGGAGAGGGGAGAGGGGAGAGGGGAGAGGGGAGAGGGGAGAGGGGAGAGGGAGAGGCAGGGGCAGGGGCAGGGGCAGGGCACATATATAAGAAGTTTCTT (p.Leu258delinsPhePhePhePhePhePhePheXaaXaaXaaXaaGlyArgGlyArgProArgGlyArgGlyGluArgGlyGluGlyArgGlyGluArgGlyGluGlyArgGlyArgGlyArgGlyArgGlyArgGlyArgAlaHisIleTer)	Pathogenic
2127490	NM_005548.3(KARS1):c.346C>T (p.Gln116Ter)	Pathogenic
2423782	NC_000016.9:g.(?75674062)(75674267_?)del	Pathogenic
2868499	NM_005548.3(KARS1):c.1420A>T (p.Lys474Ter)	Pathogenic
2982881	NM_005548.3(KARS1):c.613C>G (p.Leu205Val)	Pathogenic
3236113	NM_005548.3(KARS1):c.336T>G (p.Tyr112Ter)	Pathogenic
3242246	NM_005548.3(KARS1):c.682C>T (p.Arg228Cys)	Pathogenic
437930	NM_005548.3(KARS1):c.1513C>T (p.Pro505Ser)	Pathogenic
4536024	NM_005548.3(KARS1):c.829G>T (p.Gly277Ter)	Pathogenic
560389	NM_005548.3(KARS1):c.1354del (p.Leu452fs)	Pathogenic
8169	NM_005548.3(KARS1):c.314T>A (p.Leu105His)	Pathogenic
8170	NM_005548.3(KARS1):c.430_431dup (p.Tyr145fs)	Pathogenic
997977	NM_005548.3(KARS1):c.1573G>A (p.Glu525Lys)	Pathogenic
997983	NM_005548.3(KARS1):c.1702C>T (p.Leu568Phe)	Pathogenic
997984	NM_005548.3(KARS1):c.795+1G>A	Pathogenic
1679388	NM_005548.3(KARS1):c.256C>T (p.Gln86Ter)	Likely pathogenic
2137846	NM_005548.3(KARS1):c.1382T>G (p.Phe461Cys)	Likely pathogenic
225009	NM_005548.3(KARS1):c.22G>T (p.Glu8Ter)	Likely pathogenic
2499553	NM_005548.3(KARS1):c.1514C>G (p.Pro505Arg)	Likely pathogenic
2504075	NM_005548.3(KARS1):c.1657C>T (p.Arg553Ter)	Likely pathogenic
2574736	NM_005548.3(KARS1):c.1540G>T (p.Glu514Ter)	Likely pathogenic
2576965	NM_005548.3(KARS1):c.1328T>C (p.Leu443Pro)	Likely pathogenic
2630614	NM_005548.3(KARS1):c.1152_1177dup (p.Arg393fs)	Likely pathogenic
2662803	NM_005548.3(KARS1):c.238C>T (p.Arg80Cys)	Likely pathogenic
4072438	NM_005548.3(KARS1):c.958C>T (p.Arg320Cys)	Likely pathogenic
4849358	NM_005548.3(KARS1):c.1119C>G (p.Tyr373Ter)	Likely pathogenic
547985	NM_005548.3(KARS1):c.690A>T (p.Arg230Ser)	Likely pathogenic

SpliceAI

1774 predictions. Top by Δscore:

Variant	Effect	Δscore
16:75627990:CTTC:C	acceptor_gain	1.0000
16:75628565:GTAC:G	donor_loss	1.0000
16:75628566:TAC:T	donor_loss	1.0000
16:75628567:A:AC	donor_gain	1.0000
16:75628567:AC:A	donor_gain	1.0000
16:75628568:C:CA	donor_gain	1.0000
16:75628568:CC:C	donor_gain	1.0000
16:75628568:CCT:C	donor_gain	1.0000
16:75628568:CCTT:C	donor_gain	1.0000
16:75628568:CCTTG:C	donor_gain	1.0000
16:75628708:TTGGC:T	acceptor_gain	1.0000
16:75628709:TGGC:T	acceptor_gain	1.0000
16:75628713:C:CC	acceptor_gain	1.0000
16:75628713:CTAGA:C	acceptor_loss	1.0000
16:75629539:TGC:T	acceptor_gain	1.0000
16:75629542:C:CC	acceptor_gain	1.0000
16:75629542:C:CG	acceptor_loss	1.0000
16:75630416:ATCTT:A	donor_loss	1.0000
16:75630417:TCTTA:T	donor_loss	1.0000
16:75630418:CTTA:C	donor_loss	1.0000
16:75630419:TTA:T	donor_loss	1.0000
16:75630420:TAC:T	donor_loss	1.0000
16:75630421:ACCAT:A	donor_loss	1.0000
16:75630422:C:CA	donor_loss	1.0000
16:75630505:CAAG:C	acceptor_gain	1.0000
16:75630507:AGC:A	acceptor_loss	1.0000
16:75630508:GCT:G	acceptor_loss	1.0000
16:75630509:C:CC	acceptor_gain	1.0000
16:75630509:CTTA:C	acceptor_loss	1.0000
16:75630510:T:C	acceptor_gain	1.0000

