AARS1

Summary

AARS1 (alanyl-tRNA synthetase 1, HGNC:20) is a protein-coding gene on chromosome 16q22.1, encoding Alanine–tRNA ligase, cytoplasmic (P49588). Catalyzes the attachment of alanine to tRNA(Ala) in a two-step reaction: alanine is first activated by ATP to form Ala-AMP and then transferred to the acceptor end of tRNA(Ala). It is a common-essential gene (DepMap: required in 100.0% of cancer cell lines).

The human alanyl-tRNA synthetase (AARS) belongs to a family of tRNA synthases, of the class II enzymes. Class II tRNA synthases evolved early in evolution and are highly conserved. This is reflected by the fact that 498 of the 968-residue polypeptide human AARS shares 41% identity witht the E.coli protein. tRNA synthases are the enzymes that interpret the RNA code and attach specific aminoacids to the tRNAs that contain the cognate trinucleotide anticodons. They consist of a catalytic domain which interacts with the amino acid acceptor-T psi C helix of the tRNA, and a second domain which interacts with the rest of the tRNA structure.

Source: NCBI Gene 16 — RefSeq curated summary.

At a glance

• Gene–disease (curated): developmental and epileptic encephalopathy, 29 (Definitive, ClinGen) — +5 more curated relationships
• GWAS associations: 3
• Clinical variants (ClinVar): 1,756 total — 68 pathogenic, 28 likely-pathogenic (top 1% of genes corpus-wide)
• GTEx eGene: eQTL in 32 tissues, sQTL in 6 (q < 0.05)
• Phenotypes (HPO): 189
• Cancer dependency (DepMap): dependent in 100.0% of screened cell lines (common-essential)
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.77 (unconstrained)
• MANE Select transcript: NM_001605
• Interaction hub: 2,134 STRING partners (top 6% of genes corpus-wide)

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20
Approved symbol	AARS1
Name	alanyl-tRNA synthetase 1
Location	16q22.1
Locus type	gene with protein product
Status	Approved
Aliases	CMT2N, AlaRS
Ensembl gene	ENSG00000090861
Ensembl biotype	protein_coding
OMIM	601065
Entrez	16

Gene structure

Transcript identifiers

Ensembl transcripts: 80 — 33 protein_coding, 32 nonsense_mediated_decay, 13 retained_intron, 2 protein_coding_CDS_not_defined

MANE Select: ENST00000261772

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1, TSL 2: 3, TSL 3: 1, TSL 5: 2

ENST00000261772, ENST00000564359, ENST00000565361, ENST00000566969, ENST00000567490, ENST00000569790, ENST00000569825, ENST00000674512, ENST00000674652, ENST00000674691, ENST00000674768, ENST00000674811, ENST00000674848, ENST00000674962, ENST00000674963, ENST00000675035, ENST00000675045, ENST00000675120, ENST00000675133, ENST00000675155, ENST00000675270, ENST00000675297, ENST00000675338, ENST00000675371, ENST00000675403, ENST00000675569, ENST00000675588, ENST00000675643, ENST00000675691, ENST00000675751, ENST00000675853, ENST00000675917, ENST00000675953, ENST00000675986, ENST00000676004, ENST00000676040, ENST00000676065, ENST00000676168, ENST00000676209, ENST00000676211, ENST00000676212, ENST00000676247, ENST00000896284, ENST00000896285, ENST00000896286, ENST00000896287, ENST00000896288, ENST00000896289, ENST00000896290, ENST00000896291, ENST00000896292, ENST00000934581, ENST00000934582, ENST00000934583, ENST00000934584, ENST00000934585, ENST00000951922, ENST00000951923, ENST00000951924, ENST00000951925, ENST00000951926, ENST00000951927, ENST00000976913, ENST00001013862, ENST00001013863, ENST00001013865, ENST00001013868, ENST00001013870, ENST00001013871, ENST00001013872, ENST00001067381, ENST00001067382, ENST00001067383, ENST00001067384, ENST00001067385, ENST00001067386, ENST00001067387, ENST00001067388, ENST00001111339, ENST00001135449

RefSeq mRNA: 1 — MANE Select: NM_001605 NM_001605

CCDS: CCDS32474

Canonical transcript exons

ENST00000261772 — 21 exons

Exon	Start	End
ENSE00000579017	70270196	70270340
ENSE00000579020	70267659	70267809
ENSE00000694594	70258033	70258217
ENSE00000694616	70264958	70265102
ENSE00000694625	70268271	70268379
ENSE00000694628	70269618	70269763
ENSE00000694634	70271781	70271972
ENSE00000694646	70276486	70276631
ENSE00000844519	70262346	70262524
ENSE00000844528	70276966	70277154
ENSE00001111982	70282620	70282784
ENSE00001261263	70252298	70252906
ENSE00001316640	70289421	70289506
ENSE00001505580	70253268	70253381
ENSE00001505581	70253714	70253800
ENSE00003552111	70255728	70255836
ENSE00003559520	70261044	70261157
ENSE00003581725	70254621	70254734
ENSE00003583910	70258980	70259186
ENSE00003650916	70265538	70265662
ENSE00003679366	70253919	70254038

Expression profiles

Bgee: expression breadth ubiquitous, 301 present calls, max score 98.32.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 75.9456 / max 424.4070, expressed in 1815 samples.

Highest expression (Bgee): endometrium epithelium, type B pancreatic cell, frontal pole, Brodmann (1909) area 10, islet of Langerhans.

Genetic regulation across tissues (GTEx eQTL / sQTL)

AARS1 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 32 tissues and its splicing (sQTL) in 6 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 38 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Muscle Skeletal	eqtl	3.8e-15	-0.26	16:70357471:A:G
Pituitary	eqtl	5.8e-11	+0.36	16:70251998:A:G
Brain Caudate basal ganglia	eqtl	7.9e-10	+0.22	16:70269677:G:A
Colon Sigmoid	eqtl	5.8e-08	+0.89	16:69890542:T:G
Brain Hypothalamus	eqtl	6.4e-08	+0.21	16:70251998:A:G
Brain Cerebellum	eqtl	2.1e-07	+0.30	16:70251998:A:G
Cells Cultured fibroblasts	eqtl	2.2e-07	+0.12	16:70282008:T:C
Brain Nucleus accumbens basal ganglia	eqtl	1.2e-06	+0.16	16:70207663:G:A
Brain Putamen basal ganglia	eqtl	6.0e-06	+0.19	16:70406656:C:G
Brain Cerebellar Hemisphere	eqtl	9.3e-06	+0.22	16:70251998:A:G
Brain Spinal cord cervical c-1	eqtl	1.8e-05	+0.30	16:70251998:A:G
Brain Cortex	eqtl	1.9e-05	+0.15	16:70269677:G:A
Testis	eqtl	3.3e-05	+0.15	16:70282008:T:C
Esophagus Mucosa	eqtl	4.7e-05	+0.14	16:70282008:T:C
Thyroid	sqtl	6.8e-05	-0.53	16:70231687:T:A
Brain Substantia nigra	eqtl	1.9e-04	+0.29	16:70251998:A:G
Skin Not Sun Exposed Suprapubic	sqtl	3.1e-04	-1.52	16:69769045:G:A
Adipose Subcutaneous	eqtl	3.8e-04	+0.20	16:70135504:C:T
Nerve Tibial	eqtl	6.2e-04	+0.15	16:70116065:G:C
Lung	eqtl	1.2e-03	+0.21	16:70606040:T:C

FANTOM5 promoters

3 alternative TSS:

Promoter ID	TPM avg	Samples expressed
157928	51.8772	1806
157929	23.7673	1807
157927	0.3010	98

Top tissues by expression

showing 100 of 302 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
endometrium epithelium	UBERON:0004811	98.32	gold quality
type B pancreatic cell	CL:0000169	98.15	gold quality
frontal pole	UBERON:0002795	98.01	gold quality
Brodmann (1909) area 10	UBERON:0013541	98.00	gold quality
islet of Langerhans	UBERON:0000006	97.72	gold quality
right frontal lobe	UBERON:0002810	97.66	gold quality
prefrontal cortex	UBERON:0000451	97.63	gold quality
middle frontal gyrus	UBERON:0002702	97.61	gold quality
paraflocculus	UBERON:0005351	97.51	gold quality
Brodmann (1909) area 9	UBERON:0013540	97.35	gold quality
frontal cortex	UBERON:0001870	97.25	gold quality
stromal cell of endometrium	CL:0002255	97.17	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	97.02	gold quality
cingulate cortex	UBERON:0003027	96.99	gold quality
neocortex	UBERON:0001950	96.98	gold quality
cerebellar vermis	UBERON:0004720	96.97	gold quality
anterior cingulate cortex	UBERON:0009835	96.97	gold quality
hypothalamus	UBERON:0001898	96.72	gold quality
right hemisphere of cerebellum	UBERON:0014890	96.71	gold quality
cerebellar cortex	UBERON:0002129	96.70	gold quality
cerebellar hemisphere	UBERON:0002245	96.68	gold quality
olfactory bulb	UBERON:0002264	96.68	gold quality
caudate nucleus	UBERON:0001873	96.67	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	96.66	gold quality
cerebellum	UBERON:0002037	96.63	gold quality
pons	UBERON:0000988	96.62	gold quality
lateral nuclear group of thalamus	UBERON:0002736	96.60	gold quality
parotid gland	UBERON:0001831	96.57	gold quality
putamen	UBERON:0001874	96.57	gold quality
cerebral cortex	UBERON:0000956	96.52	gold quality
nucleus accumbens	UBERON:0001882	96.52	gold quality
spinal cord	UBERON:0002240	96.49	gold quality
right lobe of thyroid gland	UBERON:0001119	96.48	gold quality
telencephalon	UBERON:0001893	96.47	gold quality
Brodmann (1909) area 46	UBERON:0006483	96.39	gold quality
forebrain	UBERON:0001890	96.38	gold quality
central nervous system	UBERON:0001017	96.33	gold quality
brain	UBERON:0000955	96.32	gold quality
left lobe of thyroid gland	UBERON:0001120	96.22	gold quality
postcentral gyrus	UBERON:0002581	96.19	gold quality
parietal lobe	UBERON:0001872	96.16	gold quality
lateral globus pallidus	UBERON:0002476	96.14	gold quality
pancreas	UBERON:0001264	96.13	gold quality
corpus callosum	UBERON:0002336	95.98	gold quality
body of pancreas	UBERON:0001150	95.94	gold quality
substantia nigra	UBERON:0002038	95.91	gold quality
midbrain	UBERON:0001891	95.90	gold quality
thyroid gland	UBERON:0002046	95.88	gold quality
cartilage tissue	UBERON:0002418	95.88	gold quality
superior frontal gyrus	UBERON:0002661	95.85	gold quality
substantia nigra pars compacta	UBERON:0001965	95.81	gold quality
superior vestibular nucleus	UBERON:0007227	95.78	gold quality
amygdala	UBERON:0001876	95.77	gold quality
dorsal plus ventral thalamus	UBERON:0001897	95.75	gold quality
adenohypophysis	UBERON:0002196	95.68	gold quality
inferior vagus X ganglion	UBERON:0005363	95.68	gold quality
smooth muscle tissue	UBERON:0001135	95.63	gold quality
substantia nigra pars reticulata	UBERON:0001966	95.63	gold quality
pituitary gland	UBERON:0000007	95.58	gold quality
pancreatic ductal cell	CL:0002079	95.50	gold quality
right lobe of liver	UBERON:0001114	95.48	gold quality
Ammon’s horn	UBERON:0001954	95.44	gold quality
right adrenal gland	UBERON:0001233	95.33	gold quality
ventral tegmental area	UBERON:0002691	95.33	gold quality
temporal lobe	UBERON:0001871	95.31	gold quality
orbitofrontal cortex	UBERON:0004167	95.29	gold quality
subthalamic nucleus	UBERON:0001906	95.28	gold quality
triceps brachii	UBERON:0001509	95.26	gold quality
gluteal muscle	UBERON:0002000	95.26	gold quality
ventricular zone	UBERON:0003053	95.22	gold quality
lower esophagus muscularis layer	UBERON:0035833	95.10	gold quality
left adrenal gland	UBERON:0001234	95.08	gold quality
lower esophagus	UBERON:0013473	95.07	gold quality
CA1 field of hippocampus	UBERON:0003881	95.03	gold quality
left adrenal gland cortex	UBERON:0035825	95.00	gold quality
right adrenal gland cortex	UBERON:0035827	94.99	gold quality
globus pallidus	UBERON:0001875	94.98	gold quality
body of stomach	UBERON:0001161	94.93	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	94.93	gold quality
adrenal cortex	UBERON:0001235	94.80	gold quality
medulla oblongata	UBERON:0001896	94.79	gold quality
adrenal gland	UBERON:0002369	94.79	gold quality
medial globus pallidus	UBERON:0002477	94.79	gold quality
muscle layer of sigmoid colon	UBERON:0035805	94.75	gold quality
ileal mucosa	UBERON:0000331	94.73	gold quality
upper lobe of left lung	UBERON:0008952	94.73	gold quality
body of uterus	UBERON:0009853	94.67	gold quality
adult organism	UBERON:0007023	94.60	gold quality
occipital lobe	UBERON:0002021	94.59	gold quality
upper lobe of lung	UBERON:0008948	94.58	gold quality
middle temporal gyrus	UBERON:0002771	94.57	gold quality
corpus epididymis	UBERON:0004359	94.54	gold quality
stomach	UBERON:0000945	94.50	gold quality
adult mammalian kidney	UBERON:0000082	94.41	gold quality
entorhinal cortex	UBERON:0002728	94.40	gold quality
cranial nerve II	UBERON:0000941	94.36	gold quality
liver	UBERON:0002107	94.35	gold quality
endocervix	UBERON:0000458	94.21	gold quality
fundus of stomach	UBERON:0001160	94.21	gold quality
tibial nerve	UBERON:0001323	94.21	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	14.56

