AARS2

Summary

AARS2 (alanyl-tRNA synthetase 2, mitochondrial, HGNC:21022) is a protein-coding gene on chromosome 6p21.1, encoding Alanine–tRNA ligase, mitochondrial (Q5JTZ9). 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 selective cancer dependency (DepMap: 57.3% of cell lines).

The protein encoded by this gene belongs to the class-II aminoacyl-tRNA synthetase family. Aminoacyl-tRNA synthetases play critical roles in mRNA translation by charging tRNAs with their cognate amino acids. The encoded protein is a mitochondrial enzyme that specifically aminoacylates alanyl-tRNA. Mutations in this gene are a cause of combined oxidative phosphorylation deficiency 8.

Source: NCBI Gene 57505 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Definitive, ClinGen) — +4 more curated relationships
• Clinical variants (ClinVar): 724 total — 37 pathogenic, 31 likely-pathogenic
• Phenotypes (HPO): 52
• Cancer dependency (DepMap): dependent in 57.3% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_020745

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21022
Approved symbol	AARS2
Name	alanyl-tRNA synthetase 2, mitochondrial
Location	6p21.1
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1270, bA444E17.1
Ensembl gene	ENSG00000124608
Ensembl biotype	protein_coding
OMIM	612035
Entrez	57505

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 9 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000244571, ENST00000491573, ENST00000856735, ENST00000856736, ENST00000932746, ENST00000965662, ENST00000965663, ENST00000965664, ENST00000965665, ENST00000965666

RefSeq mRNA: 1 — MANE Select: NM_020745 NM_020745

CCDS: CCDS34464

Canonical transcript exons

ENST00000244571 — 22 exons

Exon	Start	End
ENSE00000850315	44304181	44304321
ENSE00000850316	44304420	44304533
ENSE00000850318	44305054	44305198
ENSE00001140133	44301156	44301266
ENSE00001140140	44301381	44301464
ENSE00001140145	44302060	44302170
ENSE00001140148	44302391	44302513
ENSE00001140152	44302802	44302910
ENSE00001140161	44303066	44303175
ENSE00001140170	44303286	44303423
ENSE00001140194	44304645	44304817
ENSE00001140207	44305653	44305786
ENSE00001140215	44306280	44306391
ENSE00001140221	44306494	44306532
ENSE00001140228	44306923	44307031
ENSE00001140234	44307249	44307394
ENSE00001140239	44310299	44310443
ENSE00001140243	44310994	44311161
ENSE00001140248	44311390	44311535
ENSE00001140256	44312072	44312263
ENSE00001176942	44298731	44300711
ENSE00001176945	44313081	44313347

Expression profiles

Bgee: expression breadth ubiquitous, 246 present calls, max score 90.27.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 22.2480 / max 370.3760, expressed in 1804 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
73772	21.6598	1804
73771	0.5881	286

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cardiac muscle of right atrium	UBERON:0003379	90.27	gold quality
tendon of biceps brachii	UBERON:0008188	90.08	gold quality
left ventricle myocardium	UBERON:0006566	90.01	gold quality
pancreatic ductal cell	CL:0002079	89.04	silver quality
nipple	UBERON:0002030	88.24	gold quality
kidney epithelium	UBERON:0004819	87.56	silver quality
upper arm skin	UBERON:0004263	86.92	silver quality
cerebellar vermis	UBERON:0004720	86.72	gold quality
vena cava	UBERON:0004087	86.18	silver quality
epithelial cell of pancreas	CL:0000083	85.19	silver quality
ileal mucosa	UBERON:0000331	85.03	gold quality
endothelial cell	CL:0000115	83.55	gold quality
mammalian vulva	UBERON:0000997	83.33	gold quality
pylorus	UBERON:0001166	83.11	gold quality
cardia of stomach	UBERON:0001162	82.49	gold quality
thymus	UBERON:0002370	82.48	gold quality
renal medulla	UBERON:0000362	82.03	gold quality
nasal cavity epithelium	UBERON:0005384	81.99	silver quality
penis	UBERON:0000989	81.79	gold quality
inferior vagus X ganglion	UBERON:0005363	81.58	gold quality
pharyngeal mucosa	UBERON:0000355	81.25	gold quality
trabecular bone tissue	UBERON:0002483	81.16	gold quality
granulocyte	CL:0000094	81.09	gold quality
Brodmann (1909) area 23	UBERON:0013554	81.02	gold quality
tibia	UBERON:0000979	80.92	gold quality
gingival epithelium	UBERON:0001949	80.84	silver quality
medial globus pallidus	UBERON:0002477	80.80	gold quality
lower esophagus mucosa	UBERON:0035834	80.56	gold quality
trachea	UBERON:0003126	80.50	gold quality
cerebellum	UBERON:0002037	80.43	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	3.31