AlphaMissense

3987 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:75631766:G:C	F335L	1.000
16:75631766:G:T	F335L	1.000
16:75631768:A:G	F335L	1.000
16:75631780:G:C	H331D	1.000
16:75635785:T:A	R230S	1.000
16:75635785:T:G	R230S	1.000
16:75635792:C:G	R228P	1.000
16:75635990:G:C	S197R	1.000
16:75635990:G:T	S197R	1.000
16:75635992:T:G	S197R	1.000
16:75636024:C:T	G186E	1.000
16:75636025:C:G	G186R	1.000
16:75636025:C:T	G186R	1.000
16:75636043:C:G	D180H	1.000
16:75636045:C:T	G179E	1.000
16:75636046:C:G	G179R	1.000
16:75636046:C:T	G179R	1.000
16:75636504:G:C	F144L	1.000
16:75636504:G:T	F144L	1.000
16:75636506:A:G	F144L	1.000
16:75636511:A:G	L142P	1.000
16:75627979:A:C	F570L	0.999
16:75627979:A:T	F570L	0.999
16:75627981:A:G	F570L	0.999
16:75628569:C:A	K565N	0.999
16:75628569:C:G	K565N	0.999
16:75628606:C:G	R553P	0.999
16:75628616:C:G	G550R	0.999
16:75628622:C:G	G548R	0.999
16:75628627:C:T	G546D	0.999

dbSNP variants (sampled 300 via entrez): RS1000016910 (16:75636493 C>A,T), RS1000059860 (16:75628885 CAA>C), RS1000165150 (16:75649105 G>A,T), RS1000302079 (16:75649639 C>G), RS1000325102 (16:75633532 T>G), RS1000499646 (16:75646483 G>A,C), RS1000526670 (16:75631500 G>A,T), RS1000589998 (16:75634824 C>G), RS1000705824 (16:75645108 T>C), RS1000774581 (16:75637612 C>A,G), RS1000924545 (16:75640041 G>C,T), RS1001018230 (16:75635052 G>A), RS1001057058 (16:75627497 C>T), RS1001523828 (16:75630005 C>T), RS1001539120 (16:75649332 T>G)

Disease associations

OMIM: gene MIM:601421 | disease phenotypes: MIM:613916, MIM:613641, MIM:619147, MIM:220290, MIM:607197, MIM:619196, MIM:118220, MIM:312080

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal recessive nonsyndromic hearing loss 89	Strong	Autosomal recessive
leukoencephalopathy, progressive, infantile-onset, with or without deafness	Strong	Autosomal recessive
Charcot-Marie-Tooth disease recessive intermediate B	Moderate	Autosomal recessive
hearing loss, autosomal recessive	Supportive	Autosomal recessive
nonsyndromic genetic hearing loss	Limited	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
nonsyndromic genetic hearing loss	Limited	AR

Mondo (14): autosomal recessive nonsyndromic hearing loss 89 (MONDO:0013489), Charcot-Marie-Tooth disease recessive intermediate B (MONDO:0013338), leukoencephalopathy, progressive, infantile-onset, with or without deafness (MONDO:0030893), microcephaly (MONDO:0001149), pathologic nystagmus (MONDO:0004843), optic nerve disorder (MONDO:0002135), hearing loss, autosomal recessive (MONDO:0019588), deafness, congenital, and adult-onset progressive leukoencephalopathy (MONDO:0030967), hearing loss disorder (MONDO:0005365), lactic acidosis (MONDO:0006040), sensorineural hearing loss disorder (MONDO:0020678), nonsyndromic genetic hearing loss (MONDO:0019497), Charcot-Marie-Tooth disease (MONDO:0015626), leukodystrophy (MONDO:0019046)

