IARS2

Summary

IARS2 (isoleucyl-tRNA synthetase 2, mitochondrial, HGNC:29685) is a protein-coding gene on chromosome 1q41, encoding Isoleucine–tRNA ligase, mitochondrial (Q9NSE4). Aminoacyl-tRNA synthetase that catalyzes the specific attachment of isoleucine to its cognate tRNA (tRNA(Ile)). It is a selective cancer dependency (DepMap: 84.9% of cell lines).

Aminoacyl-tRNA synthetases catalyze the aminoacylation of tRNA by their cognate amino acid. Because of their central role in linking amino acids with nucleotide triplets contained in tRNAS, aminoacyl-tRNA synthetases are thought to be among the first proteins that appeared in evolution. Two forms of isoleucine-tRNA synthetase exist, a cytoplasmic form and a mitochondrial form. This gene encodes the mitochondrial isoleucine-tRNA synthetase which belongs to the class-I aminoacyl-tRNA synthetase family.

Source: NCBI Gene 55699 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 642 total — 16 pathogenic, 10 likely-pathogenic
• Phenotypes (HPO): 167
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 84.9% of screened cell lines
• MANE Select transcript: NM_018060

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29685
Approved symbol	IARS2
Name	isoleucyl-tRNA synthetase 2, mitochondrial
Location	1q41
Locus type	gene with protein product
Status	Approved
Aliases	FLJ10326
Ensembl gene	ENSG00000067704
Ensembl biotype	protein_coding
OMIM	612801
Entrez	55699

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 10 protein_coding, 3 protein_coding_CDS_not_defined

ENST00000366922, ENST00000467924, ENST00000488777, ENST00000490891, ENST00000873464, ENST00000873465, ENST00000930953, ENST00000930954, ENST00000930955, ENST00000948320, ENST00000948321, ENST00000948322, ENST00000948323

RefSeq mRNA: 1 — MANE Select: NM_018060 NM_018060

CCDS: CCDS1523

Canonical transcript exons

ENST00000366922 — 23 exons

Exon	Start	End
ENSE00000801814	220137918	220138043
ENSE00000801816	220140183	220140289
ENSE00000801820	220145509	220145653
ENSE00001068892	220096104	220096226
ENSE00001126532	220110786	220110937
ENSE00001126542	220105891	220106060
ENSE00001126549	220142944	220143134
ENSE00001126557	220107061	220107151
ENSE00001126574	220103447	220103562
ENSE00001126581	220102687	220102777
ENSE00001126592	220102495	220102604
ENSE00001126601	220102129	220102277
ENSE00001126701	220136809	220136911
ENSE00001126728	220114314	220114474
ENSE00001126738	220102363	220102412
ENSE00001126748	220100490	220100649
ENSE00001442995	220147493	220148041
ENSE00001442996	220094132	220094483
ENSE00003498042	220139008	220139139
ENSE00003544887	220125237	220125339
ENSE00003550127	220134402	220134510
ENSE00003600754	220141803	220141948
ENSE00003670141	220126750	220126843

Expression profiles

Bgee: expression breadth ubiquitous, 293 present calls, max score 97.32.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 59.6216 / max 365.8320, expressed in 1827 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
8636	59.6216	1827

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
diaphragm	UBERON:0001103	97.32	gold quality
parietal pleura	UBERON:0002400	97.04	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	97.01	gold quality
esophagus squamous epithelium	UBERON:0006920	96.85	gold quality
bronchial epithelial cell	CL:0002328	96.68	gold quality
tongue squamous epithelium	UBERON:0006919	96.68	gold quality
left ventricle myocardium	UBERON:0006566	96.66	gold quality
adrenal tissue	UBERON:0018303	96.65	gold quality
heart right ventricle	UBERON:0002080	96.62	gold quality
biceps brachii	UBERON:0001507	96.55	gold quality
epithelium of esophagus	UBERON:0001976	96.44	gold quality
vastus lateralis	UBERON:0001379	96.43	gold quality
myocardium	UBERON:0002349	96.34	gold quality
epithelium of bronchus	UBERON:0002031	96.27	gold quality
epithelium of nasopharynx	UBERON:0001951	96.17	gold quality
tendon of biceps brachii	UBERON:0008188	96.14	gold quality
quadriceps femoris	UBERON:0001377	96.12	gold quality
mucosa of sigmoid colon	UBERON:0004993	96.10	gold quality
cardiac muscle of right atrium	UBERON:0003379	96.08	gold quality
colonic mucosa	UBERON:0000317	96.07	gold quality
bronchus	UBERON:0002185	96.05	gold quality
pleura	UBERON:0000977	95.99	gold quality
rectum	UBERON:0001052	95.90	gold quality
upper arm skin	UBERON:0004263	95.88	gold quality
secondary oocyte	CL:0000655	95.87	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	95.85	gold quality
oral cavity	UBERON:0000167	95.76	gold quality
islet of Langerhans	UBERON:0000006	95.66	gold quality
palpebral conjunctiva	UBERON:0001812	95.57	gold quality
right adrenal gland	UBERON:0001233	95.39	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.14