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ATF4

miRNA regulators (miRDB)

43 targeting AARS2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-944	99.82	70.85	3042
HSA-MIR-205-5P	99.81	70.05	1557
HSA-MIR-4446-5P	99.72	69.19	2544
HSA-MIR-548M	99.70	68.87	1749
HSA-MIR-670-5P	99.67	69.94	1565
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-6134	99.63	65.68	1537
HSA-MIR-569	99.42	66.32	1009
HSA-MIR-504-3P	99.30	67.18	1745
HSA-MIR-6744-3P	99.22	64.41	972
HSA-MIR-6852-5P	99.17	66.69	2073
HSA-MIR-4426	99.17	66.74	1949
HSA-MIR-4757-5P	99.12	64.51	981
HSA-MIR-939-3P	98.97	65.07	2347
HSA-MIR-520G-3P	98.91	67.38	1914
HSA-MIR-520H	98.91	67.38	1914
HSA-MIR-367-5P	98.84	67.18	902
HSA-MIR-7851-3P	98.72	64.88	980
HSA-MIR-4718	98.55	68.61	814
HSA-MIR-6827-5P	98.46	64.88	1256
HSA-MIR-4691-5P	98.41	66.77	1343
HSA-MIR-6792-3P	98.41	66.86	1359
HSA-MIR-5088-3P	98.29	66.63	1310
HSA-MIR-660-3P	98.14	66.04	1434
HSA-MIR-6742-3P	97.95	64.50	1490

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 57.3% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 13)

• Mutations in AARS2 found in lethal mitochondrial myopathy (PMID:22277967)
• A new phenotype caused by AARS2 mutations is characterized by leukoencephalopathy and ovarian failure in female patients, indicating that the phenotypic spectrum associated with AARS2 variants is much wider than previously reported. (PMID:24808023)
• we describe a Japanese woman with novel compound heterozygous mutations in AARS2, the first report of leukodystrophy caused by AARS2 mutations in Asia. (PMID:27251004)
• This paper documented a new, nonsense AARS2 gene mutation (c.578T>G, p.Leu193*) and a known missense mutation (c.595C>T, p.Arg199Cys) associated with leukoencephalopathy in a male patient. (PMID:27734837)
• Mutations in AARS2 in a Series of CSF1R-Negative Patients With Adult-Onset Leukoencephalopathy With Axonal Spheroids and Pigmented Glia. (PMID:27749956)
• Missense variants in the AARS2 gene are the likely cause of the retinopathy and optic atrophy in this patient. This finding expands the phenotypic spectrum of the AARS2 gene. (PMID:28820624)
• Two AARS2 variants, (c.2872C > T) and (c.1774C > T), were identified in a child with cardiomyopathy with early-onset brain disease. (PMID:29440775)
• Three patients with ovarioleukodystrophy, carrying AARS2 compound heterozygous mutations have been found. (PMID:29749055)
• clinical, biochemical and molecular investigations of two unrelated boys presenting with fatal infantile cardiomyopathy, lactic acidosis and respiratory failure (PMID:30285085)
• AARS2-related leukoencephalopathy is a new variant of mitochondrial encephalomyopathy. (PMID:30706699)
• This is the first report of a homozygous pathogenic AARS2 mutation in premature ovarian insufficiency. (PMID:31280959)
• Phenotypic diversity of brain MRI patterns in mitochondrial aminoacyl-tRNA synthetase mutations. (PMID:33972171)
• AARS2 as a novel biomarker for prognosis and its molecular characterization in pan-cancer. (PMID:37990642)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	aars2	ENSDARG00000107385
mus_musculus	Aars2	ENSMUSG00000023938
rattus_norvegicus	Aars2	ENSRNOG00000025808
drosophila_melanogaster	AlaRS-m	FBGN0028962

Paralogs (2): AARS1 (ENSG00000090861), AARSD1 (ENSG00000266967)

Protein

Protein identifiers

Alanine–tRNA ligase, mitochondrial — Q5JTZ9 (reviewed: Q5JTZ9)

Alternative names: Alanyl-tRNA synthetase, Protein lactyltransferase AARS2

All UniProt accessions (1): Q5JTZ9

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 CGAS. Acts as an inhibitor of cGAS/STING signaling by catalyzing lactylation of CGAS, preventing the formation of liquid-like droplets in which CGAS is activated.