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Postcentral gyrus	tissue	146.9
Locus coeruleus	tissue	117.3
Pons	tissue	99.5
Thalamus	tissue	99.1
Midbrain	tissue	96.5
Superior colliculi	tissue	94.3
Spinal cord	tissue	91.9
Cerebral cortex	tissue	91.4	medium
Somatosensory cortex	tissue	91.4
Nucleus accumbens	tissue	90.6
Medulla oblongata	tissue	90.2
Substantia nigra	tissue	83.2
Hypothalamus	tissue	79.7
Hippocampus	tissue	78.8	medium
Occipital cortex	tissue	78.5
Periaqueductal gray	tissue	72.6
Pancreas	tissue	71.6	medium
Motor cortex	tissue	71.6
Prefrontal cortex	tissue	71.3
Parathyroid gland	tissue	70.5	low
Hippocampal formation	tissue	68.7
Choroid plexus	tissue	68.1
Retrosplenial and cingulate cortex	tissue	67.8
Entorhinal cortex	tissue	66.8
Temporal cortex	tissue	66.0
Septum	tissue	65.1
Retrosplenial cortex	tissue	63.6
Thyroid gland	tissue	62.3	medium
Liver	tissue	60.8	medium
Ventral forebrain	tissue	58.9
Putamen	tissue	58.5
Frontal cortex	tissue	57.9
Corpus callosum	tissue	57.9
Insular cortex	tissue	55.2
Retina	tissue	55.1
Cerebellum	tissue	55.1	medium
Olfactory bulb	tissue	50.8
Salivary gland	tissue	50.3	medium
Amygdala	tissue	49.9
Caudate putamen	tissue	49.7
Basal ganglia	tissue	47.9	medium
Epididymis	tissue	46.8	low
Skeletal muscle	tissue	45.1	low
Smooth muscle	tissue	44.7	low
Seminal vesicle	tissue	44.5	medium
Kidney	tissue	40.8	medium
Tongue	tissue	37.1
Adrenal gland	tissue	36.3	medium
Adipose tissue	tissue	36.2	low
Heart muscle	tissue	35.4	low
Pituitary gland	tissue	34.8
Cervix	tissue	34.1	medium
Prostate	tissue	34.0	low
Thymus	tissue	34.0
Placenta	tissue	33.5	low
Tonsil	tissue	33.3	medium
Stomach 1	tissue	31.7	medium
Appendix	tissue	31.6	medium
Fallopian tube	tissue	29.8	medium
Lymph node	tissue	28.1	medium

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Pontine nuclei (141.9), Occipital cortex (white matter) (136.5), Nucleus raphe magnus (128.2), Habenula (121.8), Nuclei of the trapezoid body (121.0).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting AARS1 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

23 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-9718	99.94	68.91	918
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-3934-3P	99.76	65.51	1351
HSA-MIR-10394-5P	99.65	66.83	1852
HSA-MIR-1205	99.65	66.76	1826
HSA-MIR-3158-5P	99.65	67.51	1763
HSA-MIR-24-3P	99.59	69.97	1934
HSA-MIR-182-3P	99.57	67.57	825
HSA-MIR-17-3P	99.55	66.77	1311
HSA-MIR-140-5P	99.44	67.20	792
HSA-MIR-4460	99.37	68.52	615
HSA-MIR-5589-5P	98.34	64.82	1148
HSA-MIR-7843-5P	98.12	65.26	1421
HSA-MIR-6842-3P	98.07	66.33	1325
HSA-MIR-5088-5P	97.97	64.28	487
HSA-MIR-4632-5P	97.82	65.38	1470
HSA-MIR-4329	97.68	66.26	1003
HSA-MIR-203B-5P	97.24	68.54	543
HSA-MIR-6718-5P	97.24	68.15	553
HSA-MIR-203A-5P	96.33	65.03	714

Functional genomics

gnomAD constraint: pLI 4.04e-14, LOEUF 0.772, missense Z 1.05 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000261772 — one region, missense o/e 0.97. ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 100.0% of screened cell lines, common-essential.

Most-dependent cell lines (DepMap gene-effect, lower = stronger; ≤ −0.5 shown): SK-N-FI (-3.714), VCaP (-3.363), TOV-112D (-3.356), SNU-886 (-3.294), KPL-1 (-3.177), Panc 08.13 (-3.174), NCI-H226 (-3.162), PA-TU-8988T (-3.103), NCI-H2452 (-3.064), HuH-7 (-3.041), NIH:OVCAR-3 (-3.029), RERF-LC-AI (-2.971), BT-12 (-2.962), NCI-H747 (-2.952), UACC-62 (-2.951).

Literature-anchored findings (GeneRIF, showing 9)

• A packaging model in which the gp16 Coiled coil Motif is implicated in the regulation of packaging initiation and assembly of a supramolecular DNA packaging machine on the viral concatemer. (PMID:16513134)
• The binding of gp16 to the prohead/pRNA to constitute the complete and active packaging motor was confirmed by cryo-electron microscopy three-dimensional reconstruction of the prohead/pRNA/gp16 complex (PMID:18674782)
• direct observation of the intersubunit coordination and step size of a ring ATPase, the double-stranded-DNA packaging motor in the bacteriophage phi29 (PMID:19129763)
• The full mechanochemical cycle of the motor, in which the ATPase is a pentameric-ring of gene product 16, involves two phases-an ATP-loading dwell followed by a translocation burst of four 2.5-base-pair steps triggered by hydrolysis product release. (PMID:19794496)
• Kinetic analysis of phi29 DNA packaging motor provides evidence for coordinated intersubunit ATPase activity of gp16. (PMID:22795974)
• Authors confirmed the stoichiometry of phi29 motor ATPase to be a hexamer and provide data suggesting that the phi29 motor ATPase is a member of the classical hexameric AAA+ superfamily. (PMID:23706809)
• Authors report a revolution rather than rotation mechanism for the bacteriophage phi29 DNA packaging motor. (PMID:23763768)
• Results report that the sequential action of the ATPase ring in the DNA packaging motor of bacteriophage phi29 is regulated by an arginine finger that extends from one ATPase subunit to the adjacent unit to promote noncovalent dimer formation. (PMID:27457616)
• NMR structure of a vestigial nuclease provides insight into the evolution of functional transitions in viral dsDNA packaging motors. (PMID:33089330)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	aars1	ENSDARG00000069142
mus_musculus	Aars1	ENSMUSG00000031960
rattus_norvegicus	Aars1	ENSRNOG00000018404
drosophila_melanogaster	AlaRS	FBGN0027094
caenorhabditis_elegans	aars-2	WBGENE00000197

Paralogs (2): AARS2 (ENSG00000124608), AARSD1 (ENSG00000266967)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:2384560) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 31 distinct phenotype terms.

Mouse phenotype (MP)	Records
Purkinje cell degeneration	2
abnormal myocardial fiber morphology	1
alopecia	1
focal hair loss	1
abnormal head morphology	1
tremors	1
decreased body weight	1
decreased body size	1
ataxia	1
disheveled coat	1
impaired balance	1
abnormal cardiovascular system physiology	1
small heart	1
cardiac fibrosis	1
decreased cardiac output	1
hair follicle degeneration	1
abnormal hair shaft morphology	1
increased lean body mass	1
abnormal sarcoplasmic reticulum morphology	1
abnormal myocardial fiber physiology	1
cardiac interstitial fibrosis	1
abnormal autophagy	1
decreased total body fat amount	1
hair follicle outer root sheath hyperplasia	1
preweaning lethality, complete penetrance	1

+6 more (showing top 25).

