AIMP2

Summary

AIMP2 (aminoacyl tRNA synthetase complex interacting multifunctional protein 2, HGNC:20609) is a protein-coding gene on chromosome 7p22.1, encoding Aminoacyl tRNA synthase complex-interacting multifunctional protein 2 (Q13155). Required for assembly and stability of the aminoacyl-tRNA synthase complex.

The protein encoded by this gene is part of the aminoacyl-tRNA synthetase complex, which contains nine different aminoacyl-tRNA synthetases and three non-enzymatic factors. The encoded protein is one of the non-enzymatic factors and is required for assembly and stability of the complex.

Source: NCBI Gene 7965 — RefSeq curated summary.

At a glance

• Gene–disease (curated): leukodystrophy, hypomyelinating, 17 (Definitive, ClinGen)
• GWAS associations: 5
• Clinical variants (ClinVar): 221 total — 19 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 27
• Druggable target: yes
• MANE Select transcript: NM_006303

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20609
Approved symbol	AIMP2
Name	aminoacyl tRNA synthetase complex interacting multifunctional protein 2
Location	7p22.1
Locus type	gene with protein product
Status	Approved
Aliases	p38, PRO0992, JTV-1, JTV1
Ensembl gene	ENSG00000106305
Ensembl biotype	protein_coding
OMIM	600859
Entrez	7965

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 4 protein_coding, 1 nonsense_mediated_decay

ENST00000223029, ENST00000395236, ENST00000400479, ENST00000415999, ENST00000858691

RefSeq mRNA: 8 — MANE Select: NM_006303 NM_001326606, NM_001326607, NM_001326609, NM_001326610, NM_001326611, NM_001362785, NM_001362787, NM_006303

CCDS: CCDS5344, CCDS87475, CCDS87476

Canonical transcript exons

ENST00000223029 — 4 exons

Exon	Start	End
ENSE00000669196	6017814	6018045
ENSE00000831654	6023303	6023834
ENSE00001947589	6009272	6009498
ENSE00003560762	6015146	6015352

Expression profiles

Bgee: expression breadth ubiquitous, 297 present calls, max score 99.28.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 39.9027 / max 215.6737, expressed in 1817 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
77130	37.2566	1816
77131	2.5937	1473
77132	0.0524	12

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
oocyte	CL:0000023	99.28	gold quality
secondary oocyte	CL:0000655	99.19	gold quality
vastus lateralis	UBERON:0001379	97.61	gold quality
tibialis anterior	UBERON:0001385	97.61	gold quality
quadriceps femoris	UBERON:0001377	97.58	gold quality
deltoid	UBERON:0001476	97.54	gold quality
body of tongue	UBERON:0011876	97.46	gold quality
biceps brachii	UBERON:0001507	97.23	gold quality
gastrocnemius	UBERON:0001388	97.19	gold quality
triceps brachii	UBERON:0001509	97.07	gold quality
muscle organ	UBERON:0001630	96.97	gold quality
skeletal muscle organ	UBERON:0014892	96.97	gold quality
skeletal muscle tissue	UBERON:0001134	96.86	gold quality
muscle of leg	UBERON:0001383	96.83	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	96.63	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	96.46	gold quality
diaphragm	UBERON:0001103	96.21	gold quality
hindlimb stylopod muscle	UBERON:0004252	96.16	gold quality
adult organism	UBERON:0007023	96.04	gold quality
gluteal muscle	UBERON:0002000	95.87	gold quality
endometrium epithelium	UBERON:0004811	95.20	gold quality
ileal mucosa	UBERON:0000331	95.14	gold quality
heart right ventricle	UBERON:0002080	95.00	gold quality
pharyngeal mucosa	UBERON:0000355	94.97	gold quality
mucosa of transverse colon	UBERON:0004991	94.97	gold quality
tongue	UBERON:0001723	94.73	gold quality
duodenum	UBERON:0002114	94.66	gold quality
muscle tissue	UBERON:0002385	94.32	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	94.02	gold quality
jejunum	UBERON:0002115	93.99	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.84
E-MTAB-6524	no	217.76

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MSC, MYC

miRNA regulators (miRDB)

13 targeting AIMP2, 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-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-3140-3P	99.88	68.47	2069
HSA-MIR-3663-3P	99.84	70.39	798
HSA-MIR-3176	99.25	64.35	954
HSA-MIR-3922-3P	99.25	64.96	1136
HSA-MIR-193A-3P	98.59	66.36	769
HSA-MIR-193B-3P	98.59	66.62	748
HSA-MIR-514A-3P	96.43	67.77	1048
HSA-MIR-514B-3P	96.43	67.77	1048
HSA-MIR-345-5P	96.40	66.43	663
HSA-MIR-4522	95.76	66.23	742

Literature-anchored findings (GeneRIF, showing 25)