Subunit / interactions. Monomer.

Subcellular location. Mitochondrion.

Disease relevance. Combined oxidative phosphorylation deficiency 8 (COXPD8) [MIM:614096] A mitochondrial disease characterized by a lethal infantile hypertrophic cardiomyopathy, generalized muscle dysfunction and some neurologic involvement. The liver is not affected. The disease is caused by variants affecting the gene represented in this entry. Leukoencephalopathy, progressive, with ovarian failure (LKENP) [MIM:615889] An autosomal recessive neurodegenerative disorder characterized by childhood- to adulthood-onset of signs of neurologic deterioration consisting of ataxia, spasticity, and cognitive decline with features of frontal lobe dysfunction. Brain MRI shows leukoencephalopathy with striking involvement of deep white matter, and cerebellar atrophy. All female patients develop premature ovarian failure. The disease is caused by variants affecting the gene represented in this entry.

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.

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

RefSeq proteins (1): NP_065796* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002318	Ala-tRNA-lgiase_IIc	Family
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	Ala-tRNA_ligase	Family

Pfam: PF01411, PF07973

Enzyme classification (BRENDA):

• EC 6.1.1.7 — alanine-tRNA ligase (BRENDA: 19 organisms, 30 substrates, 17 inhibitors, 71 Km, 52 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
TRNAALA	0.0001–0.028	18
ATP	0.067–812	11
ALANINE	0.23–1.41	10
L-ALANINE	0.05–502	8
GLYCINE	26–493	4
L-SERINE	31–600	4
LIPID II L-ALA	0.0331–0.04	2
LIPID II L-SER	0.125–0.146	2
LIVER TRNA	0.0006	1
TMRNA	0.024	1
TRNA	0.023	1
TRNAPHE	0.0021	1
TRNAPHE(17)	0.0019	1
TRNAPHE(38)	0.0031	1
TRNAPHE(57)	0.017	1

Catalyzed reactions (Rhea), 3 shown:

• 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 (44 total): sequence variant 14, binding site 11, mutagenesis site 6, helix 6, strand 5, transit peptide 1, chain 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
6NLQ	X-RAY DIFFRACTION	1.15
6NLY	X-RAY DIFFRACTION	2.31
6NOW	X-RAY DIFFRACTION	4.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5JTZ9-F1	88.05	0.62

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): 636; 749; 753; 110; 128; 210; 240–242; 242; 265; 269; 632

Mutagenesis-validated functional residues (6):

Position	Phenotype
79	in mutant 5a; abolished binding to lactate and protein lactylation; when associated with a-110, a-242 and 265-a–a-267.
110	in mutant 5a; abolished binding to lactate and protein lactylation; when associated with a-79, a-242 and 265-a–a-267. i
210	in atp-binding mutant; abolished ability to mediate protein lactylation; when associated with a-110 and a-269.
242	in mutant 5a; abolished binding to lactate and protein lactylation; when associated with a-79, a-110 and 265-a–a-267.
265–267	in mutant 5a; abolished binding to lactate and protein lactylation; when associated with a-79, a-110 and a-242.
269	in atp-binding mutant; abolished ability to mediate protein lactylation; when associated with a-110 and a-210.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-379726	Mitochondrial tRNA aminoacylation
R-HSA-379724	tRNA Aminoacylation
R-HSA-392499	Metabolism of proteins
R-HSA-72766	Translation

MSigDB gene sets: 220 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_DN, GOBP_AMINO_ACID_ACTIVATION, GCM_GSPT1, GCANCTGNY_MYOD_Q6, GOBP_TRNA_METABOLIC_PROCESS, GAUSSMANN_MLL_AF4_FUSION_TARGETS_A_DN, GOBP_MITOCHONDRIAL_TRANSLATION, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, NKX61_01, GOBP_TRANSLATION, GOBP_POSITIVE_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, GOBP_REGULATION_OF_RESPONSE_TO_STRESS, GOBP_MITOCHONDRIAL_RNA_METABOLIC_PROCESS