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Pongo abelii	Q5RC02	98.9%	Diamond
Mesocricetus auratus	Q8CFX8	96.5%	Diamond
Saccharomyces cerevisiae S288C	P40825	67.8%	Diamond
Candida albicans SC5314	Q5A8K2	67.8%	Diamond
Bombyx mori	P21894	65.7%	Diamond
Aspergillus nidulans FGSC A4	Q5AQL1	62.4%	Diamond
Schizosaccharomyces pombe 972h-	O13914	61.9%	Diamond
Arabidopsis thaliana	P36428	58.5%	Diamond
Dictyostelium discoideum	Q54Y20	51.2%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
EXOSC6	protein-coding	118460
CLEC18C	protein-coding	283971
DDX19B	protein-coding	11269
DDX19A	protein-coding	55308
ST3GAL2	protein-coding	6483
DDX19A-DT	ncRNA	100506083

Protein

Protein identifiers

Alanine–tRNA ligase, cytoplasmic — P49588 (reviewed: P49588)

Alternative names: Alanyl-tRNA synthetase, Protein lactyltransferase AARS1, Renal carcinoma antigen NY-REN-42

All UniProt accessions (18): A0A6Q8PF33, A0A6Q8PF77, A0A6Q8PFK3, A0A6Q8PFY2, A0A6Q8PG28, A0A6Q8PG62, A0A6Q8PGB5, A0A6Q8PGE8, A0A6Q8PGI8, A0A6Q8PGN5, A0A6Q8PGR9, A0A6Q8PH44, A0A6Q8PHJ2, A0A6Q8PHN5, A0A6Q8PHP3, A0A6Q8PHP7, P49588, H3BPK7

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the attachment of alanine to tRNA(Ala) in a two-step reaction: alanine is first activated by ATP to form Ala-AMP and then transferred to the acceptor end of tRNA(Ala). Also edits incorrectly charged tRNA(Ala) via its editing domain. In presence of high levels of lactate, also acts as a protein lactyltransferase that mediates lactylation of lysine residues in target proteins, such as TEAD1, TP53/p53 and YAP1. Protein lactylation takes place in a two-step reaction: lactate is first activated by ATP to form lactate-AMP and then transferred to lysine residues of target proteins. Acts as an inhibitor of TP53/p53 activity by catalyzing lactylation of TP53/p53. Acts as a positive regulator of the Hippo pathway by mediating lactylation of TEAD1 and YAP1.

Subunit / interactions. Monomer. Interacts with ANKRD16; the interaction is direct.

Subcellular location. Cytoplasm. Nucleus.

Post-translational modifications. ISGylated. Methylation at ‘Lys-943’ by METTL21C.

Disease relevance. Charcot-Marie-Tooth disease, axonal, type 2N (CMT2N) [MIM:613287] An axonal form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Neuropathies of the CMT2 group are characterized by signs of axonal degeneration in the absence of obvious myelin alterations, normal or slightly reduced nerve conduction velocities, and progressive distal muscle weakness and atrophy. The disease is caused by variants affecting the gene represented in this entry. Developmental and epileptic encephalopathy 29 (DEE29) [MIM:616339] A form of epileptic encephalopathy, a heterogeneous group of severe early-onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. DEE29 patients manifest severe infantile epileptic encephalopathy, clubfoot, absent deep tendon reflexes, extrapyramidal symptoms, and persistently deficient myelination. The disease is caused by variants affecting the gene represented in this entry. Leukoencephalopathy, hereditary diffuse, with spheroids 2 (HDLS2) [MIM:619661] An autosomal dominant neurodegenerative disorder characterized by progressive cognitive and executive dysfunction, psychiatric disturbances, and neurologic symptoms, such as gait abnormalities, paresis, seizures, and rigidity. Symptom onset is usually in adulthood, although earlier onset has been reported. Some patients have an acute encephalopathic course with severe neurologic decline resulting in early death, whereas other patients have a more protracted and chronic disease course. Neuropathologic examination shows a leukoencephalopathy with axonal spheroids and myelination defects. The disease may be caused by variants affecting the gene represented in this entry. Trichothiodystrophy 8, non-photosensitive (TTD8) [MIM:619691] A form of trichothiodystrophy, a disease characterized by sulfur-deficient brittle hair and multisystem variable abnormalities. The spectrum of clinical features varies from mild disease with only hair involvement to severe disease with cutaneous, neurologic and profound developmental defects. Ichthyosis, intellectual and developmental disabilities, decreased fertility, abnormal characteristics at birth, ocular abnormalities, short stature, and infections are common manifestations. There are both photosensitive and non-photosensitive forms of the disorder. TTD8 is an autosomal recessive, non-photosensitive form characterized by brittle hair and nails, scaly skin, accompanied by failure to thrive, microcephaly, and neuromotor developmental delay. The disease may be caused by variants affecting the gene represented in this entry.

Activity regulation. The protein lactyltransferase activity is inhibited by beta-alanine.

Cofactor. Binds 1 zinc ion per subunit.

Domain organisation. Consists of three domains; the N-terminal catalytic domain, the editing domain and the C-terminal C-Ala domain. The editing domain removes incorrectly charged amino acids, while the C-Ala domain, along with tRNA(Ala), serves as a bridge to cooperatively bring together the editing and aminoacylation centers thus stimulating deacylation of misacylated tRNAs. The C-terminal C-Ala domain (residues 756 to 968) is not required for catalytic activity and can bind DNA (in vitro). The C-terminal C-Ala domain (residues 756 to 968), along with tRNA(Ala), serves as a bridge to cooperatively bring together the editing and aminoacylation centers thus stimulating deacylation of misacylated tRNAs. The human domain can be used in vitro to replace the corresponding domain in E.coli.

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

Isoforms (2)

UniProt ID	Names	Canonical?
P49588-1	1	yes
P49588-2	2

RefSeq proteins (1): NP_001596* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002318	Ala-tRNA-lgiase_IIc	Family
IPR003156	DHHA1_dom	Domain
IPR009000	Transl_B-barrel_sf	Homologous_superfamily
IPR012947	tRNA_SAD	Domain
IPR018162	Ala-tRNA-ligase_IIc_anticod-bd	Homologous_superfamily
IPR018163	Thr/Ala-tRNA-synth_IIc_edit	Homologous_superfamily
IPR018164	Ala-tRNA-synth_IIc_N	Domain
IPR018165	Ala-tRNA-synth_IIc_core	Domain
IPR023033	Ala_tRNA_ligase_euk/bac	Family
IPR045864	aa-tRNA-synth_II/BPL/LPL	Homologous_superfamily
IPR050058

Pfam: PF01411, PF02272, PF07973

Catalyzed reactions (Rhea)

• tRNA(Ala) + L-alanine + ATP = L-alanyl-tRNA(Ala) + AMP + diphosphate (RHEA:12540)
• (S)-lactate + ATP + H(+) = (S)-lactoyl-AMP + diphosphate (RHEA:80271)
• (S)-lactoyl-AMP + L-lysyl-[protein] = N(6)-[(S)-lactoyl]-L-lysyl-[protein] + AMP + 2 H(+) (RHEA:80275)

UniProt features (118 total): helix 37, sequence variant 16, strand 15, mutagenesis site 14, binding site 11, modified residue 10, turn 7, sequence conflict 4, splice variant 2, chain 1, short sequence motif 1

Structure

Experimental structures (PDB)

10 structures by resolution:

PDB	Title	Method	Resolution (Å)
4XEM	Crystal Structure of wild type human AlaRS catalytic domain	X-RAY DIFFRACTION	1.28
4XEO	Crystal Structure of human AlaRS catalytic domain with R329H mutation	X-RAY DIFFRACTION	1.38
9X2K	AARS1 bound with XY353 and Gly-SA	X-RAY DIFFRACTION	1.71
9X2I	AARS1 bound with XY353-1	X-RAY DIFFRACTION	1.86
9X2H	AARS1 bound with XY353	X-RAY DIFFRACTION	1.9
9X2J	AARS1 bound with Gly-SA.	X-RAY DIFFRACTION	1.93
5T76	A fragment of a human tRNA synthetase	X-RAY DIFFRACTION	2
5V59	Crystal structure of catalytic fragment of human AlaRS in complex with Aze-SA	X-RAY DIFFRACTION	2.03
5T5S	A fragment of a human tRNA synthetase	X-RAY DIFFRACTION	2.2
5KNN	Evolutionary gain of alanine mischarging to non-cognate tRNAs with a G4:U69 base pair	X-RAY DIFFRACTION	2.68