• a splicing variant of AIMP2 lacking exon 2 (AIMP2-DX2) is highly expressed by alternative splicing in human lung cancer cells and patient’s tissues (PMID:21483803)
• ribozyme could selectively deliver the activity of a suicide gene into the AIMP2-DX2 RNA expressing lung cancer cells and thereby specifically and effectively retard the growth of the cancer cells with prodrug treatment. (PMID:22285955)
• AIMP2-DX2, a splicing variant of tumor suppressor AIMP2, can be a therapeutic target to control chemoresistant epithelial ovarian cancer . (PMID:22532625)
• downregulation of AIMP2 lacking exon 2 (AIMP2-DX2), expressed in different cancer cells, suppressed the epidermal growth factor receptor/mitogen activated protein kinase signaling pathway (PMID:22562359)
• These findings suggested that, although excessive accumulation of oxidative DNA damage was present in LSCs, the relatively decreased phosphorylation of p38 might help leukemic cells escape senescence and apoptosis. (PMID:22684553)
• The tumorigenic activity of AIMP2-DX2 can be controlled by the small chemical BC-DXI01, which can selectively suppress the AIMP2-DX2 mRNA transcript. (PMID:23815603)
• Transgeneic overexpression of AIMP2 led to a selective, age-dependent, progressive loss of dopaminergic neurons. (PMID:23974709)
• Ubiquitin and SUMO compete for the same lysine (K242) on influenza A virus M1 and the interaction of viral NS2 with human AIMP2 facilitates the switch of the M1 modification from ubiquitination to SUMOylation, thus increasing viral replication. (PMID:25320310)
• analysis of the heterotetrameric complex structure of the glutathione transferase (GST) domains shared among the four MSC components, methionyl-tRNA synthetase (MRS), glutaminyl-prolyl-tRNA synthetase (EPRS), AIMP2 and AIMP3 (PMID:26472928)
• AIMP2 underexpression is associated with lung neoplasms. (PMID:27197155)
• our findings show how DX2 promotes lung cancer progression and how its activity may be thwarted as a strategy to treat patients with lung cancers exhibiting elevated DX2 levels (PMID:27302160)
• These data indicate monomer-dimer equilibrium of AIMP2-DX2 in solution. These results form the basis for the structure-function study of oncogenic AIMP2-DX2. (PMID:28185908)
• These findings provide new mechanistic insights into the role of VPS35 in the regulation of AIMP2 levels and cell death. (PMID:28383562)
• Homozygosity for a nonsense variant in AIMP2 is associated with a progressive neurodevelopmental disorder with microcephaly, seizures, and spastic quadriparesis. (PMID:29215095)
• AIMP2-DX2 plays an important role in the regulation of Nasopharyngeal carcinoma. (PMID:29854811)
• developed a label-free method based on the formation of split G-quadruplex in the presence of target DNA combined with strand displacement to detect exon 2 deletion of AIMP2 (DE2) sensitively and selectively (PMID:30345633)
• Retractile lysyl-tRNA synthetase-AIMP2 assembly in the human multi-aminoacyl-tRNA synthetase complex. (PMID:30733335)
• heat-shock protein HSP70 is a critical determinant for the level of AIMP2-DX2 (PMID:31792442)
• Structural insight into the interaction between p53 TAD1 and AIMP2-DX2 by NMR. (PMID:32448505)
• An Isoform of the Oncogenic Splice Variant AIMP2-DX2 Detected by a Novel Monoclonal Antibody. (PMID:32471182)
• Single-cell analysis of AIMP2 splice variants informs on drug sensitivity and prognosis in hematologic cancer. (PMID:33128014)
• Discovery of two distinct aminoacyl-tRNA synthetase complexes anchored to the Plasmodium surface tRNA import protein. (PMID:35487244)
• AIMP2-DX2 provides therapeutic interface to control KRAS-driven tumorigenesis. (PMID:35546148)
• AIMP2 restricts EV71 replication by recruiting SMURF2 to promote the degradation of 3D polymerase. (PMID:38945214)
• AIMP2 accumulation in brain leads to cognitive deficits and blood secretion in Parkinson’s disease. (PMID:39390613)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	aimp2	ENSDARG00000018903
mus_musculus	Aimp2	ENSMUSG00000029610
rattus_norvegicus	Aimp2	ENSRNOG00000001044
drosophila_melanogaster	AIMP2	FBGN0036515

Protein

Protein identifiers

Aminoacyl tRNA synthase complex-interacting multifunctional protein 2 — Q13155 (reviewed: Q13155)

Alternative names: Multisynthase complex auxiliary component p38, Protein JTV-1

All UniProt accessions (3): A8MU58, Q13155, F8WCL2

UniProt curated annotations — full annotation on UniProt →

Function. Required for assembly and stability of the aminoacyl-tRNA synthase complex. Mediates ubiquitination and degradation of FUBP1, a transcriptional activator of MYC, leading to MYC down-regulation which is required for aveolar type II cell differentiation. Blocks MDM2-mediated ubiquitination and degradation of p53/TP53. Functions as a proapoptotic factor.

Subunit / interactions. Part of the multisynthetase complex (MSC), 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 (via N-terminus) with KARS1. Interacts with EPRS1. Forms a linear complex that contains MARS1, EEF1E1, EPRS1 and AIMP2 that is at the core of the multisubunit complex. Binds FUBP1 (via C-terminus). Interacts in both its unphosphorylated and phosphorylated forms with p53/TP53 (via N-terminus) in the nucleus following UV irradiation. Interacts (via N-terminus) with PRKN/parkin (via first RING-type domain). Interacts with TARS3.

Subcellular location. Cytoplasm. Cytosol. Nucleus.

Post-translational modifications. Phosphorylated on serine residues in response to UV irradiation. Ubiquitinated by PRKN, leading to its degradation by the proteasome. Mutant PRKN fails to ubiquitinate AIMP2 efficiently, allowing its accumulation which may contribute to neurodegeneration associated with Parkinson disease.