GO Biological Process (7): mitochondrial alanyl-tRNA aminoacylation (GO:0070143), negative regulation of cGAS/STING signaling pathway (GO:0160049), translation (GO:0006412), alanyl-tRNA aminoacylation (GO:0006419), tRNA aminoacylation (GO:0043039), aminoacyl-tRNA metabolism involved in translational fidelity (GO:0106074), cGAS/STING signaling pathway (GO:0140896)

GO Molecular Function (13): tRNA binding (GO:0000049), aminoacyl-tRNA deacylase activity (GO:0002161), alanine-tRNA ligase activity (GO:0004813), ATP binding (GO:0005524), zinc ion binding (GO:0008270), 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), protein binding (GO:0005515), ligase activity (GO:0016874), metal ion binding (GO:0046872)

GO Cellular Component (2): mitochondrion (GO:0005739), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
tRNA Aminoacylation	1
Translation	1
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
tRNA metabolic process	2
catalytic activity, acting on a tRNA	2
binding	2
mitochondrion	1
alanyl-tRNA aminoacylation	1
tRNA aminoacylation for mitochondrial protein translation	1
negative regulation of cytoplasmic pattern recognition receptor signaling pathway	1
cGAS/STING 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 aminoacylation for protein translation	1
amino acid activation	1
regulation of translational fidelity	1
cytoplasmic pattern recognition receptor signaling pathway	1
RNA binding	1
carboxylic ester hydrolase activity	1
aminoacyl-tRNA metabolism involved in translational fidelity	1
deacylase activity	1
aminoacyl-tRNA ligase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate 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
cytoplasm	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

3202 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AARS2	DARS2	Q6PI48	870
AARS2	RARS2	Q5T160	864
AARS2	WARS2	Q9UGM6	848
AARS2	IARS2	Q9NSE4	846
AARS2	PARS2	Q7L3T8	838
AARS2	QARS1	P47897	832
AARS2	TARS2	Q9BW92	832
AARS2	TARS3	A2RTX5	821
AARS2	WARS1	P23381	815
AARS2	TARS1	P26639	812
AARS2	EARS2	Q5JPH6	809
AARS2	YARS2	Q9Y2Z4	809
AARS2	FARS2	O95363	807
AARS2	GARS1	P41250	795
AARS2	LARS2	Q15031	792

IntAct

106 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
FAM90A1	KPNA3	psi-mi:“MI:0914”(association)	0.670
NDUFS7	NDUFS8	psi-mi:“MI:0914”(association)	0.640
FGL1	LCMT2	psi-mi:“MI:0914”(association)	0.640
PTPA	AARS2	psi-mi:“MI:0915”(physical association)	0.560
EHHADH	AARS2	psi-mi:“MI:0915”(physical association)	0.560
SCGB1D1	FAM234B	psi-mi:“MI:0914”(association)	0.530
EPHA1	EXOC5	psi-mi:“MI:0914”(association)	0.530
RBM3	PRMT5	psi-mi:“MI:0914”(association)	0.530
SUCLG1	LARS2	psi-mi:“MI:0914”(association)	0.530
DHRS4	NDUFS2	psi-mi:“MI:0914”(association)	0.530
CD70	METTL15	psi-mi:“MI:0914”(association)	0.530
RBM3	AARS2	psi-mi:“MI:0914”(association)	0.530
HSCB	NDUFS8	psi-mi:“MI:0914”(association)	0.460
COQ7	AARS2	psi-mi:“MI:0915”(physical association)	0.400
MEGF10	AARS2	psi-mi:“MI:0915”(physical association)	0.370
SIRT4	VWA8	psi-mi:“MI:0914”(association)	0.350
RAP1B	KLC1	psi-mi:“MI:0914”(association)	0.350
FOXB1	DDX39A	psi-mi:“MI:0914”(association)	0.350
FOXL1	DDX39A	psi-mi:“MI:0914”(association)	0.350
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350

BioGRID (387): AARS2 (Affinity Capture-MS), AARS2 (Affinity Capture-MS), AARS2 (Affinity Capture-MS), AARS2 (Affinity Capture-MS), AARS2 (Affinity Capture-MS), AARS2 (Affinity Capture-MS), AARS2 (Affinity Capture-MS), AARS2 (Affinity Capture-MS), AARS2 (Affinity Capture-MS), AARS2 (Affinity Capture-MS), AARS2 (Affinity Capture-MS), AARS2 (Affinity Capture-MS), AARS2 (Affinity Capture-MS), AARS2 (Affinity Capture-MS), AARS2 (Affinity Capture-MS)

