QARS1

Summary

QARS1 (glutaminyl-tRNA synthetase 1, HGNC:9751) is a protein-coding gene on chromosome 3p21.31, encoding Glutamine–tRNA ligase (P47897). Glutamine–tRNA ligase. It is a common-essential gene (DepMap: required in 99.9% of cancer cell lines).

Aminoacyl-tRNA synthetases catalyze the aminoacylation of tRNA by their cognate amino acid. Because of their central role in linking amino acids with nucleotide triplets contained in tRNAs, aminoacyl-tRNA synthetases are thought to be among the first proteins that appeared in evolution. In metazoans, 9 aminoacyl-tRNA synthetases specific for glutamine (gln), glutamic acid (glu), and 7 other amino acids are associated within a multienzyme complex. Although present in eukaryotes, glutaminyl-tRNA synthetase (QARS) is absent from many prokaryotes, mitochondria, and chloroplasts, in which Gln-tRNA(Gln) is formed by transamidation of the misacylated Glu-tRNA(Gln). Glutaminyl-tRNA synthetase belongs to the class-I aminoacyl-tRNA synthetase family. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 5859 — RefSeq curated summary.

At a glance

• Gene–disease (curated): diffuse cerebral and cerebellar atrophy - intractable seizures - progressive microcephaly syndrome (Definitive, ClinGen) — +1 more curated relationship
• Clinical variants (ClinVar): 1,008 total — 40 pathogenic, 23 likely-pathogenic
• Phenotypes (HPO): 25
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 99.9% of screened cell lines (common-essential)
• MANE Select transcript: NM_005051

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9751
Approved symbol	QARS1
Name	glutaminyl-tRNA synthetase 1
Location	3p21.31
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000172053
Ensembl biotype	protein_coding
OMIM	603727
Entrez	5859

Gene structure

Transcript identifiers

Ensembl transcripts: 63 — 26 protein_coding, 17 retained_intron, 12 nonsense_mediated_decay, 8 protein_coding_CDS_not_defined

ENST00000306125, ENST00000414533, ENST00000417025, ENST00000418549, ENST00000430182, ENST00000452739, ENST00000453392, ENST00000459870, ENST00000464962, ENST00000466179, ENST00000470113, ENST00000470225, ENST00000470619, ENST00000478561, ENST00000479495, ENST00000482248, ENST00000482261, ENST00000482438, ENST00000482468, ENST00000487495, ENST00000494767, ENST00000494838, ENST00000494984, ENST00000497635, ENST00000634336, ENST00000634359, ENST00000634425, ENST00000634432, ENST00000634473, ENST00000634527, ENST00000634602, ENST00000634609, ENST00000634724, ENST00000634802, ENST00000634953, ENST00000635052, ENST00000635194, ENST00000635231, ENST00000635278, ENST00000635292, ENST00000635375, ENST00000635443, ENST00000635494, ENST00000635501, ENST00000635541, ENST00000635622, ENST00000636018, ENST00000636669, ENST00000637113, ENST00000637281, ENST00000637543, ENST00000637908, ENST00000870701, ENST00000913518, ENST00000965960, ENST00000965961, ENST00000965962, ENST00000965963, ENST00000965964, ENST00000965965, ENST00000965966, ENST00000965967, ENST00000965968

RefSeq mRNA: 2 — MANE Select: NM_005051 NM_001272073, NM_005051

CCDS: CCDS2788, CCDS63633

Canonical transcript exons

ENST00000306125 — 24 exons

Exon	Start	End
ENSE00003466831	49102419	49102472
ENSE00003471280	49103631	49103706
ENSE00003472073	49103863	49103972
ENSE00003473742	49100575	49100674
ENSE00003487048	49099510	49099647
ENSE00003490776	49099961	49100091
ENSE00003503914	49102205	49102265
ENSE00003516014	49100380	49100458
ENSE00003540328	49095932	49096079
ENSE00003572060	49099110	49099253
ENSE00003573378	49099761	49099853
ENSE00003591633	49103345	49103409
ENSE00003595358	49098600	49098692
ENSE00003604428	49104617	49104757
ENSE00003614114	49100190	49100298
ENSE00003654596	49104324	49104471
ENSE00003657423	49099344	49099431
ENSE00003658389	49101828	49101899
ENSE00003660958	49101620	49101705
ENSE00003661976	49097992	49098117
ENSE00003663607	49098192	49098258
ENSE00003668410	49101355	49101441
ENSE00003684005	49098353	49098480
ENSE00003684278	49098885	49098989