Orphanet (6): Rare autosomal recessive non-syndromic sensorineural deafness type DFNB (Orphanet:90636), Autosomal recessive intermediate Charcot-Marie-Tooth disease type B (Orphanet:254334), Rare autosomal dominant non-syndromic sensorineural deafness type DFNA (Orphanet:90635), Rare non-syndromic genetic deafness (Orphanet:87884), Charcot-Marie-Tooth disease/Hereditary motor and sensory neuropathy (Orphanet:166), Leukodystrophy (Orphanet:68356)

HPO phenotypes

78 total (30 of 78 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000083	Renal insufficiency
HP:0000160	Narrow mouth
HP:0000252	Microcephaly
HP:0000343	Long philtrum
HP:0000365	Hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000529	Progressive visual loss
HP:0000639	Nystagmus
HP:0000821	Hypothyroidism
HP:0001047	Atopic dermatitis
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001265	Hyporeflexia
HP:0001268	Mental deterioration
HP:0001270	Motor delay
HP:0001276	Hypertonia
HP:0001284	Areflexia
HP:0001321	Cerebellar hypoplasia
HP:0001332	Dystonia
HP:0001344	Absent speech
HP:0001347	Hyperreflexia
HP:0001508	Failure to thrive
HP:0001510	Growth delay
HP:0001518	Small for gestational age
HP:0001756	Vestibular hyporeflexia
HP:0001761	Pes cavus
HP:0001873	Thrombocytopenia

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST002553_10	Pancreatic cancer	1.000000e-10

MeSH disease descriptors (8)

Descriptor	Name	Tree numbers
D000140	Acidosis, Lactic	C18.452.076.176.180
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
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341
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
D009901	Optic Nerve Diseases	C10.292.700; C11.640
C564609	Deafness, Autosomal Recessive (supp.)
C580334	Nonsyndromic Deafness (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5575 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 111,611 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL941	IMATINIB	4	111,611

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

ChEMBL bioactivities

79 potent at pChembl≥5 of 95 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.22	IC50	0.6	nM	CHEMBL2069346
9.07	IC50	0.86	nM	STAUROSPORINE
8.74	IC50	1.8	nM	CHEMBL2069345
8.40	IC50	4	nM	CHEMBL2069349
8.40	IC50	4	nM	CHEMBL2069350
8.40	IC50	4	nM	CHEMBL2069352
8.40	IC50	4	nM	CHEMBL2069358
8.30	IC50	5	nM	CHEMBL2069353
8.22	IC50	6	nM	CHEMBL2069355
8.15	IC50	7	nM	CHEMBL2069357
8.14	IC50	7.2	nM	CHEMBL4286991
8.10	IC50	8	nM	CHEMBL2069351
8.10	IC50	8	nM	CHEMBL2069359
8.05	IC50	9	nM	CHEMBL2069356
8.00	IC50	10	nM	CHEMBL2069360
7.97	IC50	10.7	nM	CHEMBL4293812
7.85	IC50	14	nM	CHEMBL2069341
7.65	IC50	22.4	nM	CHEMBL4292650
7.57	IC50	27	nM	CHEMBL2069344
7.56	IC50	27.7	nM	DEHYDROABIETIC ACID
7.55	IC50	28	nM	CHEMBL2069354
7.47	IC50	34.1	nM	18-OXOFERRUGINOL
7.47	IC50	34	nM	CHEMBL282342
7.37	IC50	43	nM	CHEMBL2069348
7.33	IC50	46.4	nM	POMIFERIN A
7.31	IC50	49.1	nM	CHEMBL598566
7.21	IC50	62	nM	CHEMBL2069347
7.19	IC50	65	nM	CHEMBL2323633
7.15	IC50	71	nM	CHEMBL2323632
7.15	IC50	71	nM	CHEMBL2323635
7.15	EC50	71	nM	CHEMBL459850
7.10	IC50	79	nM	CHEMBL2323631
7.07	IC50	85.3	nM	CHEMBL4279751
7.04	IC50	91	nM	CHEMBL2069337
6.94	IC50	114	nM	CHEMBL2069343
6.85	IC50	140.2	nM	CHEMBL4590082
6.80	IC50	160	nM	CHEMBL2069340
6.70	IC50	200	nM	CHEMBL2069336
6.66	Ki	220	nM	CHEMBL1835870
6.64	IC50	230	nM	CHEMBL482175
6.54	IC50	286	nM	TAE-684
6.35	IC50	450	nM	CHEMBL2069342
6.28	IC50	528	nM	CHEMBL2069334
6.16	IC50	690	nM	CHEMBL511829
6.14	IC50	720	nM	CHEMBL2178352
6.12	IC50	760	nM	CHEMBL479820
6.12	Kd	758	nM	CHEMBL3752910
6.12	ED50	758	nM	CHEMBL3752910
5.83	IC50	1474	nM	TAE-684
5.83	EC50	1474	nM	TAE-684