ESM2 similar proteins: A0A5F8AH41, A0AVI4, A0JMH2, A1Y9I9, A5WVX1, B0X4N1, B4P925, D3ZX08, O55171, O88512, O95050, O97972, P0DPD7, P0DPE0, P0DPE1, P10937, P10938, P11086, P40935, P40936, Q06AU9, Q08DK0, Q14CH7, Q32PE2, Q32Q92, Q3SZG9, Q3URQ7, Q568P9, Q5E9L5, Q5JTZ9, Q5RCH4, Q5RFR7, Q6NTR1, Q6NZB1, Q7QIL2, Q7TMC8, Q80YU0, Q8HY87, Q8K304, Q8NFF5

Diamond homologs: A1AEN7, A1ATU9, A1AZL6, A1BD33, A1K991, A1V3F2, A1WXK5, A2S3D4, A2SI90, A3MJ36, A3N8K7, A3NUB0, A3PLJ1, A4SGJ6, A4SZL8, A4VJB3, A4WV47, A4XWE2, A5ICV6, A5UY81, A5W0D9, A6H0Y3, A6L1L8, A6LEZ8, A6VA71, A7NQA5, A7ZQC5, A8A3H4, A8ANQ1, A8GA09, A8LL20, A9IK31, B0KR43, B1IUY2, B1JCG9, B1LQ15, B1M0N0, B1XCM5, B1Y1G9, B2U049

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
ATF4	“up-regulates quantity by expression”	AARS2	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 122 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
mitochondrial translation	8	12.5×	2e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	37
Likely pathogenic	31
Uncertain significance	317
Likely benign	193
Benign	61

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1064699	NM_020745.4(AARS2):c.277C>T (p.Arg93Ter)	Pathogenic
1064700	NM_020745.4(AARS2):c.845C>G (p.Ser282Cys)	Pathogenic
1176510	NM_020745.4(AARS2):c.2007+1G>C	Pathogenic
1322029	NM_020745.4(AARS2):c.2255+1G>A	Pathogenic
143044	NM_020745.4(AARS2):c.647dup (p.Cys218fs)	Pathogenic
143045	NM_020745.4(AARS2):c.149T>G (p.Phe50Cys)	Pathogenic
143046	NM_020745.4(AARS2):c.1561C>T (p.Arg521Ter)	Pathogenic
1456685	NC_000006.11:g.(?44274640)(44278200_?)del	Pathogenic
1527236	GRCh37/hg19 6p21.1-12.3(chr6:43636308-50947320)	Pathogenic
1685483	NM_020745.4(AARS2):c.2487+1G>C	Pathogenic
1685485	NM_020745.4(AARS2):c.964C>T (p.Arg322Cys)	Pathogenic
1699307	NM_020745.4(AARS2):c.87_88dup (p.Leu30fs)	Pathogenic
1916293	NM_020745.4(AARS2):c.1703_1704del (p.Gln568fs)	Pathogenic
1918304	NM_020745.4(AARS2):c.367C>T (p.Arg123Ter)	Pathogenic
2064057	NM_020745.4(AARS2):c.1329T>A (p.Cys443Ter)	Pathogenic
2124832	NM_020745.4(AARS2):c.2607del (p.Thr871fs)	Pathogenic
213970	NM_020745.4(AARS2):c.1008dup (p.Asp337Ter)	Pathogenic
2576588	NM_020745.4(AARS2):c.2611dup (p.Thr871fs)	Pathogenic
2581473	NM_020745.4(AARS2):c.2308C>T (p.Gln770Ter)	Pathogenic
2971836	NM_020745.4(AARS2):c.2871_2872inv (p.Arg958Ter)	Pathogenic
2980940	NM_020745.4(AARS2):c.2393del (p.Gln798fs)	Pathogenic
30941	NM_020745.4(AARS2):c.464T>G (p.Leu155Arg)	Pathogenic
3696430	NM_020745.4(AARS2):c.2430del (p.Ser811fs)	Pathogenic
3725883	NM_020745.4(AARS2):c.2057del (p.Glu686fs)	Pathogenic
3765547	NM_020745.4(AARS2):c.179C>A (p.Pro60His)	Pathogenic
3768707	NC_000006.11:g.(44274270_44274659)_(44278181_44278730)del	Pathogenic
4528275	NM_020745.4(AARS2):c.452T>C (p.Met151Thr)	Pathogenic
4730248	NM_020745.4(AARS2):c.2730_2757dup (p.Met920fs)	Pathogenic
4778355	NM_020745.4(AARS2):c.941del (p.Glu314fs)	Pathogenic
4797595	NM_020745.4(AARS2):c.2775_2776del (p.Ala926fs)	Pathogenic