Expression profiles

Bgee: expression breadth ubiquitous, 299 present calls, max score 98.94.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 101.5187 / max 380.6294, expressed in 1827 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
42213	96.1653	1827
42212	5.0756	1628
42211	0.2685	124
42214	0.0094	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mammalian vulva	UBERON:0000997	98.94	gold quality
upper arm skin	UBERON:0004263	98.91	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	98.83	gold quality
mucosa of sigmoid colon	UBERON:0004993	98.81	gold quality
colonic mucosa	UBERON:0000317	98.80	gold quality
lower esophagus mucosa	UBERON:0035834	98.79	gold quality
gingiva	UBERON:0001828	98.73	gold quality
tonsil	UBERON:0002372	98.73	gold quality
upper leg skin	UBERON:0004262	98.72	gold quality
gingival epithelium	UBERON:0001949	98.71	gold quality
palpebral conjunctiva	UBERON:0001812	98.70	gold quality
tongue squamous epithelium	UBERON:0006919	98.69	gold quality
rectum	UBERON:0001052	98.64	gold quality
apex of heart	UBERON:0002098	98.61	gold quality
nasal cavity epithelium	UBERON:0005384	98.58	gold quality
metanephros cortex	UBERON:0010533	98.50	gold quality
skin of leg	UBERON:0001511	98.49	gold quality
esophagus mucosa	UBERON:0002469	98.47	gold quality
mouth mucosa	UBERON:0003729	98.47	gold quality
minor salivary gland	UBERON:0001830	98.46	gold quality
oral cavity	UBERON:0000167	98.45	gold quality
transverse colon	UBERON:0001157	98.45	gold quality
saliva-secreting gland	UBERON:0001044	98.43	gold quality
nipple	UBERON:0002030	98.42	gold quality
epithelium of esophagus	UBERON:0001976	98.41	gold quality
zone of skin	UBERON:0000014	98.36	gold quality
squamous epithelium	UBERON:0006914	98.36	gold quality
skin of abdomen	UBERON:0001416	98.35	gold quality
esophagus squamous epithelium	UBERON:0006920	98.35	gold quality
granulocyte	CL:0000094	98.34	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	14.51
E-MTAB-6379	no	490.65

Regulation

Is transcription factor: no

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 99.9% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 8)

• Data indicate that glutaminyl-tRNA synthetase splice variant GlnRSDeltaiABD was present in exosomes extruded from Jurkat cells and functional in protein synthesis. (PMID:24003230)
• results highlight the importance of QARS during brain development and that epilepsy due to impairment of QARS activity is unusually severe in comparison to other aminoacyl-tRNA synthetase disorders (PMID:24656866)
• interactions between the N-terminal domains of ArgRS and AIMP1 are important for the catalytic and noncatalytic activities of ArgRS and for the assembly of the higher-order MSC protein complex with ArgRS-GlnRS-AIMP1 (PMID:25288775)
• Data indicate compound heterozygous mutations [c.169T>C (p.Tyr57His) and c.1485dup (p.Lys496*)] in QARS, which encodes glutaminyl-tRNA synthetase, in two siblings with early-onset epileptic encephalopathy (EOEE). (PMID:25471517)
• Pathological mutations mapping in the N-terminal domain alter the domain structure, and decrease catalytic activity and stability of GlnRS, whereas missense mutations in the catalytic domain induce misfolding of the enzyme. (PMID:26869582)
• hcmv-miR-US4-1 may involve in promoting cell apoptosis and benefiting discharge of infectious virus particles via down-regulation of QARS in HCMV-infected HELF cells. (PMID:27240979)
• patient’s fibroblasts demonstrated markedly reduced QARS amino acylation activity in vitro (PMID:28620870)
• [QARS1 gene related glutaminyl-tRNA synthetase deficiency syndrome: report of three cases and a review of literature]. (PMID:33256324)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	qars1	ENSDARG00000010316
mus_musculus	Qars1	ENSMUSG00000032604
rattus_norvegicus	Qars1	ENSRNOG00000060912
drosophila_melanogaster	GlnRS	FBGN0027090
caenorhabditis_elegans		WBGENE00001336

Paralogs (2): EARS2 (ENSG00000103356), EPRS1 (ENSG00000136628)

Protein

Protein identifiers

Glutamine–tRNA ligase — P47897 (reviewed: P47897)

Alternative names: Glutaminyl-tRNA synthetase

All UniProt accessions (23): P47897, A0A0U1RQC3, A0A0U1RQE9, A0A0U1RQJ6, A0A0U1RQL2, A0A0U1RQM8, A0A0U1RQQ5, A0A0U1RQT0, A0A0U1RQU2, A0A0U1RQX5, A0A0U1RQX9, A0A0U1RR66, A0A0U1RR79, A0A0U1RRC8, A0A0U1RRI9, A0A0U1RRJ7, A0A1B0GTT3, A0A1B0GU21, A0A1B0GVU9, B4DDN1, C9J165, F2Z2V6, H7C0R3

UniProt curated annotations — full annotation on UniProt →

Function. Glutamine–tRNA ligase. Plays a critical role in brain development.