Disease relevance. Leukodystrophy, hypomyelinating, 17 (HLD17) [MIM:618006] An autosomal recessive neurodevelopmental disorder characterized by atrophy of cerebral cortex, spinal cord and cerebellum, thin corpus callosum, abnormal signals in the basal ganglia, and features suggesting hypo- or demyelination observed on brain imaging. Clinical manifestations include lack of development, absent speech, microcephaly, spasticity, seizures, and contractures. The disease may be caused by variants affecting the gene represented in this entry.

Miscellaneous. Accumulates in brains affected by autosomal-recessive juvenile parkinsonism, idiopathic Parkinson disease and diffuse Lewy body disease.

Isoforms (2)

UniProt ID	Names	Canonical?
Q13155-1	1	yes
Q13155-2	2, DX2

RefSeq proteins (8): NP_001313535, NP_001313536, NP_001313538, NP_001313539, NP_001313540, NP_001349714, NP_001349716, NP_006294* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004046	GST_C	Domain
IPR031889	AIMP2_LysRS-bd	Domain
IPR036282	Glutathione-S-Trfase_C_sf	Homologous_superfamily
IPR041503	AIMP2_thioredoxin	Domain
IPR042360	AIMP2	Family

Pfam: PF00043, PF16780, PF18569

UniProt features (41 total): helix 12, strand 11, sequence variant 6, mutagenesis site 4, turn 3, region of interest 2, chain 1, domain 1, splice variant 1

Structure

Experimental structures (PDB)

13 structures.

PDB	Method	Resolution (Å)
6K39	X-RAY DIFFRACTION	1.4
6ILD	X-RAY DIFFRACTION	1.88
4YCU	X-RAY DIFFRACTION	2.1
5A1N	X-RAY DIFFRACTION	2.1
6JPV	X-RAY DIFFRACTION	2.15
5A5H	X-RAY DIFFRACTION	2.32
5A34	X-RAY DIFFRACTION	2.6
9DPL	ELECTRON MICROSCOPY	2.8
4DPG	X-RAY DIFFRACTION	2.84
4YCW	X-RAY DIFFRACTION	2.9
5Y6L	X-RAY DIFFRACTION	2.9
8J9S	X-RAY DIFFRACTION	3.01
6IY6	X-RAY DIFFRACTION	3.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13155-F1	81.65	0.59

Functional residue map

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

Mutagenesis-validated functional residues (4):

Position	Phenotype
163–164	reduced interaction with tp53, loss of tp53 activation and loss of proapoptotic activity.
172–173	reduced interaction with tp53, loss of tp53 activation and loss of proapoptotic activity.
215	nearly abolishes interaction with eprs1.
238	nearly abolishes interaction with eprs1.

Function

Pathways and Gene Ontology

Reactome pathways

10 pathways

ID	Pathway
R-HSA-2408522	Selenoamino acid metabolism
R-HSA-379716	Cytosolic 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: 304 (showing top): SHEPARD_BMYB_MORPHOLINO_UP, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_LUNG_EPITHELIUM_DEVELOPMENT, GOBP_AMINO_ACID_ACTIVATION, TGCGCANK_UNKNOWN, BASSO_B_LYMPHOCYTE_NETWORK, GOBP_LUNG_CELL_DIFFERENTIATION, GOBP_TRNA_METABOLIC_PROCESS, MORF_HDAC2, MODULE_16, chr7p22, GOBP_TRANSLATION, SCHUHMACHER_MYC_TARGETS_UP, MUELLER_PLURINET, WANG_LMO4_TARGETS_DN

GO Biological Process (9): translation (GO:0006412), apoptotic process (GO:0006915), negative regulation of cell population proliferation (GO:0008285), protein ubiquitination (GO:0016567), positive regulation of protein ubiquitination (GO:0031398), positive regulation of neuron apoptotic process (GO:0043525), type II pneumocyte differentiation (GO:0060510), protein-containing complex assembly (GO:0065003), cell differentiation (GO:0030154)

GO Molecular Function (3): protein-macromolecule adaptor activity (GO:0030674), protein binding (GO:0005515), molecular adaptor activity (GO:0060090)

GO Cellular Component (5): nucleus (GO:0005634), cytosol (GO:0005829), membrane (GO:0016020), aminoacyl-tRNA synthetase multienzyme complex (GO:0017101), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
Metabolism of amino acids and derivatives	1
tRNA Aminoacylation	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
binding	2
peptidyltransferase activity	1
translational initiation	1
translational elongation	1
translational termination	1
macromolecule biosynthetic process	1
protein metabolic process	1
protein biosynthetic process	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
protein modification by small protein conjugation	1
protein ubiquitination	1
regulation of protein ubiquitination	1
positive regulation of protein modification by small protein conjugation or removal	1
positive regulation of apoptotic process	1
regulation of neuron apoptotic process	1
neuron apoptotic process	1
lung secretory cell differentiation	1
cellular component assembly	1
protein-containing complex organization	1
cellular developmental process	1
protein binding	1
molecular adaptor activity	1
molecular_function	1
intracellular membrane-bounded organelle	1
cytoplasm	1
intracellular protein-containing complex	1
catalytic complex	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1852 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AIMP2	EEF1E1	O43324	993
AIMP2	AIMP1	Q12904	979
AIMP2	EPRS1	P07814	935
AIMP2	KARS1	Q15046	934
AIMP2	QARS1	P47897	892
AIMP2	MARS1	P56192	891
AIMP2	MARS2	Q96GW9	882
AIMP2	AARS1	P49588	871
AIMP2	RARS2	Q5T160	852
AIMP2	PRKN	O60260	761
AIMP2	LARS1	Q9P2J5	757
AIMP2	LARS2	Q15031	748
AIMP2	HSD17B4	P51659	742
AIMP2	RARS1	P54136	730
AIMP2	FUBP1	Q96AE4	726