SpliceAI

3411 predictions. Top by Δscore:

Variant	Effect	Δscore
6:44301273:C:CT	acceptor_gain	1.0000
6:44301376:CTCA:C	donor_gain	1.0000
6:44301377:TCACT:T	donor_loss	1.0000
6:44301378:CAC:C	donor_loss	1.0000
6:44301379:A:AC	donor_gain	1.0000
6:44301379:AC:A	donor_loss	1.0000
6:44301380:C:CA	donor_gain	1.0000
6:44301380:CT:C	donor_gain	1.0000
6:44301380:CTG:C	donor_gain	1.0000
6:44301380:CTGA:C	donor_gain	1.0000
6:44301380:CTGAG:C	donor_gain	1.0000
6:44301393:AG:A	donor_gain	1.0000
6:44301394:G:C	donor_gain	1.0000
6:44301460:GCAGC:G	acceptor_gain	1.0000
6:44301461:CAGC:C	acceptor_gain	1.0000
6:44301461:CAGCC:C	acceptor_gain	1.0000
6:44301462:AGC:A	acceptor_gain	1.0000
6:44301463:GC:G	acceptor_gain	1.0000
6:44301463:GCC:G	acceptor_loss	1.0000
6:44301464:CCTA:C	acceptor_gain	1.0000
6:44301465:C:CC	acceptor_gain	1.0000
6:44301465:CTAT:C	acceptor_loss	1.0000
6:44301466:T:G	acceptor_loss	1.0000
6:44301467:A:AC	acceptor_gain	1.0000
6:44301467:A:C	acceptor_gain	1.0000
6:44301473:C:CT	acceptor_gain	1.0000
6:44301474:A:T	acceptor_gain	1.0000
6:44302058:ACC:A	donor_loss	1.0000
6:44302078:A:AC	donor_gain	1.0000
6:44302079:C:CC	donor_gain	1.0000

AlphaMissense

6283 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:44310381:T:A	E271V	0.990
6:44311022:A:G	W241R	0.990
6:44311022:A:T	W241R	0.990
6:44311403:A:G	W190R	0.986
6:44311403:A:T	W190R	0.986
6:44313186:A:C	F46L	0.986
6:44313186:A:T	F46L	0.986
6:44313188:A:G	F46L	0.986
6:44300681:A:G	W942R	0.985
6:44300681:A:T	W942R	0.985
6:44307325:G:T	R322S	0.985
6:44312114:A:C	F131L	0.985
6:44312114:A:T	F131L	0.985
6:44312116:A:G	F131L	0.985
6:44304712:G:A	T562I	0.981
6:44307304:G:T	R329S	0.981
6:44307324:C:G	R322P	0.981
6:44312072:C:A	K145N	0.980
6:44312072:C:G	K145N	0.980
6:44312195:G:C	N104K	0.980
6:44312195:G:T	N104K	0.980
6:44307313:C:G	D326H	0.979
6:44311008:G:C	F245L	0.979
6:44311008:G:T	F245L	0.979
6:44311010:A:G	F245L	0.979
6:44313196:C:A	R43M	0.979
6:44307312:T:A	D326V	0.978
6:44311524:A:C	C149W	0.976
6:44312099:A:C	N136K	0.976
6:44312099:A:T	N136K	0.976

dbSNP variants (sampled 300 via entrez): RS1000435417 (6:44299689 T>C), RS1000505260 (6:44314030 C>A), RS1000653674 (6:44298678 G>A), RS1000760074 (6:44298480 G>C), RS1000944121 (6:44302057 C>T), RS1001106759 (6:44307800 C>A), RS1001338031 (6:44308533 ACT>A), RS1001415506 (6:44308249 T>C,G), RS1001847561 (6:44303675 A>C), RS1001963737 (6:44315031 T>A), RS1001980388 (6:44315117 T>A), RS1002243341 (6:44308515 G>A), RS1002395331 (6:44302428 G>A), RS1002897185 (6:44299695 T>G), RS1002951042 (6:44299422 G>A)