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P49588-F1	90.66	0.70

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Ligase, Metabolic proteins, Predicted intracellular proteins, Plasma proteins, Disease related genes, Potential drug targets, Human disease related genes, Epilepsy, Essential proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): cytosol

Antibody reliability (HPA): IH supported · IF supported

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 (11)

Position	Role
609	Zn(2+)
723	Zn(2+)
727	Zn(2+)
77	ATP
95	ATP
176	ATP
214–216	ATP
216	L-alanine
239	L-alanine
243	ATP
605	Zn(2+)

Post-translational modifications (10)

Type	Positions
N-acetylmethionine	1
Phosphoserine	3, 8, 399, 555
N6-acetyllysine	19, 876
N6,n6,n6-trimethyllysine	943
N6,n6-dimethyllysine	943
N6-methyllysine	943

Mutagenesis-validated functional residues (14)

Position	Phenotype
46	in mutant 5a; abolished binding to lactate and protein lactylation; when associated with a-77, a-216 and 239-a–a-241.
77	in mutant 5a; abolished binding to lactate and protein lactylation; when associated with a-46, a-216 and 239-a–a-241. in mutant 5m …
100	in mutant 5m; abolished binding to lactate and protein lactylation; when associated with a-77, e-176, d-218 and a-239.
176	in atp-binding mutant; abolished ability to mediate protein lactylation; when associated with a-77 and a-243.
176	in mutant 5m; abolished binding to lactate and protein lactylation; when associated with a-77, a-100, d-218 and a-239.
216	in mutant 5a; abolished binding to lactate and protein lactylation; when associated with a-46, a-77 and 239-a–a-241.
218	in mutant 5m; abolished binding to lactate and protein lactylation; when associated with a-77, a-100, e-176 and a-239.
239–241	in mutant 5a; abolished binding to lactate and protein lactylation; when associated with a-46, a-77 and a-216.
239	in mutant 5m; abolished binding to lactate and protein lactylation; when associated with a-77, a-100, e-176 and d-218.
243	in atp-binding mutant; abolished ability to mediate protein lactylation; when associated with a-77 and a-176.
448	decreases misincorporation of cys instead of ala.
723	decreases editing activity.
750–763	abolished nuclear translocation in presence of lactate.
943	abrogates mettl21c methylation of aars1.

Function

Pathways and Gene Ontology

Reactome pathways

1 curated (TAS) of 4; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

4 pathways:

ID	Pathway	Evidence
R-HSA-379716	Cytosolic tRNA aminoacylation	curated
R-HSA-392499	Metabolism of proteins	—
R-HSA-72766	Translation	—
R-HSA-379724	tRNA Aminoacylation	—

MSigDB gene sets: 643 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_DN, GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_DN, GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_DN, GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_DN, GOBP_CYTOPLASMIC_TRANSLATION, GOBP_HINDBRAIN_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_NEURON_APOPTOTIC_PROCESS, GOBP_METENCEPHALON_DEVELOPMENT, GOBP_AMINO_ACID_ACTIVATION, chr16q22, BHATI_G2M_ARREST_BY_2METHOXYESTRADIOL_DN, GOBP_TRNA_METABOLIC_PROCESS, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, HSIAO_HOUSEKEEPING_GENES, GOBP_REGULATION_OF_TRANSLATIONAL_ELONGATION

GO Biological Process (10): tRNA modification (GO:0006400), tRNA aminoacylation for protein translation (GO:0006418), alanyl-tRNA aminoacylation (GO:0006419), tRNA processing (GO:0008033), positive regulation of hippo signaling (GO:0035332), regulation of cytoplasmic translational fidelity (GO:0140018), negative regulation of signal transduction by p53 class mediator (GO:1901797), translation (GO:0006412), tRNA aminoacylation (GO:0043039), aminoacyl-tRNA metabolism involved in translational fidelity (GO:0106074)

GO Molecular Function (14): tRNA binding (GO:0000049), aminoacyl-tRNA deacylase activity (GO:0002161), Ser-tRNA(Ala) deacylase activity (GO:0002196), alanine-tRNA ligase activity (GO:0004813), ATP binding (GO:0005524), zinc ion binding (GO:0008270), amino acid binding (GO:0016597), peptide lactyltransferase (ATP-dependent) activity (GO:0141207), nucleotide binding (GO:0000166), nucleic acid binding (GO:0003676), RNA binding (GO:0003723), aminoacyl-tRNA ligase activity (GO:0004812), ligase activity (GO:0016874), metal ion binding (GO:0046872)

GO Cellular Component (5): nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829), membrane (GO:0016020), extracellular exosome (GO:0070062)

Reactome top-level categories

3 top-level categories:

Category	Pathways
tRNA Aminoacylation	1
Translation	1
Metabolism of proteins	1

GO top-level categories

48 GO namespaces:

Category	Terms
tRNA metabolic process	3
cellular anatomical structure	3
regulation of translational fidelity	2
catalytic activity, acting on a tRNA	2
binding	2
tRNA processing	1
RNA modification	1
translation	1
tRNA aminoacylation	1
tRNA aminoacylation for protein translation	1
RNA processing	1
hippo signaling	1
regulation of hippo signaling	1
positive regulation of intracellular signal transduction	1
regulation of cytoplasmic translational elongation	1
signal transduction by p53 class mediator	1
regulation of signal transduction by p53 class mediator	1
negative regulation of intracellular signal transduction	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
amino acid activation	1
RNA binding	1
carboxylic ester hydrolase activity	1
aminoacyl-tRNA metabolism involved in translational fidelity	1
deacylase activity	1
aminoacyl-tRNA deacylase activity	1
aminoacyl-tRNA ligase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
anion binding	1
transition metal ion binding	1
ligase activity, forming phosphoric ester bonds	1
catalytic activity, acting on a protein	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
nucleic acid binding	1
ligase activity, forming carbon-oxygen bonds	1
catalytic activity	1
cation binding	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cytoplasm	1
extracellular vesicle	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 11 of 29 annotations. The rest are phylogenetic / computational / electronic (IEA).

11 experimentally-supported GO terms:

GO term	NS	Evidence
alanyl-tRNA aminoacylation	BP	direct assay
negative regulation of signal transduction by p53 class mediator	BP	direct assay
positive regulation of hippo signaling	BP	direct assay
cytoplasm	CC	direct assay
cytosol	CC	direct assay
extracellular exosome	CC	high-throughput assay
membrane	CC	high-throughput assay
nucleus	CC	direct assay
alanine-tRNA ligase activity	MF	direct assay
aminoacyl-tRNA deacylase activity	MF	direct assay
peptide lactyltransferase (ATP-dependent) activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 2,134 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AARS1	YARS1	P54577	982
AARS1	KARS1	Q15046	978
AARS1	DARS1	P14868	922
AARS1	YARS2	Q9Y2Z4	913
AARS1	TARS3	A2RTX5	897
AARS1	TARS1	P26639	897
AARS1	TARS2	Q9BW92	897
AARS1	IARS2	Q9NSE4	895
AARS1	IARS1	P41252	879
AARS1	LARS1	Q9P2J5	871
AARS1	ADAT1	Q9BUB4	858
AARS1	C9J5N1	C9J5N1	854
AARS1	AARSD1	Q9BTE6	854
AARS1	LARS2	Q15031	850
AARS1	MARS1	P56192	840

IntAct

Human interaction partners of AARS1 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

10 partners by confidence:

Partner	Interaction type	MIscore	Records
SAP18	physical association	0.400	1
TIMM44	physical association	0.400	1
YWHAZ	physical association	0.400	1
AURKB	physical association	0.000	1
DISC1	physical association	0.000	1
ETS1	physical association	0.000	1
HUNK	physical association	0.000	1
MEF2C	physical association	0.000	1
MICU1	physical association	0.000	1
RIN3	physical association	0.000	1

SIGNOR signaling

7 signaling interactions:

A	Effect	B	Mechanism
ATF4	“up-regulates quantity by expression”	AARS1	“transcriptional regulation”
AARS1	“down-regulates quantity”	tRNA(Ala)	“chemical modification”
AARS1	“down-regulates quantity”	alanine	“chemical modification”
AARS1	“up-regulates quantity”	Ala-tRNA(Ala)	“chemical modification”
AARS1	“down-regulates quantity”	ATP(4-)	“chemical modification”
AARS1	“up-regulates quantity”	diphosphate(3-)	“chemical modification”
AARS1	“up-regulates quantity”	AMP	“chemical modification”

Disease & clinical

Genetic variants

Variant evidence for AARS1: 1,756 ClinVar records (96 pathogenic / likely pathogenic); 3 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

1,756 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	68
Likely pathogenic	28
Uncertain significance	867
Likely benign	605
Benign	43

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 96 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
1682338	NM_001605.3(AARS1):c.37C>T (p.Arg13Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
651906	NM_001605.3(AARS1):c.304G>C (p.Gly102Arg)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	3
422259	NM_001605.3(AARS1):c.985C>T (p.Arg329Cys)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	2
1323797	NM_001605.3(AARS1):c.1009G>A (p.Glu337Lys)	Pathogenic	criteria provided, single submitter	2
412289	NM_001605.3(AARS1):c.2017del (p.Leu673fs)	Pathogenic	criteria provided, single submitter	1
577403	NM_001605.3(AARS1):c.1618_1619dup (p.Gln541fs)	Pathogenic	criteria provided, single submitter	1
639888	NM_001605.3(AARS1):c.1967delinsAGGTGATTGAGG (p.Ala656fs)	Pathogenic	criteria provided, single submitter	1
648377	NM_001605.3(AARS1):c.1998_1999del (p.Thr668fs)	Pathogenic	criteria provided, single submitter	1
652115	NM_001605.3(AARS1):c.111dup (p.Thr38fs)	Pathogenic	criteria provided, single submitter	1
861615	NM_001605.3(AARS1):c.962+1del	Pathogenic	criteria provided, single submitter	1
937659	NM_001605.3(AARS1):c.1679_1680del (p.Glu560fs)	Pathogenic	criteria provided, single submitter	1
1037702	NM_001605.3(AARS1):c.651del (p.Val218fs)	Pathogenic	criteria provided, single submitter	1
1164091	NM_001605.3(AARS1):c.296A>G (p.Glu99Gly)	Pathogenic	criteria provided, single submitter	1
1164093	NM_001605.3(AARS1):c.562_563inv (p.Ser188Leu)	Pathogenic	criteria provided, single submitter	1
1323796	NM_001605.3(AARS1):c.11_15del (p.Thr4fs)	Pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

Explore AARS1’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 34 predictions of 1,899):

Position(s)	Effect	Δscore	Sites
16:70252907–70252908	acceptor_loss	1.0000	6
16:70253243	donor_gain	1.0000
16:70253266–70253267	donor_loss	1.0000	5
16:70253382–70253383	acceptor_loss	1.0000	4
16:70253718	donor_gain	1.0000
16:70253801–70253802	acceptor_loss	1.0000	3
16:70253917–70253918	donor_loss	1.0000	4
16:70254039–70254040	acceptor_loss	1.0000	5
16:70254046	acceptor_gain	1.0000
16:70254619–70254620	donor_loss	1.0000	4

AlphaMissense

2,787 missense substitutions predicted likely pathogenic (of 6,371 scored), across 664 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M100	9	0.998	1.000
M178	9	0.983	0.997
M46	9	0.970	0.996
M602	9	0.867	0.962
D84	8	1.000	1.000
H94	8	0.999	1.000
F98	8	0.998	1.000
N216	8	0.998	0.999
H605	8	0.998	0.999
H82	8	0.997	0.999
D239	8	0.997	0.999
D300	8	0.997	0.999
D91	8	0.996	0.999
H301	8	0.996	0.998
H609	8	0.996	0.999
F41	8	0.994	1.000
D637	8	0.994	0.998
D423	8	0.993	0.997
D544	8	0.993	0.998
D193	8	0.990	0.996

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

2 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	9.29e-06
Breast Invasive Carcinoma (TCGA)	unfavorable	0.000791

Disease associations

OMIM: gene MIM:601065 | disease phenotypes: MIM:616339, MIM:619661, MIM:221820, MIM:613287, MIM:619691, MIM:619649, MIM:118220

GenCC curated gene-disease

5 curated gene-disease records:

Disease	Classification	Inheritance	Records
Charcot-Marie-Tooth disease axonal type 2N	Definitive	Autosomal dominant	4
undetermined early-onset epileptic encephalopathy	Definitive	Autosomal recessive	2
developmental and epileptic encephalopathy, 29	Strong	Autosomal recessive	3
trichothiodystrophy 8, nonphotosensitive	Moderate	Autosomal recessive	3
leukoencephalopathy, hereditary diffuse, with spheroids 2	Moderate	Autosomal dominant

ClinGen Gene-Disease Validity

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

3 validity classifications:

Disease	Classification	Inheritance
AARS1-related leukoencephalopathy	Limited	AD
developmental and epileptic encephalopathy, 29	Definitive	AR
Charcot-Marie-Tooth disease axonal type 2N	Definitive	AD

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (16 panels, 12 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

16 panels:

Panel	Rating
DDG2P	green
Early onset or syndromic epilepsy	green
Hereditary neuropathy	green
Hereditary neuropathy or pain disorder	green
Hypotonic infant	green
Intellectual disability	green
Leukodystrophy, adult onset	green
Leukodystrophy, childhood onset	green
Paediatric disorders	green
Severe microcephaly	green
Unexplained death in infancy and sudden unexplained death in childhood	green
White matter disorders and cerebral calcification - childhood onset	green
Adult-onset neurological disorders	amber
Fetal anomalies	amber
Hereditary ataxia, adult onset	amber
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome	amber

Mondo (9): Charcot-Marie-Tooth disease type 2 (MONDO:0018993), developmental and epileptic encephalopathy, 29 (MONDO:0014593), leukoencephalopathy, hereditary diffuse, with spheroids 2 (MONDO:0030634), leukoencephalopathy, hereditary diffuse, with spheroids (MONDO:0030796), Charcot-Marie-Tooth disease axonal type 2N (MONDO:0013212), trichothiodystrophy 8, nonphotosensitive (MONDO:0030517), chromosome 16q12 duplication syndrome (MONDO:0859210), Charcot-Marie-Tooth disease (MONDO:0015626), undetermined early-onset epileptic encephalopathy (MONDO:0018614)

Orphanet (5): Autosomal dominant Charcot-Marie-Tooth disease type 2 (Orphanet:64746), Non-specific early-onset epileptic encephalopathy (Orphanet:442835), Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (Orphanet:313808), Autosomal dominant Charcot-Marie-Tooth disease type 2N (Orphanet:228174), Charcot-Marie-Tooth disease/Hereditary motor and sensory neuropathy (Orphanet:166)