PubChem BioAssay actives

88 with measured affinity, of 188 total; 50 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
6-(3-piperazin-1-ylphenyl)-N-[4-(trifluoromethyl)-2-pyridinyl]pyridin-2-amine	678181: Inhibition of human recombinant full-length Syk using poly-GT as substrate after 40 mins by radioactive filtration assay	ic50	0.0006	uM
(2S,3R,4R,6R)-3-methoxy-2-methyl-4-(methylamino)-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-16-one	1410144: Inhibition of SYK (unknown origin) by mobility shift assay	ic50	0.0009	uM
6-(2-piperazin-1-yl-4-pyridinyl)-N-[4-(trifluoromethyl)-2-pyridinyl]pyridin-2-amine	678181: Inhibition of human recombinant full-length Syk using poly-GT as substrate after 40 mins by radioactive filtration assay	ic50	0.0018	uM
5-[[(1S,2R)-2-aminocyclohexyl]amino]-7-(3,5-dimethoxyanilino)-[1,2,4]triazolo[1,5-c]pyrimidine-8-carboxamide	342540: Inhibition of human Syk	ic50	0.0040	uM
4-N-methyl-6-(2-piperazin-1-yl-4-pyridinyl)-2-N-pyrazin-2-ylpyridine-2,4-diamine	678181: Inhibition of human recombinant full-length Syk using poly-GT as substrate after 40 mins by radioactive filtration assay	ic50	0.0040	uM
N-[2-(2-piperazin-1-yl-4-pyridinyl)-6-(pyrazin-2-ylamino)-4-pyridinyl]piperidine-4-carboxamide	678181: Inhibition of human recombinant full-length Syk using poly-GT as substrate after 40 mins by radioactive filtration assay	ic50	0.0040	uM
6-(2-piperazin-1-yl-4-pyridinyl)-2-N-pyrazin-2-ylpyridine-2,4-diamine	678181: Inhibition of human recombinant full-length Syk using poly-GT as substrate after 40 mins by radioactive filtration assay	ic50	0.0040	uM
N-[2-(2-piperazin-1-yl-4-pyridinyl)-6-(pyrazin-2-ylamino)-4-pyridinyl]-2-pyridin-3-ylacetamide	678181: Inhibition of human recombinant full-length Syk using poly-GT as substrate after 40 mins by radioactive filtration assay	ic50	0.0040	uM
1-acetyl-N-[2-(2-piperazin-1-yl-4-pyridinyl)-6-(pyrazin-2-ylamino)-4-pyridinyl]piperidine-4-carboxamide	678181: Inhibition of human recombinant full-length Syk using poly-GT as substrate after 40 mins by radioactive filtration assay	ic50	0.0050	uM
N-[2-(2-piperazin-1-yl-4-pyridinyl)-6-(pyrazin-2-ylamino)-4-pyridinyl]pyridine-3-carboxamide	678181: Inhibition of human recombinant full-length Syk using poly-GT as substrate after 40 mins by radioactive filtration assay	ic50	0.0060	uM
2,5-dimethyl-N-[2-(2-piperazin-1-yl-4-pyridinyl)-6-(pyrazin-2-ylamino)-4-pyridinyl]pyrazole-3-carboxamide	678181: Inhibition of human recombinant full-length Syk using poly-GT as substrate after 40 mins by radioactive filtration assay	ic50	0.0070	uM
(1S,4aS,10aR)-1-(hydroxymethyl)-4a-methyl-7-propan-2-yl-2,3,4,9,10,10a-hexahydrophenanthrene-1-carboxylic acid	1410144: Inhibition of SYK (unknown origin) by mobility shift assay	ic50	0.0072	uM
4-[[2-(2-piperazin-1-yl-4-pyridinyl)-6-(pyrazin-2-ylamino)-4-pyridinyl]carbamoyl]benzoic acid	678181: Inhibition of human recombinant full-length Syk using poly-GT as substrate after 40 mins by radioactive filtration assay	ic50	0.0080	uM
4-[[[2-(2-piperazin-1-yl-4-pyridinyl)-6-(pyrazin-2-ylamino)-4-pyridinyl]amino]methyl]phenol	678181: Inhibition of human recombinant full-length Syk using poly-GT as substrate after 40 mins by radioactive filtration assay	ic50	0.0080	uM
5-(2-aminoethylamino)-7-(3,5-dimethoxyanilino)-[1,2,4]triazolo[4,3-c]pyrimidine-8-carboxamide	342540: Inhibition of human Syk	ic50	0.0090	uM