IntAct

355 interactions, top by confidence:

A	B	Type	Score
KARS1	AIMP2	psi-mi:“MI:0915”(physical association)	0.970
AIMP2	KARS1	psi-mi:“MI:0915”(physical association)	0.970
	TP53	psi-mi:“MI:0914”(association)	0.970
KARS1	AIMP2	psi-mi:“MI:0407”(direct interaction)	0.970
AIMP2	KARS1	psi-mi:“MI:2364”(proximity)	0.970
PSMA1	PSMA7	psi-mi:“MI:0914”(association)	0.950
AIMP2	FHL3	psi-mi:“MI:0915”(physical association)	0.910
FHL3	AIMP2	psi-mi:“MI:0915”(physical association)	0.910
DARS1	AIMP2	psi-mi:“MI:0915”(physical association)	0.830
AIMP2	DARS1	psi-mi:“MI:0915”(physical association)	0.830
AIMP2	BRME1	psi-mi:“MI:0915”(physical association)	0.830
LNX1	AIMP2	psi-mi:“MI:0915”(physical association)	0.830
BRME1	AIMP2	psi-mi:“MI:0915”(physical association)	0.830
AIMP2	LNX1	psi-mi:“MI:0915”(physical association)	0.830

BioGRID (660): AIMP2 (Two-hybrid), AIMP2 (Two-hybrid), AIMP2 (Two-hybrid), AIMP2 (Two-hybrid), AIMP2 (Two-hybrid), AIMP2 (Two-hybrid), AIMP2 (Two-hybrid), AIMP2 (Two-hybrid), AIMP1 (Two-hybrid), BCAS2 (Two-hybrid), TFIP11 (Two-hybrid), MIS18A (Two-hybrid), NECAB2 (Two-hybrid), C19orf57 (Two-hybrid), PLEKHF2 (Two-hybrid)

ESM2 similar proteins: A0A1U8QXK4, A2Q127, O04487, O14617, O75061, P06625, P08240, P12261, P15368, P26641, P26642, P29547, P29694, P30111, P35611, P36008, P40921, P54412, P78615, Q0II26, Q13155, Q17N71, Q27974, Q29387, Q32PX2, Q3MHE8, Q3SZV3, Q4R7H5, Q4WB03, Q5RA10, Q5Z627, Q68FR6, Q6PE25, Q6YW46, Q7PZD5, Q80TZ3, Q865S1, Q8R010, Q90YC0, Q91375

Diamond homologs: Q0II26, Q13155, Q32PX2, Q8R010, Q9WVM7

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
AIMP2	“form complex”	“Multiaminoacyl-tRNA synthetase”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 83 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Cytosolic tRNA aminoacylation	7	61.5×	5e-09
tRNA Aminoacylation	7	40.0×	6e-08
Selenoamino acid metabolism	7	27.6×	6e-07
Transcriptional and post-translational regulation of MITF-M expression and activity	7	25.0×	9e-07
MITF-M-regulated melanocyte development	7	16.0×	2e-05
Metabolism of amino acids and derivatives	7	9.5×	5e-04
Translation	7	8.7×	7e-04

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	19
Likely pathogenic	3
Uncertain significance	119
Likely benign	52
Benign	17

Top pathogenic / likely-pathogenic (22)

Variant ID	HGVS	Classification
1072971	NC_000007.13:g.(?6042074)(6049099_?)del	Pathogenic
1072972	NC_000007.13:g.(?6031594)(6049099_?)del	Pathogenic
1355763	NC_000007.13:g.(?6045672)(6054968_?)del	Pathogenic
1384204	NC_000007.13:g.(?6043311)(6049099_?)del	Pathogenic
1455078	NC_000007.13:g.(?6045513)(6049099_?)del	Pathogenic
1455079	NC_000007.13:g.(?6038729)(6049099_?)del	Pathogenic
1459232	NC_000007.13:g.(?6035155)(6049099_?)del	Pathogenic
2499066	GRCh37/hg19 7p22.1(chr7:6022454-6057676)x1	Pathogenic
3062019	Single allele	Pathogenic
3245661	NC_000007.13:g.(?6042150)(6113173_?)del	Pathogenic
3245665	NC_000007.13:g.(?6026370)(6057696_?)del	Pathogenic
3245666	NC_000007.14:g.(?5986749)(6009468_?)del	Pathogenic
4279238	GRCh37/hg19 7p22.1(chr7:5948815-6135748)x1	Pathogenic
443071	GRCh37/hg19 7p22.3-21.3(chr7:43360-12098696)x3	Pathogenic
4682690	GRCh37/hg19 7p22.1(chr7:6037641-6069165)x1	Pathogenic
688102	GRCh37/hg19 7p22.1(chr7:5606650-6185838)x3	Pathogenic
831202	NC_000007.14:g.(?6008925)(6009468_?)del	Pathogenic
832074	NC_000007.14:g.(?5972239)(6010106_?)del	Pathogenic
984997	NM_006303.4(AIMP2):c.75C>A (p.Tyr25Ter)	Pathogenic
3062023	NM_006303.4(AIMP2):c.656_659del (p.Ser219fs)	Likely pathogenic
428589	NM_006303.4(AIMP2):c.105C>A (p.Tyr35Ter)	Likely pathogenic
982311	NM_006303.4(AIMP2):c.74A>G (p.Tyr25Cys)	Likely pathogenic