HPO phenotypes

showing 60 of 189 phenotypes (HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000133	Gonadal dysgenesis
HP:0000219	Thin upper lip vermilion
HP:0000252	Microcephaly
HP:0000278	Retrognathia
HP:0000280	Coarse facial features
HP:0000286	Epicanthus
HP:0000316	Hypertelorism
HP:0000320	Bird-like facies
HP:0000343	Long philtrum
HP:0000348	High forehead
HP:0000407	Sensorineural hearing impairment
HP:0000411	Protruding ear
HP:0000448	Prominent nose
HP:0000482	Microcornea
HP:0000483	Astigmatism
HP:0000486	Strabismus
HP:0000494	Downslanted palpebral fissures
HP:0000504	Abnormality of vision
HP:0000508	Ptosis
HP:0000509	Conjunctivitis
HP:0000519	Developmental cataract
HP:0000545	Myopia
HP:0000546	Retinal degeneration
HP:0000565	Esotropia
HP:0000601	Hypotelorism
HP:0000608	Macular degeneration
HP:0000613	Photophobia
HP:0000639	Nystagmus
HP:0000643	Blepharospasm
HP:0000648	Optic atrophy
HP:0000656	Ectropion
HP:0000668	Hypodontia
HP:0000670	Carious teeth
HP:0000708	Atypical behavior
HP:0000717	Autism
HP:0000726	Dementia
HP:0000750	Delayed speech and language development
HP:0000751	Personality changes
HP:0000938	Osteopenia
HP:0000958	Dry skin
HP:0000964	Eczematoid dermatitis
HP:0000973	Cutis laxa
HP:0000992	Cutaneous photosensitivity
HP:0001097	Keratoconjunctivitis sicca
HP:0001197	Abnormality of prenatal development or birth
HP:0001217	Clubbing
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001264	Spastic diplegia
HP:0001265	Hyporeflexia
HP:0001268	Mental deterioration
HP:0001273	Abnormal corpus callosum morphology
HP:0001276	Hypertonia

GWAS associations

3 associations:

Study	Trait	p-value
GCST010703_143	Brain morphology (MOSTest)	2e-40
GCST010988_151	Adult body size	6e-14
GCST010725_22	Malaria	6e-7

EFO canonical traits (from GWAS)

1 canonical traits:

EFO ID	Trait name
EFO:0004346	neuroimaging measurement

MeSH disease descriptors

2 disease descriptors:

Descriptor	Name	Tree numbers
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
C567653	Charcot-Marie-Tooth Disease, Axonal, Type 2n *(supp.)*

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3574 (SINGLE PROTEIN)

PharmGKB: 1 entry (CPIC guideline: no)

Binding affinities (BindingDB)

1 measured of 6 human assays (7 total across all organisms); most potent 1 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CHEMBL5653589	KD	1440 nM

ChEMBL bioactivities

2 potent at pChembl≥5 of 4 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.43	Kd	3.729	nM	CHEMBL3752910
8.43	ED50	3.729	nM	CHEMBL3752910

PubChem BioAssay actives

1 with measured affinity, of 9 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147765: Binding affinity to human AARS incubated for 45 mins by Kinobead based pull down assay	kd	0.0037	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Cyclosporine	increases expression	7
bisphenol A	affects expression, decreases expression, increases expression	6
Tunicamycin	increases expression	6
Cadmium Chloride	decreases reaction, increases abundance, increases palmitoylation, affects localization, decreases expression (+1 more)	5
sodium arsenite	decreases expression, increases expression	4
Benzo(a)pyrene	affects methylation, decreases expression	3
Cisplatin	affects reaction, decreases expression, affects expression	3
perfluorooctane sulfonic acid	increases expression	2
entinostat	increases expression, affects cotreatment	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment, decreases expression	2
2,2’,4,4’-tetrabromodiphenyl ether	increases expression, decreases expression	2
Cadmium	decreases reaction, increases abundance, increases palmitoylation, increases expression	2
Smoke	decreases expression	2
GSK-J4	decreases expression	1
FR900359	increases phosphorylation	1
bisphenol F	increases expression	1
chloroacetaldehyde	decreases expression	1
triphenyl phosphate	affects expression	1
deoxynivalenol	decreases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, increases expression	1
arsenite	affects binding, increases reaction	1
methylparaben	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
cobaltous chloride	decreases expression	1
2-bromopalmitate	increases abundance, increases palmitoylation, decreases reaction	1
perfluorooctanoic acid	increases expression	1
ochratoxin A	decreases expression	1
N,N,N’,N’-tetrakis(2-pyridylmethyl)ethylenediamine	decreases expression	1
brequinar	increases expression	1
di-n-butylphosphoric acid	affects expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5650807	Binding	Binding affinity to human AARS 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)

Via MONDO — disease-level, not drug-specific.

showing 60 of 240 trials:

NCT	Phase	Status	Title
NCT04564430	Phase 4	UNKNOWN	Clonidine for Tourniquet-related Pain in Children
NCT04766684	Phase 4	COMPLETED	Clubfoot Tenotomy Trial
NCT00380965	Phase 4	COMPLETED	Evaluation of the Efficacy of Cesamet™ for the Treatment of Pain in Patients With Chemotherapy-Induced Neuropathy
NCT00487981	Phase 4	TERMINATED	Spinal Cord Stimulation for Painful Diabetic Neuropathy
NCT00904202	Phase 4	COMPLETED	A Study Of Lidocaine Patch 5% Alone, Gabapentin Alone, And Lidocaine Patch 5% And Gabapentin In Combination For The Relief Of Pain In Patients With Diverse Peripheral Neuropathic Pain Conditions
NCT01192113	Phase 4	COMPLETED	Safety and Efficacy of Mecobalamin Injection in Peripheral Neuropathies Patients (Study JGAZSY091109)
NCT01373983	Phase 4	COMPLETED	Intrathecal Bolus Doses of Ziconotide
NCT01458015	Phase 4	TERMINATED	Tapentadol Versus Oxycodone - a Mechanism-based Treatment Approach in Neuropathic Pain
NCT02074267	Phase 4	COMPLETED	Clinical Study for Assessment of the Efficacy of Gabapentin (Carbatin and Neurontin) in Patients With Neuropathy Pain
NCT02372149	Phase 4	UNKNOWN	IVIg for Demyelination in Diabetes Mellitus
NCT02670161	Phase 4	ENROLLING_BY_INVITATION	Quality Improvement and Practice Based Research in Neurology Using the EMR
NCT07022938	Phase 4	COMPLETED	Nutritional Supplement for Treating Chemotherapy Induced Neuropathy
NCT07025005	Phase 4	RECRUITING	Fenofibrate Role in the Prophylaxis From Peripheral Neuropathy Induced by Bortezomib, Lenalidomide and Dexamethasone (VRd) Protocol in the Treatment of Patients With Multiple Myeloma (MM)
NCT04762758	Phase 3	UNKNOWN	Phase III Trial Assessing the Efficacy and Safety of PXT3003 in CMT1A Patients
NCT03414970	Phase 3	ACTIVE_NOT_RECRUITING	Hypofractionated Radiation Therapy After Mastectomy in Preventing Recurrence in Patients With Stage IIa-IIIa Breast Cancer
NCT00058071	Phase 3	COMPLETED	Amifostine in Treating Peripheral Neuropathy in Patients Who Have Received Chemotherapy for Cancer
NCT00125268	Phase 3	TERMINATED	Near Infrared Light for the Treatment of Painful Peripheral Neuropathy
NCT00195013	Phase 3	COMPLETED	Randomized Placebo-Controlled Trial of Glutamine for Breast Cancer Patients With Peripheral Neuropathy
NCT00232141	Phase 3	COMPLETED	Study of Pregabalin Versus Placebo in the Treatment of Nerve Pain Associated With HIV Neuropathy
NCT00264875	Phase 3	COMPLETED	Open Label Safety And Efficacy Study Of Pregabalin In Subjects With Nerve Pain Asociated With Human Immunodeficiency Virus (HIV) Neuropathy
NCT00369564	Phase 3	COMPLETED	Glutamic Acid in Reducing Nerve Damage Caused by Vincristine in Young Patients With Cancer
NCT00471445	Phase 3	COMPLETED	Topical Amitriptyline and Ketamine Cream in Treating Peripheral Neuropathy Caused by Chemotherapy in Cancer Patients
NCT00489411	Phase 3	COMPLETED	Duloxetine in Treating Peripheral Neuropathy Caused by Chemotherapy in Patients With Cancer
NCT00710554	Phase 3	COMPLETED	A Study of Sativex® for Pain Relief of Peripheral Neuropathic Pain, Associated With Allodynia
NCT00711880	Phase 3	COMPLETED	A Study of Sativex® for Relief of Peripheral Neuropathic Pain Associated With Allodynia.
NCT00713323	Phase 3	COMPLETED	A Study to Compare the Safety and Tolerability of Sativex® in Patients With Neuropathic Pain.
NCT00713817	Phase 3	COMPLETED	A Study to Determine the Maintenance of Effect After Long-term Treatment of Sativex® in Subjects With Neuropathic Pain
NCT00775645	Phase 3	COMPLETED	S0715: Acetyl-L-Carnitine in Preventing Neuropathy in Women With Stage I, II, or IIIA Breast Cancer Undergoing Chemo
NCT00872352	Phase 3	UNKNOWN	Evaluation of Bortezomib Induced Peripheral Neuropathy of Multiple Myeloma (MM) Patients
NCT00998738	Phase 3	TERMINATED	Calcium and Magnesium in Preventing Peripheral Neuropathy Caused by Ixabepilone in Patients With Breast Cancer
NCT01049217	Phase 3	TERMINATED	Pregabalin Versus Placebo In The Treatment Of Neuropathic Pain Associated With HIV Neuropathy
NCT01099449	Phase 3	COMPLETED	Calcium Gluconate and Magnesium Sulfate in Preventing Neurotoxicity in Patients With Colon Cancer or Rectal Cancer Receiving Oxaliplatin-Based Combination Chemotherapy
NCT01288937	Phase 3	TERMINATED	A Placebo Controlled, Randomized, Double Blind Trial of Milnacipran for the Treatment of Idiopathic Neuropathy Pain
NCT01492920	Phase 3	WITHDRAWN	Acetyl-L-Carnitine Hydrochloride in Preventing Peripheral Neuropathy in Patients With Recurrent Ovarian Epithelial Cancer, Primary Peritoneal Cavity Cancer, or Fallopian Tube Cancer Undergoing Chemotherapy
NCT01775449	Phase 3	COMPLETED	Prevention of Oxaliplatin-induced Neuropathic Pain by a Specific Diet
NCT02024191	Phase 3	UNKNOWN	The Role of Glutamine for Preventing Oxaliplatin-Induced Peripheral Neuropathy
NCT02217267	Phase 3	COMPLETED	Long Term Outcome After Serial Lidocaine Infusion in Peripheral Neuropathic Pain
NCT02294149	Phase 3	UNKNOWN	Vit D3 and Omega 3 in Chemo Induced Neuropathy
NCT02311907	Phase 3	COMPLETED	Glutathione in Preventing Peripheral Neuropathy Caused by Paclitaxel and Carboplatin in Patients With Ovarian Cancer, Fallopian Tube Cancer, and/or Primary Peritoneal Cancer
NCT06071936	Phase 3	UNKNOWN	Efficacy and Tolerability of AP707 in Patients With Chronic Pain Due to Traumatic or Post-operative Peripheral Neuropathy
NCT06071975	Phase 3	UNKNOWN	Long Term Efficacy and Tolerability of AP707 in Patients With Chronic Pain Due to Diabetic Polyneuropathy
NCT06071988	Phase 3	UNKNOWN	Long Term Efficacy and Tolerability of AP707 in Patients With Chronic Pain Due to Traumatic or Post-operative Peripheral Neuropathy
NCT06072573	Phase 3	UNKNOWN	Efficacy and Tolerability of AP707 in Patients With Chronic Pain Due to Diabetic Polyneuropathy
NCT07287592	Phase 3	NOT_YET_RECRUITING	Glutamine for the Prophylaxis of Vincristine-induced Neuropathy in Children and Adolescents With Cancer.
NCT00271635	Phase 2	COMPLETED	Ascorbic Acid Treatment in CMT1A Trial (AATIC)
NCT01401257	Phase 2	COMPLETED	Phase II, Randomized, Placebo-controlled Trial in Patients With Charcot-marie-tooth Disease Type 1A
NCT02561702	Phase 2	COMPLETED	Mexiletine for Muscle Cramps in Charcot Marie Tooth Disease
NCT02967679	Phase 2	COMPLETED	SERENDEM : MD1003 in Patients Suffering From Demyelinating Neuropathies, an Open Label Pilot Study
NCT03124459	Phase 2	TERMINATED	Study of ACE-083 in Patients With Charcot-Marie-Tooth Disease
NCT03254199	Phase 2	TERMINATED	A Study to Assess the Safety and Effectiveness of FLX-787 in Subjects With Charcot-Marie-Tooth Disease Experiencing Muscle Cramps.
NCT03943290	Phase 2	TERMINATED	Extension Study to Evaluate the Long-Term Effects of ACE-083 in Patients With Facioscapulohumeral Muscular Dystrophy (FSHD) and Charcot-Marie Tooth (CMT) Disease Types 1 and X (CMT1 and CMTX)
NCT05777226	Phase 2	UNKNOWN	Research of SORD-CMT Natural History and Epalrestat Treatment
NCT06482437	Phase 2	COMPLETED	Safety and Efficacy of NMD670 in Adult Patients With Type 1 and Type 2 Charcot-Marie-Tooth Disease
NCT00461344	Phase 2	TERMINATED	Docetaxel + Doxorubicin as Neoadjuvant Chemotherapy in Patients With Breast Cancer
NCT07499999	Phase 2	NOT_YET_RECRUITING	Randomized Double-Blind Phase II Trial of Baby Exemestane Versus Baby Tamoxifen in Post-Menopausal Women at High Risk for Breast Cancer
NCT00006072	Phase 2	UNKNOWN	A Study of Rituxan in the Treatment of Polyneuropathies Associated With Serum IgM Autoantibodies
NCT00365768	Phase 2	COMPLETED	Glutamine in Treating Neuropathy Caused by Vincristine in Young Patients With Lymphoma, Leukemia, or Solid Tumors
NCT00475904	Phase 2	COMPLETED	A Comparison of EpiCept™ NP-1 Topical Cream vs. Oral Gabapentin in Postherpetic Neuralgia (PHN)
NCT00528593	Phase 2	WITHDRAWN	Epoetin Alfa for HIV-Associated Neuropathy Trial
NCT00603265	Phase 2	COMPLETED	Safety and Efficacy Study of ADL5859 in Participants With Neuropathic Pain Associated With Diabetic Peripheral Neuropathy

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for AARS1 across ~30M SureChEMBL compounds — explore on Sugi Predict.