5-[[(1S,2R)-2-aminocyclohexyl]amino]-7-(3,5-dimethoxyanilino)-[1,2,4]triazolo[4,3-c]pyrimidine-8-carboxamide	342540: Inhibition of human Syk	ic50	0.0090	uM
N-[2-(2-piperazin-1-yl-4-pyridinyl)-6-(pyrazin-2-ylamino)-4-pyridinyl]pyrimidine-5-carboxamide	678181: Inhibition of human recombinant full-length Syk using poly-GT as substrate after 40 mins by radioactive filtration assay	ic50	0.0090	uM
5-[[2-(2-piperazin-1-yl-4-pyridinyl)-6-(pyrazin-2-ylamino)-4-pyridinyl]carbamoyl]pyridine-2-carboxylic acid	678181: Inhibition of human recombinant full-length Syk using poly-GT as substrate after 40 mins by radioactive filtration assay	ic50	0.0100	uM
(1S,4aS,10aR)-1-(2-methoxy-2-oxoethyl)-4a-methyl-7-prop-1-en-2-yl-2,3,4,9,10,10a-hexahydrophenanthrene-1-carboxylic acid	1410144: Inhibition of SYK (unknown origin) by mobility shift assay	ic50	0.0107	uM
N-(4-methyl-2-pyridinyl)-6-(2-piperazin-1-yl-4-pyridinyl)pyridin-2-amine	678181: Inhibition of human recombinant full-length Syk using poly-GT as substrate after 40 mins by radioactive filtration assay	ic50	0.0140	uM
(1S,4aS,10aR)-1-(2-methoxy-2-oxoethyl)-4a-methyl-7-propan-2-yl-2,3,4,9,10,10a-hexahydrophenanthrene-1-carboxylic acid	1410144: Inhibition of SYK (unknown origin) by mobility shift assay	ic50	0.0224	uM
6-[2-(1,4-diazepan-1-yl)-4-pyridinyl]-N-(4-methyl-2-pyridinyl)pyridin-2-amine	678181: Inhibition of human recombinant full-length Syk using poly-GT as substrate after 40 mins by radioactive filtration assay	ic50	0.0270	uM
(1R,4aS,10aR)-1,4a-dimethyl-7-propan-2-yl-2,3,4,9,10,10a-hexahydrophenanthrene-1-carboxylic acid	1410144: Inhibition of SYK (unknown origin) by mobility shift assay	ic50	0.0277	uM
N-[2-(2-piperazin-1-yl-4-pyridinyl)-6-(pyrazin-2-ylamino)-4-pyridinyl]benzamide	678181: Inhibition of human recombinant full-length Syk using poly-GT as substrate after 40 mins by radioactive filtration assay	ic50	0.0280	uM
N’-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridin-5-yl]butane-1,4-diamine	390098: Inhibition of SYK	ic50	0.0340	uM
(1R,4aS,10aR)-6-hydroxy-1,4a-dimethyl-7-propan-2-yl-2,3,4,9,10,10a-hexahydrophenanthrene-1-carbaldehyde	1410144: Inhibition of SYK (unknown origin) by mobility shift assay	ic50	0.0341	uM
2-(2-aminoethylamino)-4-[3-(trifluoromethyl)anilino]pyrimidine-5-carboxamide	342540: Inhibition of human Syk	ic50	0.0410	uM
N-[6-(3-piperazin-1-ylphenyl)-2-pyridinyl]pyrazin-2-amine	678181: Inhibition of human recombinant full-length Syk using poly-GT as substrate after 40 mins by radioactive filtration assay	ic50	0.0430	uM
[(1R,4aS,10aR)-1,4a-dimethyl-7-propan-2-yl-2,3,4,9,10,10a-hexahydrophenanthren-1-yl]methanol	1410144: Inhibition of SYK (unknown origin) by mobility shift assay	ic50	0.0464	uM
(1R,4aS,10aR)-7-(2-hydroxypropan-2-yl)-1,4a-dimethyl-2,3,4,9,10,10a-hexahydrophenanthrene-1-carboxylic acid	1410144: Inhibition of SYK (unknown origin) by mobility shift assay	ic50	0.0491	uM
5-[[(1S,2R)-2-aminocyclohexyl]amino]-2-(2-chlorophenyl)-7-(3,5-dimethoxyanilino)-[1,2,4]triazolo[1,5-c]pyrimidine-8-carboxamide	342540: Inhibition of human Syk	ic50	0.0500	uM
N-[6-(2-piperazin-1-yl-4-pyridinyl)-2-pyridinyl]pyrazin-2-amine	678181: Inhibition of human recombinant full-length Syk using poly-GT as substrate after 40 mins by radioactive filtration assay	ic50	0.0620	uM