SpliceAI

969 predictions. Top by Δscore:

Variant	Effect	Δscore
7:6015352:GGTA:G	donor_loss	1.0000
7:6015353:G:GA	donor_loss	1.0000
7:6017808:CCCCA:C	acceptor_loss	1.0000
7:6017809:CCCA:C	acceptor_loss	1.0000
7:6017810:CCA:C	acceptor_loss	1.0000
7:6017811:CA:C	acceptor_loss	1.0000
7:6017812:AG:A	acceptor_gain	1.0000
7:6017813:G:T	acceptor_loss	1.0000
7:6017813:GG:G	acceptor_gain	1.0000
7:6018041:GAATG:G	donor_gain	1.0000
7:6018043:ATGG:A	donor_loss	1.0000
7:6018044:TGG:T	donor_loss	1.0000
7:6018046:G:GG	donor_gain	1.0000
7:6018047:TAA:T	donor_loss	1.0000
7:6015144:A:AG	acceptor_gain	0.9900
7:6015145:G:GG	acceptor_gain	0.9900
7:6015145:GGAA:G	acceptor_gain	0.9900
7:6015348:GGAAG:G	donor_gain	0.9900
7:6015349:GAAG:G	donor_gain	0.9900
7:6015349:GAAGG:G	donor_gain	0.9900
7:6017800:T:A	acceptor_gain	0.9900
7:6017812:A:AG	acceptor_gain	0.9900
7:6017813:G:GA	acceptor_gain	0.9900
7:6017813:GGATT:G	acceptor_gain	0.9900
7:6018042:AATG:A	donor_gain	0.9900
7:6018043:ATG:A	donor_gain	0.9900
7:6018044:TG:T	donor_gain	0.9900
7:6018045:GG:G	donor_gain	0.9900
7:6023301:A:AG	acceptor_gain	0.9900
7:6023302:G:GG	acceptor_gain	0.9900

AlphaMissense

2108 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:6018036:T:A	W189R	0.999
7:6018036:T:C	W189R	0.999
7:6023632:T:A	W302R	0.996
7:6023632:T:C	W302R	0.996
7:6017839:T:A	V123E	0.995
7:6017847:G:C	A126P	0.995
7:6017936:C:A	H155Q	0.995
7:6017936:C:G	H155Q	0.995
7:6018025:T:C	F185S	0.995
7:6018037:G:C	W189S	0.995
7:6018038:G:C	W189C	0.995
7:6018038:G:T	W189C	0.995
7:6017842:T:A	I124N	0.994
7:6018034:T:A	I188N	0.993
7:6015228:T:A	V73D	0.992
7:6017832:G:C	D121H	0.992
7:6023372:G:C	R215P	0.992
7:6017928:C:G	H153D	0.990
7:6017934:C:G	H155D	0.990
7:6018031:T:C	L187S	0.990
7:6018034:T:G	I188S	0.990
7:6023318:T:A	M197K	0.990
7:6023318:T:G	M197R	0.990
7:6023348:T:A	I207N	0.990
7:6023369:C:A	A214E	0.990
7:6023375:T:C	F216S	0.990
7:6015207:T:C	L66P	0.989
7:6015216:T:C	L69S	0.989
7:6018036:T:G	W189G	0.989
7:6023371:C:A	R215S	0.989

dbSNP variants (sampled 300 via entrez): RS1000022382 (7:6017295 C>G,T), RS1000124086 (7:6015191 G>C), RS1000130106 (7:6012619 G>A,C), RS1000267917 (7:6012816 T>G), RS1000306148 (7:6007636 A>G), RS1000598642 (7:6007921 A>ACGAT), RS1000790886 (7:6017248 G>C,T), RS1000877261 (7:6020768 G>A), RS1000990016 (7:6020942 A>C), RS1001040501 (7:6018528 C>T), RS1001515848 (7:6011703 G>C), RS1001697594 (7:6016276 G>A), RS1001772979 (7:6022549 C>T), RS1001864242 (7:6008872 C>A), RS1001903891 (7:6013763 CAT>C)

Disease associations

OMIM: gene MIM:600859 | disease phenotypes: MIM:618006

GenCC curated gene-disease

Disease	Classification	Inheritance
leukodystrophy, hypomyelinating, 17	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
leukodystrophy, hypomyelinating, 17	Definitive	AR

Mondo (3): 7p22.1 microduplication syndrome (MONDO:0017792), leukodystrophy, hypomyelinating, 17 (MONDO:0054817), Lynch syndrome (MONDO:0005835)

Orphanet (2): 7p22.1 microduplication syndrome (Orphanet:314034), Lynch syndrome (Orphanet:144)