Subunit / interactions. Monomer. Part of a multisubunit complex that groups tRNA ligases for Arg (RARS1), Asp (DARS1), Gln (QARS1), Ile (IARS1), Leu (LARS1), Lys (KARS1), Met (MARS1) the bifunctional ligase for Glu and Pro (EPRS1) and the auxiliary subunits AIMP1/p43, AIMP2/p38 and EEF1E1/p18. Interacts with RARS1. Part of a complex composed of RARS1, QARS1 and AIMP1.

Subcellular location. Cytoplasm. Cytosol.

Tissue specificity. Highly expressed in fetal cerebral cortex, particularly in the ventricular zone, inner subventricular zone, outer subventricular zone, and cortical plate.

Disease relevance. Microcephaly, progressive, with seizures and cerebral and cerebellar atrophy (MSCCA) [MIM:615760] A severe, autosomal recessive, neurodevelopmental and neurodegenerative disorder characterized by progressive microcephaly, severe seizures in infancy, atrophy of the cerebral cortex and cerebellar vermis, and mild atrophy of the cerebellar hemispheres, resulting in profoundly delayed development and hypotonia. The disease is caused by variants affecting the gene represented in this entry.

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

Isoforms (2)

UniProt ID	Names	Canonical?
P47897-1	1	yes
P47897-2	2

RefSeq proteins (2): NP_001259002, NP_005042* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000924	Glu/Gln-tRNA-synth	Family
IPR001412	aa-tRNA-synth_I_CS	Conserved_site
IPR004514	Gln-tRNA-synth	Family
IPR007638	Gln-tRNA-synth_Ib_RNA-bd_2	Domain
IPR007639	Gln-tRNA-synth_Ib_RNA-bd_N	Domain
IPR011035	Ribosomal_bL25/Gln-tRNA_synth	Homologous_superfamily
IPR014729	Rossmann-like_a/b/a_fold	Homologous_superfamily
IPR020056	Rbsml_bL25/Gln-tRNA_synth_N	Homologous_superfamily
IPR020058	Glu/Gln-tRNA-synth_Ib_cat-dom	Domain
IPR020059	Glu/Gln-tRNA-synth_Ib_codon-bd	Domain
IPR042558	Gln-tRNA-synth_Ib_RNA-bd_N_1	Homologous_superfamily
IPR042559	Gln-tRNA-synth_Ib_RNA-bd_N_2	Homologous_superfamily
IPR049437	tRNA-synt_1c_C2	Domain
IPR050132	Gln/Glu-tRNA_Ligase	Family

Pfam: PF00749, PF03950, PF04557, PF04558, PF20974

Enzyme classification (BRENDA):

• EC 6.1.1.18 — glutamine-tRNA ligase (BRENDA: 16 organisms, 51 substrates, 27 inhibitors, 68 Km, 50 kcat entries)

Substrate kinetics (BRENDA)

6 substrates with measured Km, best-characterized 6. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
L-GLUTAMINE	0.05–46.3	23
ATP	0.038–660	16
TRNAGLN	—	11
GLN	0.028–17.8	8
L-GLUTAMATE	240	1
TRNAGLN IN UNFRACTIONATED TRNA	0.0001	1

Catalyzed reactions (Rhea), 1 shown:

• tRNA(Gln) + L-glutamine + ATP = L-glutaminyl-tRNA(Gln) + AMP + diphosphate (RHEA:20121)

UniProt features (86 total): strand 30, helix 28, binding site 7, turn 7, modified residue 4, sequence variant 4, short sequence motif 2, initiator methionine 1, chain 1, splice variant 1, mutagenesis site 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
4YE6	X-RAY DIFFRACTION	2.4
4YE9	X-RAY DIFFRACTION	2.7
4YE8	X-RAY DIFFRACTION	3.3
4R3Z	X-RAY DIFFRACTION	4.03

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P47897-F1	89.96	0.78

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 (7): 494–496; 271–273; 277–283; 303; 438; 457; 486–487

Post-translational modifications (4): 2, 70, 309, 495

Mutagenesis-validated functional residues (1):

Position	Phenotype
175	decreases catalytic efficiency about 60-fold.