5-[[1-[7-(3,4-dimethoxyanilino)-[1,3]thiazolo[5,4-d]pyrimidin-5-yl]piperidine-3-carbonyl]amino]pyridine-2-carboxylic acid	725838: Inhibition of human Gst-tagged Syk expressed in sf9 cells	ic50	0.0650	uM
N-[3-(7-amino-1-methyl-2-oxo-4H-pyrimido[4,5-d]pyrimidin-3-yl)-4-methylphenyl]-3-(trifluoromethyl)benzamide	383096: Inhibition of Syk by cellular assay	ec50	0.0710	uM
4-[[1-[7-(3,4-dimethoxyanilino)-[1,3]thiazolo[5,4-d]pyrimidin-5-yl]piperidine-3-carbonyl]amino]-2-hydroxybenzoic acid	725838: Inhibition of human Gst-tagged Syk expressed in sf9 cells	ic50	0.0710	uM
3-[7-(3,4-dimethoxyanilino)-[1,3]thiazolo[5,4-d]pyrimidin-5-yl]-N-[4-(methylcarbamoyl)phenyl]benzamide	725838: Inhibition of human Gst-tagged Syk expressed in sf9 cells	ic50	0.0710	uM
[3-[7-(3,4-dimethoxyanilino)-[1,3]thiazolo[5,4-d]pyrimidin-5-yl]phenyl]methanol	725838: Inhibition of human Gst-tagged Syk expressed in sf9 cells	ic50	0.0790	uM
5-[[(1S,2R)-2-aminocyclohexyl]amino]-7-(3,5-dimethoxyanilino)-2-phenyl-[1,2,4]triazolo[1,5-c]pyrimidine-8-carboxamide	342540: Inhibition of human Syk	ic50	0.0830	uM
(1S,4aS,10aR)-1-(hydroxymethyl)-4a-methyl-7-prop-1-en-2-yl-2,3,4,9,10,10a-hexahydrophenanthrene-1-carboxylic acid	1410144: Inhibition of SYK (unknown origin) by mobility shift assay	ic50	0.0853	uM
N’-[3-[6-[(4-methyl-2-pyridinyl)amino]-2-pyridinyl]phenyl]ethane-1,2-diamine	678181: Inhibition of human recombinant full-length Syk using poly-GT as substrate after 40 mins by radioactive filtration assay	ic50	0.0910	uM
6-[2-(4-aminopiperidin-1-yl)-4-pyridinyl]-N-(4-methyl-2-pyridinyl)pyridin-2-amine	678181: Inhibition of human recombinant full-length Syk using poly-GT as substrate after 40 mins by radioactive filtration assay	ic50	0.1140	uM
5-[[(1S,2R)-2-aminocyclohexyl]amino]-7-(3,5-dimethoxyanilino)-2-(3-methoxyphenyl)-[1,2,4]triazolo[1,5-c]pyrimidine-8-carboxamide	342540: Inhibition of human Syk	ic50	0.1200	uM
3-[2-[5-methyl-2-(4-morpholin-4-ylanilino)pyrimidin-4-yl]-6,7-dihydro-4H-furo[3,2-c]pyridin-5-yl]-3-oxopropanenitrile	1544092: Inhibition of SYK (unknown origin)	ic50	0.1402	uM
5-[(2-amino-2-methylpropyl)amino]-7-(3,5-dimethoxyanilino)-[1,2,4]triazolo[4,3-c]pyrimidine-8-carboxamide	342540: Inhibition of human Syk	ic50	0.1500	uM
6-[3-(2-aminoethyl)phenyl]-N-(4-methyl-2-pyridinyl)pyridin-2-amine	678181: Inhibition of human recombinant full-length Syk using poly-GT as substrate after 40 mins by radioactive filtration assay	ic50	0.1600	uM
N’-[4-[6-[(4-methyl-2-pyridinyl)amino]-2-pyridinyl]-2-pyridinyl]ethane-1,2-diamine	678181: Inhibition of human recombinant full-length Syk using poly-GT as substrate after 40 mins by radioactive filtration assay	ic50	0.2000	uM
3-N-[4-(4-morpholin-4-ylcyclohexyl)phenyl]-1-pyridin-2-yl-1,2,4-triazole-3,5-diamine	649411: Inhibition of SYK	ki	0.2200	uM
5-(2-aminoethylamino)-7-(3,5-dimethoxyanilino)imidazo[1,2-c]pyrimidine-8-carboxamide	412424: Inhibition of human Syk (Met343 to Asn635) expressed in Sf9 cells by coupled spectrophotometric enzyme assay	ic50	0.2300	uM
5-chloro-2-N-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]-4-N-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine	383345: Inhibition of Syk	ic50	0.2860	uM
6-[2-(3-aminopyrrolidin-1-yl)-4-pyridinyl]-N-(4-methyl-2-pyridinyl)pyridin-2-amine	678181: Inhibition of human recombinant full-length Syk using poly-GT as substrate after 40 mins by radioactive filtration assay	ic50	0.4500	uM