HPO phenotypes

27 total (27 of 27 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000212	Gingival overgrowth
HP:0000252	Microcephaly
HP:0000303	Mandibular prognathia
HP:0000463	Anteverted nares
HP:0000687	Widely spaced teeth
HP:0001007	Hirsutism
HP:0001250	Seizure
HP:0001272	Cerebellar atrophy
HP:0001344	Absent speech
HP:0001347	Hyperreflexia
HP:0001371	Flexion contracture
HP:0001510	Growth delay
HP:0001522	Death in infancy
HP:0002059	Cerebral atrophy
HP:0002079	Hypoplasia of the corpus callosum
HP:0002187	Profound intellectual disability
HP:0002415	Leukodystrophy
HP:0002521	Hypsarrhythmia
HP:0002540	Inability to walk
HP:0002751	Kyphoscoliosis
HP:0003593	Infantile onset
HP:0003676	Progressive
HP:0009765	Low hanging columella
HP:0011968	Feeding difficulties
HP:0012471	Thick vermilion border
HP:0012736	Profound global developmental delay

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST004619_147	Reticulocyte fraction of red cells	3.000000e-12
GCST90002385_178	High light scatter reticulocyte count	5.000000e-15
GCST90002386_125	High light scatter reticulocyte percentage of red cells	8.000000e-16
GCST90002405_218	Reticulocyte count	6.000000e-20
GCST90002406_237	Reticulocyte fraction of red cells	1.000000e-22

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007986	reticulocyte count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523285 (SINGLE PROTEIN)

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1062372	AIMP2, PMS2		0.00	0

ChEMBL bioactivities

25 potent at pChembl≥5 of 35 total, top 25 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.27	Kd	5.344	nM	CHEMBL3752910
8.27	ED50	5.344	nM	CHEMBL3752910
7.30	Kd	49.49	nM	CHEMBL5653589
7.30	ED50	49.49	nM	CHEMBL5653589
6.97	IC50	106.3	nM	CHEMBL5185433
6.61	IC50	244	nM	CHEMBL5201141
6.55	IC50	280	nM	CHEMBL5169384
6.14	IC50	724	nM	CHEMBL5205863
6.04	IC50	920	nM	CHEMBL4558745
5.92	IC50	1210	nM	CHEMBL5179442
5.69	IC50	2060	nM	CHEMBL6173329
5.62	IC50	2370	nM	CHEMBL6174347
5.51	Kd	3070	nM	CHEMBL4558745
5.45	IC50	3580	nM	CHEMBL4576024
5.42	Kd	3850	nM	CHEMBL4562996
5.38	IC50	4200	nM	CHEMBL4533418
5.25	IC50	5684	nM	CHEMBL1343907
5.24	IC50	5728	nM	CHEMBL5176027
5.13	IC50	7379	nM	CHEMBL3191785
5.09	IC50	8200	nM	CHEMBL4562996
5.09	IC50	8146	nM	CHEMBL5204979
5.05	IC50	8892	nM	CHEMBL5191679
5.05	IC50	8890	nM	CHEMBL5180687
5.01	IC50	9725	nM	CHEMBL5182133
5.00	IC50	1.011e+04	nM	CHEMBL3191785