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: 141 (showing top): GOBP_AMINO_ACID_ACTIVATION, GOBP_REGULATION_OF_STRESS_ACTIVATED_PROTEIN_KINASE_SIGNALING_CASCADE, GOBP_TRNA_METABOLIC_PROCESS, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, HSIAO_HOUSEKEEPING_GENES, RIZKI_TUMOR_INVASIVENESS_3D_DN, GOBP_NEGATIVE_REGULATION_OF_MAPK_CASCADE, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, GOBP_TRANSLATION, GOBP_APOPTOTIC_SIGNALING_PATHWAY, BLALOCK_ALZHEIMERS_DISEASE_UP, GOBP_REGULATION_OF_RESPONSE_TO_STRESS, GOBP_HEAD_DEVELOPMENT, LASTOWSKA_NEUROBLASTOMA_COPY_NUMBER_DN, MODULE_110

GO Biological Process (8): tRNA aminoacylation for protein translation (GO:0006418), glutaminyl-tRNA aminoacylation (GO:0006425), brain development (GO:0007420), negative regulation of stress-activated MAPK cascade (GO:0032873), negative regulation of DNA-templated transcription (GO:0045892), negative regulation of apoptotic signaling pathway (GO:2001234), translation (GO:0006412), tRNA aminoacylation (GO:0043039)

GO Molecular Function (8): glutamine-tRNA ligase activity (GO:0004819), protein kinase inhibitor activity (GO:0004860), ATP binding (GO:0005524), protein kinase binding (GO:0019901), nucleotide binding (GO:0000166), aminoacyl-tRNA ligase activity (GO:0004812), protein binding (GO:0005515), ligase activity (GO:0016874)

GO Cellular Component (6): cytoplasm (GO:0005737), mitochondrial matrix (GO:0005759), cytosol (GO:0005829), aminoacyl-tRNA synthetase multienzyme complex (GO:0017101), protein-containing complex (GO:0032991), 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	3
translation	1
tRNA aminoacylation	1
tRNA aminoacylation for protein translation	1
central nervous system development	1
animal organ development	1
head development	1
regulation of stress-activated MAPK cascade	1
negative regulation of MAPK cascade	1
stress-activated MAPK cascade	1
negative regulation of stress-activated protein kinase signaling cascade	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
negative regulation of signal transduction	1
negative regulation of apoptotic process	1
apoptotic signaling pathway	1
regulation of apoptotic signaling pathway	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
tRNA metabolic process	1
amino acid activation	1
aminoacyl-tRNA ligase activity	1
protein kinase activity	1
kinase inhibitor activity	1
protein kinase regulator activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
kinase binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
ligase activity, forming carbon-oxygen bonds	1
catalytic activity, acting on a tRNA	1
binding	1
catalytic activity	1

Protein interactions and networks

STRING

3469 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
QARS1	KARS1	Q15046	998
QARS1	RARS2	Q5T160	998
QARS1	RARS1	P54136	996
QARS1	LARS1	Q9P2J5	992
QARS1	IARS1	P41252	991
QARS1	MARS1	P56192	987
QARS1	LARS2	Q15031	986
QARS1	IARS2	Q9NSE4	982
QARS1	MARS2	Q96GW9	981
QARS1	PARS2	Q7L3T8	965
QARS1	EPRS1	P07814	920
QARS1	AARS1	P49588	905
QARS1	DARS1	P14868	899
QARS1	AIMP1	Q12904	895
QARS1	AIMP2	Q13155	892

IntAct

389 interactions, top by confidence:

A	B	Type	Score
QARS1	RNF11	psi-mi:“MI:0915”(physical association)	0.830
QARS1	TRIP13	psi-mi:“MI:0915”(physical association)	0.720
QARS1	LZTS2	psi-mi:“MI:0915”(physical association)	0.720
TRAF4	QARS1	psi-mi:“MI:0915”(physical association)	0.720
TRIP13	QARS1	psi-mi:“MI:0915”(physical association)	0.720
LZTS2	QARS1	psi-mi:“MI:0915”(physical association)	0.720
QARS1	TRAF4	psi-mi:“MI:0915”(physical association)	0.720
TCF12	QARS1	psi-mi:“MI:0915”(physical association)	0.670
QARS1	TCF12	psi-mi:“MI:0915”(physical association)	0.670
TLE5	QARS1	psi-mi:“MI:0915”(physical association)	0.560
KLC3	QARS1	psi-mi:“MI:0915”(physical association)	0.560
QARS1	TLE5	psi-mi:“MI:0915”(physical association)	0.560
QARS1	KLC3	psi-mi:“MI:0915”(physical association)	0.560
ACTN2	QARS1	psi-mi:“MI:0915”(physical association)	0.560
QARS1	LGALS9C	psi-mi:“MI:0915”(physical association)	0.560
QARS1	HOXA1	psi-mi:“MI:0915”(physical association)	0.560
QARS1	MCCD1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (547): QARS (Affinity Capture-MS), QARS (Two-hybrid), TCF12 (Two-hybrid), TRIP13 (Two-hybrid), TRAF4 (Two-hybrid), VPS37B (Two-hybrid), LZTS2 (Two-hybrid), DTX2 (Two-hybrid), KLC3 (Two-hybrid), QARS (Affinity Capture-RNA), QARS (Affinity Capture-RNA), QARS (Affinity Capture-MS), QARS (Affinity Capture-MS), QARS (Affinity Capture-MS), QARS (Affinity Capture-MS)