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Acetaminophen	decreases expression	2
bisphenol A	decreases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, increases expression	1
kojic acid	decreases expression	1
sodium arsenite	decreases expression	1
CD 437	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
3-(4’-hydroxy-3’-adamantylbiphenyl-4-yl)acrylic acid	decreases expression	1
thifluzamide	decreases expression	1
LDN 193189	affects cotreatment, decreases expression	1
(+)-JQ1 compound	decreases expression	1
Air Pollutants	affects expression, increases abundance	1
Atrazine	increases expression	1
Benztropine	affects cotreatment, decreases expression	1
Caffeine	increases phosphorylation	1
Cuprizone	affects cotreatment, decreases expression	1
Doxorubicin	decreases expression	1
Estradiol	affects binding, increases reaction	1
Furaldehyde	affects cotreatment, affects localization, increases expression	1
Ivermectin	decreases expression	1
Lead	decreases expression	1
Ozone	affects expression, increases abundance	1
Ribonucleotides	affects binding	1
Smoke	decreases expression	1
Sodium Chloride	increases expression, affects cotreatment, affects localization	1
Tretinoin	decreases expression	1
Valproic Acid	affects expression	1
1-Methyl-4-phenylpyridinium	decreases expression	1
Copper Sulfate	decreases expression	1