Disease associations

OMIM: gene MIM:612035 | disease phenotypes: MIM:615889, MIM:614096

GenCC curated gene-disease

Disease	Classification	Inheritance
leukoencephalopathy, progressive, with ovarian failure	Definitive	Autosomal recessive
combined oxidative phosphorylation defect type 8	Strong	Autosomal recessive
hereditary diffuse leukoencephalopathy with axonal spheroids and pigmented glia	Supportive	Autosomal dominant
ovarioleukodystrophy	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
mitochondrial disease	Definitive	AR

Mondo (6): leukoencephalopathy, progressive, with ovarian failure (MONDO:0014387), combined oxidative phosphorylation defect type 8 (MONDO:0013570), pulmonary hypoplasia (MONDO:0800133), mitochondrial disease (MONDO:0044970), (MONDO:0009096), (MONDO:0020506)

Orphanet (3): Ovarioleukodystrophy (Orphanet:99853), Combined oxidative phosphorylation defect type 8 (Orphanet:319504), Mitochondrial disease (Orphanet:68380)

HPO phenotypes

52 total (30 of 52 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000639	Nystagmus
HP:0000709	Psychosis
HP:0000716	Depression
HP:0000726	Dementia
HP:0001251	Ataxia
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001265	Hyporeflexia
HP:0001270	Motor delay
HP:0001272	Cerebellar atrophy
HP:0001324	Muscle weakness
HP:0001332	Dystonia
HP:0001347	Hyperreflexia
HP:0001508	Failure to thrive
HP:0001522	Death in infancy
HP:0001635	Congestive heart failure
HP:0001639	Hypertrophic cardiomyopathy
HP:0001640	Cardiomegaly
HP:0001942	Metabolic acidosis
HP:0002089	Pulmonary hypoplasia
HP:0002151	Increased circulating lactate concentration
HP:0002180	Neurodegeneration
HP:0002186	Apraxia
HP:0002352	Leukoencephalopathy
HP:0002353	EEG abnormality
HP:0002371	Loss of speech
HP:0002376	Developmental regression
HP:0002378	Hand tremor
HP:0003128	Lactic acidosis

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

21 total (human), top 21 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases methylation	2
Cadmium Chloride	decreases expression	2
GSK-J4	decreases expression	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
methylparaben	increases expression	1
butylparaben	increases expression	1
di-n-butylphosphoric acid	affects expression	1
2,3,5-(triglutathion-S-yl)hydroquinone	increases ADP-ribosylation	1
bisphenol S	decreases methylation	1
Acetaminophen	affects cotreatment, decreases expression	1
Atrazine	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Ivermectin	decreases expression	1
Lipopolysaccharides	affects cotreatment, decreases expression	1
Rotenone	decreases expression	1
Smoke	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
1-Methyl-4-phenylpyridinium	decreases expression	1
Aflatoxin B1	increases methylation	1
Acrylamide	decreases expression	1