PubChem BioAssay actives

20 with measured affinity, of 113 total; 18 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	2147826: Binding affinity to human AIMP2 incubated for 45 mins by Kinobead based pull down assay	kd	0.0053	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147826: Binding affinity to human AIMP2 incubated for 45 mins by Kinobead based pull down assay	kd	0.0495	uM
N-(2,3-dihydro-1,4-benzodioxin-3-ylmethyl)-2-(4-phenylphenyl)acetamide	1851079: Inhibition of AIMP2-DX2 in human A549 cells by nanoluciferase based assay	ic50	0.1063	uM
N-(2,3-dihydro-1,4-benzodioxin-3-ylmethyl)-2-(4-ethylphenyl)acetamide	1851079: Inhibition of AIMP2-DX2 in human A549 cells by nanoluciferase based assay	ic50	0.2440	uM
N-(2,3-dihydro-1,4-benzodioxin-3-ylmethyl)-2-(5,6-dimethyl-1-benzofuran-3-yl)acetamide	1851079: Inhibition of AIMP2-DX2 in human A549 cells by nanoluciferase based assay	ic50	0.2800	uM
N-(2,3-dihydro-1,4-benzodioxin-3-ylmethyl)-2-(4-hydroxy-2-methylphenyl)acetamide	1851079: Inhibition of AIMP2-DX2 in human A549 cells by nanoluciferase based assay	ic50	0.7240	uM
(2S)-3-(1H-indol-3-yl)-N-[4-(4-methoxyphenyl)-1,3-thiazol-2-yl]-2-[(4-methylphenyl)sulfonylamino]propanamide	1561872: Inhibition of nanoluciferase-tagged AIMP2 DX2 isoform (unknown origin) expressed in human A549 cells measured after 4 hrs by luminescence assay	ic50	0.9200	uM
N-(2,3-dihydro-1,4-benzodioxin-3-ylmethyl)-2-(4-fluorophenyl)acetamide	1851079: Inhibition of AIMP2-DX2 in human A549 cells by nanoluciferase based assay	ic50	1.2100	uM
4-(4-chlorophenyl)-6-(3-methoxypiperidin-1-yl)-N-[3-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]pyrimidin-2-amine	1605920: Inhibition of AIMP2 DX2 isoform (unknown origin) expressed in human A549 cells incubated for 4 hrs by luciferase reporter gene assay	ic50	3.5800	uM
4-(4-chlorophenyl)-N-[3-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]pyrimidin-2-amine	1605925: Binding affinity to AIMP2 DX2 isoform (unknown origin)	kd	3.8500	uM
(2S)-3-(1H-indol-3-yl)-2-[(4-methylphenyl)sulfonylamino]-N-(4-morpholin-4-ylphenyl)propanamide	1561872: Inhibition of nanoluciferase-tagged AIMP2 DX2 isoform (unknown origin) expressed in human A549 cells measured after 4 hrs by luminescence assay	ic50	4.2000	uM
N-(2,3-dihydro-1,4-benzodioxin-3-ylmethyl)-2-(6-methyl-1-benzofuran-3-yl)acetamide	1851078: Inhibition of AIMP2-DX2 in human A549 cells by luciferase assay	ic50	5.6840	uM
3-(3-chloro-4-methylphenyl)-1-[4-(2,3-dihydro-1,4-benzodioxine-3-carbonyl)piperazin-1-yl]propan-1-one	1851078: Inhibition of AIMP2-DX2 in human A549 cells by luciferase assay	ic50	5.7280	uM
3-[5-[(E)-(2,3-dihydro-1,4-benzodioxine-3-carbonylhydrazinylidene)methyl]furan-2-yl]benzoic acid	1851078: Inhibition of AIMP2-DX2 in human A549 cells by luciferase assay	ic50	7.3790	uM
N-(2,3-dihydro-1,4-benzodioxin-3-ylmethyl)-2-(6-ethyl-1-benzofuran-3-yl)acetamide	1851078: Inhibition of AIMP2-DX2 in human A549 cells by luciferase assay	ic50	8.1460	uM
N-(2,3-dihydro-1,4-benzodioxin-3-ylmethyl)-2-(1H-indol-5-yl)acetamide	1851079: Inhibition of AIMP2-DX2 in human A549 cells by nanoluciferase based assay	ic50	8.8900	uM
N-(2,3-dihydro-1,4-benzodioxin-3-ylmethyl)-2-naphthalen-2-ylacetamide	1851078: Inhibition of AIMP2-DX2 in human A549 cells by luciferase assay	ic50	8.8920	uM
6-tert-butyl-N-[(Z)-(2,4-dihydroxyphenyl)methylideneamino]-2,3-dihydro-1,4-benzodioxine-3-carboxamide	1851078: Inhibition of AIMP2-DX2 in human A549 cells by luciferase assay	ic50	9.7250	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, affects cotreatment, increases methylation	2
sodium arsenite	decreases expression	2
cobaltous chloride	decreases expression	2
Tretinoin	decreases expression	2
Valproic Acid	affects expression, decreases expression	2
Cyclosporine	increases expression	2
FR900359	decreases phosphorylation	1
bisphenol F	increases expression	1
dicrotophos	increases expression	1
salinomycin	decreases expression	1
N-benzyloxycarbonylprolylprolinal	increases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
cylindrospermopsin	increases expression	1
perfluoro-n-nonanoic acid	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	decreases expression	1
bisphenol B	increases expression	1
bisphenol S	increases expression	1
LDN 193189	affects cotreatment, decreases expression	1
(+)-JQ1 compound	decreases expression	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
Temozolomide	increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Acetaminophen	affects response to substance	1
Air Pollutants	decreases expression, increases abundance	1
Atrazine	decreases expression	1
Dichlorodiphenyl Dichloroethylene	increases expression	1
Doxorubicin	increases expression	1