ChEMBL screening assays

46 unique, capped per target: 45 binding, 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1006347	Binding	Inhibition of Tel-fused Syk kinase-mediated mouse BaF3 cell proliferation	Identification of NVP-TAE684, a potent, selective, and efficacious inhibitor of NPM-ALK. — Proc Natl Acad Sci U S A
CHEMBL4424913	ADMET	Inhibition of human N-terminal His6-tagged SYK expressed in baculovirus infected Sf21 insect cells using Poly (Glu4-Tyr) (4:1) as substrate	Optimization of an azetidine series as inhibitors of colony stimulating factor-1 receptor (CSF-1R) Type II to lead to the clinical candidate JTE-952. — Bioorg Med Chem Lett

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00205881	PHASE4	COMPLETED	Bilateral Benefit in Adult Users of the HiRes 90K Bionic Ear System
NCT00331539	PHASE4	UNKNOWN	Relationship Between Auto NRT and Behavioural T & C Levels With the Nucleus Freedom Cochlear Implant
NCT00424307	PHASE4	UNKNOWN	Bilateral Cochlear Implant Benefit in Young Children
NCT00765635	PHASE4	COMPLETED	Chlorobutanol, Potassium Carbonate, and Irrigation in Cerumen Removal
NCT03321006	PHASE4	COMPLETED	Treating Hearing Loss to Improve Mood and Cognition in Older Adults
NCT01499901	PHASE3	WITHDRAWN	Comparison of the Bilateral Sequential and Simultaneous Cochlear Implantation in the Deaf Children
NCT02561091	PHASE3	COMPLETED	AM-111 in the Treatment of Acute Inner Ear Hearing Loss
NCT03331627	PHASE3	COMPLETED	Safety and Efficacy of STR001-IT and STR001-ER in Patients With SSHL
NCT05532657	PHASE3	ACTIVE_NOT_RECRUITING	ACHIEVE Brain Health Follow-Up Study
NCT00013455	PHASE2	COMPLETED	Quantifying Auditory Perceptual Learning Following Hearing Aid Fitting
NCT00323427	PHASE2	COMPLETED	Clinical Trial of the Living Well With Hearing Loss Workshop
NCT00552786	PHASE2	COMPLETED	Antioxidation Medication for Noise-induced Hearing Loss
NCT00802425	PHASE2	COMPLETED	Efficacy of AM-111 in Patients With Acute Sensorineural Hearing Loss
NCT01139281	PHASE2	COMPLETED	The Protective Effect of Ginkgo Biloba Extract on Cisplatin-induced Ototoxicity in Humans
NCT01451853	PHASE2	UNKNOWN	SPI-1005 for Prevention and Treatment of Chemotherapy Induced Hearing Loss
NCT01588925	PHASE2	COMPLETED	Hearing Preservation Using Dexamethasone and Hyaluronic Acid for Cochlear Implantation
NCT01773278	PHASE2	RECRUITING	Cholesterol and Antioxidant Treatment in Patients With Smith-Lemli-Opitz Syndrome (SLOS)
NCT02832128	PHASE2	COMPLETED	Evaluating Possible Improvement in Speech and Hearing Tests After 28 Days of Dosing of the Study Drug AUT00063 Compared to Placebo (QuicKfire)
NCT04915183	PHASE2	RECRUITING	Atorvastatin to Reduce Cisplatin-Induced Hearing Loss Among Individuals With Head and Neck Cancer
NCT05258773	PHASE2	COMPLETED	Evaluation of the Presence of SENS-401 in the Perilymph
NCT06340633	PHASE2	RECRUITING	SPI-1005 in Adults Receiving Cochlear Implant
NCT00582946	PHASE1	COMPLETED	Wide-Bandwidth Open Canal Hearing Aid For Better Multitalker Speech Understanding
NCT00584155	PHASE1	WITHDRAWN	Protection From Cisplatin Ototoxicity by Lactated Ringers
NCT01206829	PHASE1	UNKNOWN	Hearing Impairment, Cognitive Therapy and Coping
NCT01256229	PHASE1	COMPLETED	Outcomes In Children With Developmental Delay And Deafness
NCT01343394	PHASE1	WITHDRAWN	Safety of Autologous Human Umbilical Cord Blood Mononuclear Fraction to Treat Acquired Hearing Loss in Children
NCT01452607	PHASE1	COMPLETED	Study to Evaluate the Safety and Pharmacokinetics of SPI-1005
NCT02259595	PHASE1	COMPLETED	Study to Determine the Safety, Tolerability, and Pharmacokinetic Profile of HPN-07 and HPN-07 Plus NAC
NCT04041440	PHASE1	COMPLETED	Speech Recognition Training in Children With Hearing Loss
NCT07218913	PHASE1	RECRUITING	Testing the Addition of Pedmark to Cisplatin Chemotherapy for Reducing Drug-Induced Ear Damage in Men With Stage II-III Metastatic Testicular Germ Cell Tumors
NCT01802190	Not specified	TERMINATED	Prevalence of POU4F3 and SLC17A8 Mutations
NCT05518188	PHASE1/PHASE2	RECRUITING	Melpida: Recombinant Adeno-associated Virus (serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)
NCT00001639	Not specified	COMPLETED	Evaluation of Patients With Unresolved Chromosome Abnormalities
NCT01151462	Not specified	WITHDRAWN	Postnatal HCMV Infection in Very Preterm Infants. Implications, Morbidity, Growth and Neurodevelopmental Outcomes.
NCT01565005	Not specified	COMPLETED	Microcephaly Genetic Deficiency in Neural Progenitors
NCT02510170	Not specified	COMPLETED	Fetal and Maternal Head Circumference During Pregnancy in Israeli Population
NCT02741882	Not specified	COMPLETED	Zika and Microcephaly: Case-control Study
NCT02943304	Not specified	COMPLETED	Neurodevelopment Outcome of Newborns Exposed to Zika Virus (ZIKV) in Utero
NCT03255369	Not specified	UNKNOWN	Vertical Exposure to Zika Virus and Its Consequences for Child Neurodevelopment (ZIKVIRUSIFF)
NCT03325946	Not specified	RECRUITING	The FBRI VTC Neuromotor Research Clinic