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: A0B966, A1RRG7, A1RYD7, A2BK91, A2SRG2, A3CWJ3, A3DMR5, A3MV95, A3PHK2, A4FXG8, A4IJG6, A4WKI4, A4XVG2, A4YIL8, A5UN79, A6LJ42, A6UP25, A6UW15, A6VFU7, A7HKV0, A7IAG1, A8ABI5, A8GB43, A8M9D7, A9A423, A9AAT7, A9BGT8, B0R4Z6, B1L5U2, B1YAX4, B2GAB3, B2VBN3, B3CST4, B3R5N3, B4EV71, B4RYH7, B4U896, B5Y7R0, B6JH82, B6YSY7

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
QARS1	“form complex”	“Multiaminoacyl-tRNA synthetase”	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

1008 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	40
Likely pathogenic	23
Uncertain significance	416
Likely benign	444
Benign	19

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1068889	NM_005051.3(QARS1):c.2080C>T (p.Arg694Ter)	Pathogenic
1069375	NM_005051.3(QARS1):c.1485dup (p.Lys496Ter)	Pathogenic
1069544	NM_005051.3(QARS1):c.1690dup (p.Thr564fs)	Pathogenic
1076068	NM_005051.3(QARS1):c.679del (p.Glu227fs)	Pathogenic
1214488	NM_005051.3(QARS1):c.1362_1365del (p.Leu455fs)	Pathogenic
127115	NM_005051.3(QARS1):c.134G>T (p.Gly45Val)	Pathogenic
1350720	NM_005051.3(QARS1):c.441del (p.Leu148fs)	Pathogenic
1365890	NM_005051.3(QARS1):c.1345G>T (p.Glu449Ter)	Pathogenic
1379869	NM_005051.3(QARS1):c.184C>T (p.Arg62Ter)	Pathogenic
1449644	NM_005051.3(QARS1):c.1272_1279del (p.His426fs)	Pathogenic
1451833	NM_005051.3(QARS1):c.1194del (p.Glu399fs)	Pathogenic
1454301	NM_005051.3(QARS1):c.1391_1401dup (p.Phe468fs)	Pathogenic
1456006	NM_005051.3(QARS1):c.514C>T (p.Gln172Ter)	Pathogenic
1456556	NM_005051.3(QARS1):c.1978_1979del (p.Leu661fs)	Pathogenic
1456651	NM_005051.3(QARS1):c.1075del (p.His359fs)	Pathogenic
1957132	NM_005051.3(QARS1):c.1021C>T (p.Gln341Ter)	Pathogenic
1973279	NM_005051.3(QARS1):c.972G>A (p.Trp324Ter)	Pathogenic
2011161	NM_005051.3(QARS1):c.3G>A (p.Met1Ile)	Pathogenic
2089675	NM_005051.3(QARS1):c.352del (p.Thr118fs)	Pathogenic
2194507	NM_005051.3(QARS1):c.406del (p.Gln136fs)	Pathogenic
2697199	NM_005051.3(QARS1):c.1930dup (p.Val644fs)	Pathogenic
2778278	NM_005051.3(QARS1):c.1401C>A (p.Tyr467Ter)	Pathogenic
2888694	NM_005051.3(QARS1):c.1634_1637del (p.Gln545fs)	Pathogenic
3010950	NM_005051.3(QARS1):c.786del (p.Gln263fs)	Pathogenic
3251838	NM_005051.3(QARS1):c.561dup (p.Lys188fs)	Pathogenic
3644063	NM_005051.3(QARS1):c.2089C>T (p.Gln697Ter)	Pathogenic
3722050	NM_005051.3(QARS1):c.1896G>A (p.Trp632Ter)	Pathogenic
421411	NM_005051.3(QARS1):c.1451del (p.Tyr484fs)	Pathogenic
4717627	NM_005051.3(QARS1):c.1657dup (p.Leu553fs)	Pathogenic
477827	NM_005051.3(QARS1):c.1387C>T (p.Arg463Ter)	Pathogenic

SpliceAI

3003 predictions. Top by Δscore:

Variant	Effect	Δscore
3:49097995:T:A	donor_gain	1.0000
3:49097996:C:A	donor_gain	1.0000
3:49098351:A:AC	donor_gain	1.0000
3:49098352:C:CC	donor_gain	1.0000
3:49098352:CAGT:C	donor_gain	1.0000
3:49098693:CT:C	acceptor_loss	1.0000
3:49098881:TTA:T	donor_loss	1.0000
3:49098883:ACCT:A	donor_gain	1.0000
3:49098884:C:CT	donor_loss	1.0000
3:49098884:CCTC:C	donor_gain	1.0000
3:49098886:T:TA	donor_gain	1.0000
3:49098887:C:A	donor_gain	1.0000
3:49098985:AAGGA:A	acceptor_gain	1.0000
3:49098986:AGGA:A	acceptor_gain	1.0000
3:49098987:GGA:G	acceptor_gain	1.0000
3:49098988:GA:G	acceptor_gain	1.0000
3:49098990:C:CC	acceptor_gain	1.0000
3:49098992:A:AC	acceptor_gain	1.0000
3:49098992:A:C	acceptor_gain	1.0000
3:49098996:C:CT	acceptor_gain	1.0000
3:49098997:A:T	acceptor_gain	1.0000
3:49099003:C:CT	acceptor_gain	1.0000
3:49099004:A:T	acceptor_gain	1.0000
3:49099106:CCA:C	donor_loss	1.0000
3:49099107:CA:C	donor_loss	1.0000
3:49099108:A:AT	donor_loss	1.0000
3:49099109:C:T	donor_loss	1.0000
3:49099249:CCCAC:C	acceptor_gain	1.0000
3:49099250:CCAC:C	acceptor_gain	1.0000
3:49099250:CCACC:C	acceptor_gain	1.0000

AlphaMissense

5048 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:49099548:C:A	K496N	1.000
3:49099548:C:G	K496N	1.000
3:49099769:G:C	F460L	1.000
3:49099769:G:T	F460L	1.000
3:49099770:A:C	F460C	1.000
3:49099770:A:G	F460S	1.000
3:49099771:A:G	F460L	1.000
3:49099781:G:C	C456W	1.000
3:49099782:C:T	C456Y	1.000
3:49099783:A:G	C456R	1.000
3:49099812:T:A	D446V	1.000
3:49099813:C:G	D446H	1.000
3:49099825:G:C	H442D	1.000
3:49100643:T:A	D303V	1.000
3:49101389:G:T	A281D	1.000
3:49099546:C:A	R497M	0.999
3:49099549:T:A	K496M	0.999
3:49099588:T:A	E483V	0.999
3:49099589:C:T	E483K	0.999
3:49099592:A:G	W482R	0.999
3:49099592:A:T	W482R	0.999
3:49099593:C:A	Q481H	0.999
3:49099593:C:G	Q481H	0.999
3:49099623:G:C	C471W	0.999
3:49099771:A:C	F460V	0.999
3:49099771:A:T	F460I	0.999
3:49099774:C:T	E459K	0.999
3:49099779:G:A	T457I	0.999
3:49099789:A:G	S454P	0.999
3:49099812:T:C	D446G	0.999

dbSNP variants (sampled 300 via entrez): RS1000537703 (3:49099083 G>A), RS1000817907 (3:49105844 C>T), RS1001010440 (3:49096287 A>G), RS1001075230 (3:49103429 G>A,T), RS1001236795 (3:49097573 G>C), RS1001357206 (3:49099856 G>C), RS1001642577 (3:49106519 C>T), RS1001778332 (3:49106185 C>G), RS1001806893 (3:49100206 G>A), RS1001815943 (3:49104890 C>G,T), RS1001867014 (3:49105150 C>T), RS1001988058 (3:49105214 A>T), RS1002540476 (3:49101727 T>C), RS1003361409 (3:49097212 G>A), RS1004331100 (3:49106221 C>T)

Disease associations

OMIM: gene MIM:603727 | disease phenotypes: MIM:615760, MIM:616977

GenCC curated gene-disease

Disease	Classification	Inheritance
diffuse cerebral and cerebellar atrophy - intractable seizures - progressive microcephaly syndrome	Definitive	Autosomal recessive
microcephaly-short stature-intellectual disability-facial dysmorphism syndrome	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
diffuse cerebral and cerebellar atrophy - intractable seizures - progressive microcephaly syndrome	Definitive	AR

Mondo (5): diffuse cerebral and cerebellar atrophy - intractable seizures - progressive microcephaly syndrome (MONDO:0014335), intellectual disability, autosomal dominant 43 (MONDO:0014858), attention deficit-hyperactivity disorder (MONDO:0007743), microcephaly (MONDO:0001149), microcephaly-short stature-intellectual disability-facial dysmorphism syndrome (MONDO:0018494)

Orphanet (1): Diffuse cerebral and cerebellar atrophy-intractable seizures-progressive microcephaly syndrome (Orphanet:404437)

HPO phenotypes

25 total (25 of 25 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000218	High palate
HP:0000252	Microcephaly
HP:0000253	Progressive microcephaly
HP:0000286	Epicanthus
HP:0000340	Sloping forehead
HP:0000341	Narrow forehead
HP:0000358	Posteriorly rotated ears
HP:0000369	Low-set ears
HP:0000431	Wide nasal bridge
HP:0000601	Hypotelorism
HP:0001252	Hypotonia
HP:0001347	Hyperreflexia
HP:0002059	Cerebral atrophy
HP:0002079	Hypoplasia of the corpus callosum
HP:0002119	Ventriculomegaly
HP:0002133	Status epilepticus
HP:0003429	CNS hypomyelination
HP:0003593	Infantile onset
HP:0003623	Neonatal onset
HP:0003676	Progressive
HP:0005280	Depressed nasal bridge
HP:0006855	Cerebellar vermis atrophy
HP:0009879	Simplified gyral pattern
HP:0012736	Profound global developmental delay