Cellosaurus cell lines

3 cell lines: 3 induced pluripotent stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_ZA16	LUMCi024-A	Induced pluripotent stem cell	Male
CVCL_ZA17	LUMCi025-A	Induced pluripotent stem cell	Male
CVCL_ZA24	LUMCi026-A	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03351998	PHASE4	COMPLETED	Impact of Statin Therapy on Muscle Mitochondrial Function and Aerobic Capacity
NCT07187206	PHASE3	RECRUITING	Safety and Efficacy of FETO in CDH Phase III
NCT00432744	PHASE3	COMPLETED	Phase III Trial of Coenzyme Q10 in Mitochondrial Disease
NCT05162768	PHASE3	COMPLETED	Study to Evaluate Efficacy and Safety of Elamipretide in Subjects With Primary Mitochondrial Disease From Nuclear DNA Mutations (nPMD)
NCT06451757	PHASE3	RECRUITING	KHENERFIN Study: A Trial to Evaluate the Efficacy and Safety of Sonlicromanol in Primary Mitochondrial Diseases
NCT02875860	PHASE2	COMPLETED	‘TOTAL’ (Tracheal Occlusion To Accelerate Lung Growth) Trial
NCT02951130	PHASE2	COMPLETED	Milrinone in Congenital Diaphragmatic Hernia
NCT02398201	PHASE2	COMPLETED	A Study of Bezafibrate in Mitochondrial Myopathy
NCT02473445	PHASE2	TERMINATED	A Long-term Extension of Study RP103-MITO-001 (NCT02023866) to Assess Cysteamine Bitartrate Delayed-release Capsules (RP103) in Children With Inherited Mitochondrial Disease
NCT02500628	PHASE2	COMPLETED	Heart Rate Variability in Response to Metformin Challenge
NCT02805790	PHASE2	COMPLETED	Safety, Tolerability, Efficacy of MTP-131 for Treatment of Mitochondrial Disease in Subjects From the MMPOWER Study
NCT02909400	PHASE2	COMPLETED	The KHENERGY Study
NCT02976038	PHASE2	TERMINATED	Open-Label Extension Trial to Characterize the Long-term Safety and Tolerability of Elamipretide in Subjects With Genetically Confirmed Primary Mitochondrial Myopathy (PMM)
NCT03177798	PHASE2	COMPLETED	Mitochondria and Chronic Kidney Disease
NCT03866954	PHASE2	WITHDRAWN	Trial of Erythrocyte Encapsulated Thymidine Phosphorylase In Mitochondrial Neurogastrointestinal Encephalomyopathy
NCT04165239	PHASE2	COMPLETED	The KHENERGYZE Study
NCT04604548	PHASE2	COMPLETED	The KHENEREXT Study
NCT04802707	PHASE2	RECRUITING	Deoxynucleosides Pyrimidines as Treatment for Mitochondrial Depletion Syndrome
NCT04846036	PHASE2	SUSPENDED	The KHENERGYC Study
NCT05650229	PHASE2	RECRUITING	Efficacy of KL1333 in Adult Patients With Primary Mitochondrial Disease
NCT05972954	PHASE2	COMPLETED	OMT-28 in Patients With Primary Mitochondrial Disease (PMD) (PMD-OPTION)
NCT06017869	PHASE2	RECRUITING	Evaluate the Safety and Therapeutic Effects of a Single Intravenous Infusion (IV) of Autologous CD34+ Cells Enriched With Allogenic Placenta-derived Mitochondria in Patients With a Diagnosis of Pearson Syndrome (PS)
NCT07514338	PHASE2	NOT_YET_RECRUITING	Open Label Extension to Assess Long Term Safety and Efficacy of KL1333 in Patients With Primary Mitochondrial Disease
NCT03101891	PHASE1	ACTIVE_NOT_RECRUITING	Renal Anhydramnios Fetal Therapy
NCT00060515	PHASE1	TERMINATED	RG2133 (2’,3’,5’-Tri-O-Acetyluridine) in Mitochondrial Disease
NCT02348125	PHASE1	UNKNOWN	Does Clinical Treatment of Mitochondrial Dysfunction Impact Autism Spectrum Disorder (ASD)?
NCT02544217	PHASE1	COMPLETED	A Dose-escalating Clinical Trial With KH176
NCT03888716	PHASE1	COMPLETED	A Phase Ia/Ib, SAD and MAD Study of of KL1333 in Healthy Subjects and Patients With Primary Mitochondrial Disease
NCT04086329	PHASE1	RECRUITING	Validation of Oxygen Nanosensor in Mitochondrial Myopathy
NCT04643249	PHASE1	COMPLETED	Drug-drug Interaction Study of KL1333 in Healthy Subjects
NCT05241262	PHASE1	RECRUITING	Study of N-acetylcysteine in the Treatment of Patients With the m.3243A>G Mutation and Low Brain Glutathione Levels
NCT05569122	PHASE1	RECRUITING	Applying pGz in Mitochondrial Disease
NCT06819683	PHASE1	RECRUITING	Validation of Nanosensor Oxygen Measurement
NCT07258667	PHASE1	NOT_YET_RECRUITING	Pilot Study of the Efficacy of Nicotinamide (Vitamin B3) in Leber’s Hereditary Optic Neuropathy
NCT01240057	PHASE2/PHASE3	COMPLETED	Tracheal Occlusion To Accelerate Lung Growth (TOTAL) Trial for Severe Pulmonary Hypoplasia
NCT00763737	Not specified	COMPLETED	Fetal Surgery for Moderate Left Sided Congenital Diaphragmatic Hernia.
NCT02549820	Not specified	ACTIVE_NOT_RECRUITING	Fetoscopic Endoluminal Tracheal Occlusion in Severe Left Congenital Diaphragmatic Hernia
NCT02986087	Not specified	RECRUITING	Feto-Endoscopic Tracheal Occlusion (FETO) for Severe Congenital Diaphragmatic Hernia
NCT03138863	Not specified	RECRUITING	Fetal Endoscopic Tracheal Occlusion for Congenital Diaphragmatic Hernia (FETO)
NCT06728228	Not specified	RECRUITING	Amnioinfusion for Fetal Renal Failure