ChEMBL screening assays

23 unique, capped per target: 21 binding, 2 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4359563	ADMET	Inhibition of nanoluciferase-tagged AIMP2 (unknown origin) expressed in human A549 cells measured after 4 hrs by luminescence assay	Synthesis and Structure-Activity Relationships of Arylsulfonamides as AIMP2-DX2 Inhibitors for the Development of a Novel Anticancer Therapy. — J Med Chem
CHEMBL4359564	Binding	Inhibition of nanoluciferase-tagged AIMP2 DX2 isoform (unknown origin) expressed in human A549 cells measured after 4 hrs by luminescence assay	Synthesis and Structure-Activity Relationships of Arylsulfonamides as AIMP2-DX2 Inhibitors for the Development of a Novel Anticancer Therapy. — J Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00566644	PHASE3	TERMINATED	Intrauterine Levonorgestrel and Observation or Observation Alone in Preventing Atypical Endometrial Hyperplasia and Endometrial Cancer in Women With Hereditary Non-Polyposis Colorectal Cancer or Lynch Syndrome
NCT02000089	PHASE3	RECRUITING	The Cancer of the Pancreas Screening-5 CAPS5)Study
NCT02813824	PHASE3	ACTIVE_NOT_RECRUITING	Effect of Chemoprevention by Low-dose Aspirin of New or Recurrent Colorectal Adenomas in Patients With Lynch Syndrome
NCT02912559	PHASE3	ACTIVE_NOT_RECRUITING	Combination Chemotherapy With or Without Atezolizumab in Treating Patients With Stage III Colon Cancer and Deficient DNA Mismatch Repair
NCT04711434	PHASE3	UNKNOWN	PD-1 Antibody for The Prevention of Adenomatous Polyps and Second Primary Tumors in Lynch Syndrome Patients
NCT07609901	PHASE3	NOT_YET_RECRUITING	Preventive Dendritic Cell Vaccination for Lynch Syndrome Carriers
NCT03631641	PHASE2	TERMINATED	Nivolumab in Preventing Colon Adenomas in Participants With Lynch Syndrome and a History of Partial Colectomy
NCT03831698	PHASE2	UNKNOWN	Omega 3 Fatty Acids in Colorectal Cancer (CRC) Prevention in Patients With Lynch Syndrome (COLYNE)
NCT04920149	PHASE2	RECRUITING	Mesalamine for Colorectal Cancer Prevention Program in Lynch Syndrome
NCT05411718	PHASE2	RECRUITING	A Phase IIa Randomized, Double-Blinded Clinical Trial of Naproxen or Aspirin for Cancer Immune Interception in Lynch Syndrome
NCT05419011	PHASE2	ACTIVE_NOT_RECRUITING	Testing a Combination of Vaccines for Cancer Prevention in Lynch Syndrome
NCT02052908	PHASE1	COMPLETED	Naproxen in Preventing DNA Mismatch Repair Deficient Colorectal Cancer in Patients With Lynch Syndrome
NCT02359565	PHASE1	ACTIVE_NOT_RECRUITING	Pembrolizumab in Treating Younger Patients With Recurrent, Progressive, or Refractory High-Grade Gliomas, Diffuse Intrinsic Pontine Gliomas, Hypermutated Brain Tumors, Ependymoma or Medulloblastoma
NCT04500548	PHASE1	WITHDRAWN	Testing the Combination of Two Immunotherapy Drugs (Nivolumab and Ipilimumab) in Children, Adolescent, and Young Adult Patients With Relapsed/Refractory Cancers That Have an Increased Number of Genetic Changes, The 3CI Study
NCT07163403	PHASE1	RECRUITING	First in Human Pilot Study to Assess the Safety and Efficacy of Dendritic Cells Loaded With Frameshift Derived Neopeptides for the Prevention of Cancer in of Lynch Syndrome Carriers
NCT05078866	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Cancer Preventive Vaccine Nous-209 for Lynch Syndrome Patients
NCT07412197	PHASE1/PHASE2	NOT_YET_RECRUITING	Preventive Dendritic Cell Vaccination for Lynch Syndrome
NCT00898768	EARLY_PHASE1	COMPLETED	Capsule Endoscopy to Screen for Small Bowel Neoplasia in Lynch Syndrome
NCT03832985	EARLY_PHASE1	COMPLETED	Pediatric Reporting of Adult-Onset Genomic Results
NCT04379999	EARLY_PHASE1	COMPLETED	Atorvastatin ± Aspirin in Lynch Syndrome Syndrome
NCT04906382	EARLY_PHASE1	TERMINATED	Tislelizumab for the Treatment of Recurrent Mismatch Repair Deficient Endometrial Cancer
NCT00508573	Not specified	COMPLETED	Registry for Women Who Are At Risk Or May Have Lynch Syndrome
NCT00582296	Not specified	ACTIVE_NOT_RECRUITING	Multi-Organ Screening Recommendations in Patients With Lynch Syndrome
NCT00609505	Not specified	COMPLETED	Telemedicine vs. Face-to-Face Cancer Genetic Counseling
NCT00633607	Not specified	COMPLETED	Hereditary Colorectal and Associated Tumor Registry Study
NCT00905710	Not specified	COMPLETED	Chromoendoscopy to Decrease the Risk of Colorectal Neoplasia in Lynch Syndrome
NCT00927680	Not specified	UNKNOWN	Familial Colorectal Cancer Registry in Hispanics
NCT01199250	Not specified	WITHDRAWN	Biomarkers in Samples From Patients With Endometrial Cancer
NCT01216930	Not specified	COMPLETED	Molecular Screening for Lynch Syndrome in Southern Denmark
NCT01582841	Not specified	COMPLETED	Integrating Genetic Testing for Lynch Syndrome in a Managed Care Setting
NCT01823471	Not specified	COMPLETED	I-Scan For Colon Polyp Detection In HNPCC
NCT01845753	Not specified	COMPLETED	Molecular Screening for Lynch Syndrome in Denmark
NCT01850654	Not specified	COMPLETED	Ohio Colorectal Cancer Prevention Initiative
NCT02012699	Not specified	RECRUITING	Integrated Cancer Repository for Cancer Research
NCT02053805	Not specified	UNKNOWN	Prostate Cancer Screening Among Men With High Risk Genetic Predisposition
NCT02194387	Not specified	ACTIVE_NOT_RECRUITING	Energy Balance Interventions in Increasing Physical Activity in Breast Cancer Gene Positive Patients, Lynch Syndrome-Positive Patients, CLL Survivors or High-Risk Family Members
NCT02198092	Not specified	COMPLETED	Preliminary Evaluation of Septin9 in Patients With Hereditary Colon Cancer Syndromes
NCT02206360	Not specified	ACTIVE_NOT_RECRUITING	Pancreatic Cancer Early Detection Program
NCT02371135	Not specified	ACTIVE_NOT_RECRUITING	Metagenomic Evaluation of the Gut Microbiome in Patients With Lynch Syndrome and Other Hereditary Colonic Polyposis Syndromes
NCT02494791	Not specified	UNKNOWN	Universal Screening for Lynch Syndrome in Women With Endometrial and Non-Serous Ovarian Cancer