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3054 (SINGLE PROTEIN)

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

ChEMBL bioactivities

6 potent at pChembl≥5 of 9 total, top 6 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.97	Kd	106.8	nM	CHEMBL3752910
6.97	ED50	106.8	nM	CHEMBL3752910
6.55	Ki	280	nM	CHEMBL609187
6.07	Ki	860	nM	CHEMBL609187
5.89	Ki	1300	nM	CHEMBL609496
5.52	Ki	3000	nM	CHEMBL608302

PubChem BioAssay actives

5 with measured affinity, of 9 total; 4 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
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149162: Binding affinity to human QARS incubated for 45 mins by Kinobead based pull down assay	kd	0.1068	uM
sodium;[(2R,3S,4R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl (2,5-diamino-5-oxopentyl) phosphate;2,2,2-trifluoroacetic acid	75130: The compound was evaluated for inhibition of Glutaminyl-tRNA synthetase with respect to glutamine.	ki	0.2800	uM
[(2R,3S,4R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl] N-(2,5-diamino-5-oxopentanoyl)sulfamate	75128: The compound was evaluated for binding affinity to Glutaminyl-tRNA synthetase with respect to glutamine.	ki	1.3000	uM
4-amino-5-[[(2S,3S,4R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl-hydroxyphosphoryl]oxy-5-oxopentanoic acid	75130: The compound was evaluated for inhibition of Glutaminyl-tRNA synthetase with respect to glutamine.	ki	3.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, increases methylation	3
bisphenol A	affects expression, increases expression	2
Smoke	decreases expression	2
FR900359	decreases phosphorylation	1
bisphenol F	increases expression	1
alpha-pinene	affects cotreatment, increases expression, increases oxidation, increases abundance	1
mono-(2-ethylhexyl)phthalate	decreases expression	1
sodium arsenite	decreases expression	1
perfluorooctanoic acid	decreases expression	1
benzo(e)pyrene	decreases methylation	1
aflatoxin B2	decreases methylation	1
methacrylaldehyde	increases abundance, affects cotreatment, increases expression, increases oxidation	1
brequinar	decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
chloropicrin	increases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
pinostrobin	increases expression	1
perfluorohexanesulfonic acid	decreases expression	1
nutlin 3	affects cotreatment, increases secretion	1
bisphenol B	increases expression	1
abrine	decreases expression	1
2-amino-14,16-dimethyloctadecan-3-ol	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
jinfukang	increases expression, affects cotreatment	1
bisphenol AF	increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Glyphosate	affects methylation	1
Acrolein	increases abundance, affects cotreatment, increases expression, increases oxidation	1
Air Pollutants	affects cotreatment, increases abundance, increases expression, increases oxidation	1
Cisplatin	affects cotreatment, increases expression	1

ChEMBL screening assays

6 unique, capped per target: 6 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652204	Binding	Binding affinity to human QARS incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00152750	PHASE4	UNKNOWN	Study of Clonidine on Sleep Architecture in Children With Tourette’s Syndrome (TS) and Comorbid ADHD
NCT00181571	PHASE4	COMPLETED	A Double-Blind Comparison of Concerta and Placebo in Adults With Attention Deficit Hyperactivity Disorder
NCT00181675	PHASE4	COMPLETED	A Double-Blind Comparison of Galantamine HBr and Placebo in Adults With Attention Deficit Hyperactivity Disorder
NCT00181714	PHASE4	COMPLETED	Prevention of Cigarette Smoking in Attention Deficit Hyperactivity Disorder (ADHD) Youth With Concerta
NCT00181948	PHASE4	COMPLETED	Strattera Treatment in Children With ADHD Who Have Poor Response to Stimulant Therapy
NCT00181987	PHASE4	COMPLETED	Concerta in the Treatment of ADHD in Youth and Adults With Bipolar Disorder
NCT00190736	PHASE4	COMPLETED	Efficacy and Safety of Once-Daily Atomoxetine Hydrochloride in Adults With ADHD Over an Extended Period of Time (6 Months)
NCT00190775	PHASE4	COMPLETED	A Randomized, Double-Blind Comparison of Placebo and Atomoxetine Hydrochloride Given Once a Day in Adults With Attention-Deficit/Hyperactivity Disorder (ADHD)
NCT00190879	PHASE4	COMPLETED	Placebo-Controlled Study of Atomoxetine Hydrochloride in the Treatment of Adults With ADHD and Comorbid Social Anxiety Disorder
NCT00190957	PHASE4	COMPLETED	Atomoxetine Treatment of Adults With ADHD and Comorbid Alcohol Abuse
NCT00191035	PHASE4	COMPLETED	Maintenance of Benefit With Atomoxetine Hydrochloride in Adolescents With ADHD
NCT00191048	PHASE4	COMPLETED	Treatment With Atomoxetine Hydrochloride in Children and Adolescents With ADHD
NCT00191633	PHASE4	COMPLETED	Study of Atomoxetine in Children With ADHD to Assess Symptomatic and Functional Outcomes
NCT00191906	PHASE4	COMPLETED	Comparison of Atomoxetine and Placebo in Children With Attention-Deficit/Hyperactivity Disorder (ADHD) and/or Reading Disorder (RD)
NCT00216918	PHASE4	COMPLETED	Neuropsychological Functioning in Children With Attention-Deficit/Hyperactivity Disorder.
NCT00221962	PHASE4	COMPLETED	Study of Aripiprazole (Abilify) in Children With ADHD (Attention Deficit Hyperactivity Disorder)
NCT00223561	PHASE4	COMPLETED	Methylphenidate and Driving Ability in Adult Patients With Attention-Deficit Hyperactivity Disorder
NCT00299234	PHASE4	TERMINATED	Atomoxetine for Children With Acquired Attentional Disorders Following Completion of Chemotherapy for ALL
NCT00302406	PHASE4	COMPLETED	Naturalistic Substitution of Concerta in Adult Subject With ADHD Receiving Immediate Release Methylphenidate
NCT00305370	PHASE4	COMPLETED	Aripiprazole Associated With Methylphenidate in Children and Adolescents With Bipolar Disorder and ADHD
NCT00381758	PHASE4	COMPLETED	The COMACS Study: A Comparison of Methylphenidates in an Analog Classroom Setting
NCT00406354	PHASE4	COMPLETED	Comparison of Atomoxetine Versus Placebo in Children and Adolescents With ADHD and Comorbid ODD in Germany
NCT00434213	PHASE4	COMPLETED	Characterization of Dermal Reactions in Pediatric Patients With ADHD Using DAYTRANA
NCT00468143	PHASE4	COMPLETED	A Within-Subject Cross-Over Comparison Between Immediate Release and Extended Release Adderall
NCT00471354	PHASE4	COMPLETED	A Study for Patients With Attention-Deficit/Hyperactivity Disorder Treated With Atomoxetine
NCT00483106	PHASE4	COMPLETED	Clinical and Pharmacogenetic Study of Attention Deficit With Hyperactivity Disorder (ADHD)
NCT00485849	PHASE4	COMPLETED	A Study of Atomoxetine for Attention Deficit and Hyperactive/Impulsive Behaviour Problems in Children With ASD
NCT00485875	PHASE4	COMPLETED	Safety and Efficacy of Switching From a Stimulant Medication to Atomoxetine in Children and Adolescents With ADHD
NCT00486122	PHASE4	COMPLETED	Evaluation of Continuous Symptom Treatment of ADHD
NCT00500071	PHASE4	COMPLETED	Dose-Optimization Study Evaluating the Efficacy, Safety and Tolerability of Vyvanse (Lisdexamfetamine Dimesylate) in Children Aged 6-12 Diagnosed With ADHD
NCT00506727	PHASE4	COMPLETED	Analog Classroom Study Comparison of ADDERALL XR With STRATTERA in Children Aged 6-12 With ADHD
NCT00510276	PHASE4	COMPLETED	Treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) With Atomoxetine in Young Adults and Its Effects on Functional Outcomes
NCT00517504	PHASE4	COMPLETED	Methylphenidate Study in Young Children With Developmental Disorders
NCT00517647	PHASE4	COMPLETED	Atomoxetine Pilot Study in Preschool Children With ADHD
NCT00518232	PHASE4	COMPLETED	A Study to Determine Effective and Tolerable Titration Scheme for OROS-Methylphenidate in Children With Attention-deficit Hyperactivity Disorder
NCT00530257	PHASE4	COMPLETED	Study of the Effects of Osmotic-Release Oral System (OROS) Methylphenidate (Concerta) on Attention and Memory
NCT00536419	PHASE4	UNKNOWN	Impact of Attention Deficit/Hyperactivity Disorder and Substance Use Disorder on Motorcycle Traffic Accidents
NCT00546910	PHASE4	COMPLETED	Comparison of Atomoxetine Versus Placebo in Children With Attention-Deficit/Hyperactivity Disorder (ADHD)
NCT00552266	PHASE4	UNKNOWN	Methylphenidate in ADHD With Trichotillomania
NCT00564954	PHASE4	COMPLETED	A Study of Dex-methylphenidate Extended Release in Children (6-12 Years) With Attention-Deficit/Hyperactivity Disorder (ADHD)