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

24 targeting IARS2, 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-5011-5P	100.00	83.46	5820
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-3941	99.86	70.54	2735
HSA-MIR-544A	99.84	68.66	1965
HSA-MIR-3180-5P	99.82	69.12	2422
HSA-MIR-5571-5P	99.49	66.99	1764
HSA-MIR-4797-5P	99.39	68.01	1354
HSA-MIR-7151-5P	99.37	67.82	613
HSA-MIR-4427	99.34	70.33	1854
HSA-MIR-376A-3P	99.06	69.17	1128
HSA-MIR-376B-3P	99.06	69.17	1128
HSA-MIR-4709-3P	98.88	68.04	1594
HSA-MIR-3124-3P	98.87	68.95	2123
HSA-MIR-532-5P	98.43	67.53	760
HSA-MIR-6870-3P	98.08	65.10	692
HSA-MIR-337-3P	97.90	69.37	1052
HSA-MIR-575	97.54	65.18	718
HSA-MIR-4676-5P	97.54	65.29	715

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 84.9% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 7)

• This study is the first report of clinical findings associated with IARS2 mutations. (PMID:25130867)
• IARS2 silencing induced NSCLC cells growth inhibition, cell cycle arrest and promoted cell apoptosis (PMID:26639235)
• The expression of IARS2 gene is different in human colon cancer and surrounding tissues. IARS2 gene is probably a cancer-promoting gene (PMID:26722399)
• Patients with this very rare mutation present with a myriad of ocular findings, including infantile cataract, neurotrophic keratitis, corneal opacification, and orbital myopathy. (PMID:27078007)
• IARS2 knockdown can inhibit acute myeloid leukemia HL-60 cell proliferation and cause cell cycle arrest at the G1 phase by regulating the p53/p21/PCNA/eIF4E pathways. (PMID:30832756)
• Biallelic IARS2 mutations presenting as sideroblastic anemia. (PMID:33327715)
• IARS2 mutations lead to Leigh syndrome with a combined oxidative phosphorylation deficiency. (PMID:39169373)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	iars2	ENSDARG00000044134
mus_musculus	Iars2	ENSMUSG00000026618
rattus_norvegicus	Iars2	ENSRNOG00000002368
drosophila_melanogaster	IleRS-m	FBGN0036569
caenorhabditis_elegans	iars-2	WBGENE00002153

Paralogs (7): LARS2 (ENSG00000011376), LARS1 (ENSG00000133706), VARS2 (ENSG00000137411), MARS1 (ENSG00000166986), IARS1 (ENSG00000196305), VARS1 (ENSG00000204394), MARS2 (ENSG00000247626)

Protein

Protein identifiers

Isoleucine–tRNA ligase, mitochondrial — Q9NSE4 (reviewed: Q9NSE4)

Alternative names: Isoleucyl-tRNA synthetase

All UniProt accessions (1): Q9NSE4

UniProt curated annotations — full annotation on UniProt →

Function. Aminoacyl-tRNA synthetase that catalyzes the specific attachment of isoleucine to its cognate tRNA (tRNA(Ile)).

Subcellular location. Mitochondrion matrix.

Disease relevance. Cataracts, growth hormone deficiency, sensory neuropathy, sensorineural hearing loss, and skeletal dysplasia (CAGSSS) [MIM:616007] An autosomal recessive disorder characterized by cataracts, short-stature secondary to growth hormone deficiency, sensorineural hearing deficit, peripheral sensory neuropathy, skeletal dysplasia, scoliosis, and facial dysmorphism. The disease may be caused by variants affecting the gene represented in this entry.

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

RefSeq proteins (1): NP_060530* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001412	aa-tRNA-synth_I_CS	Conserved_site
IPR002300	aa-tRNA-synth_Ia	Domain
IPR002301	Ile-tRNA-ligase	Family
IPR009008	Val/Leu/Ile-tRNA-synth_edit	Homologous_superfamily
IPR009080	tRNAsynth_Ia_anticodon-bd	Homologous_superfamily
IPR010663	Znf_FPG/IleRS	Domain
IPR013155	M/V/L/I-tRNA-synth_anticd-bd	Domain
IPR014729	Rossmann-like_a/b/a_fold	Homologous_superfamily
IPR023585	Ile-tRNA-ligase_type1	Family
IPR033708	Anticodon_Ile_BEm	Domain
IPR050081	Ile-tRNA_ligase	Family

Pfam: PF00133, PF06827, PF08264

Enzyme classification (BRENDA):

• EC 6.1.1.5 — isoleucine-tRNA ligase (BRENDA: 24 organisms, 62 substrates, 130 inhibitors, 61 Km, 49 kcat entries)

Substrate kinetics (BRENDA)

10 substrates with measured Km, best-characterized 10. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
L-ISOLEUCINE	—	15
ATP	0.0003–4.4	12
TRNAILE1	0.0001–0.0016	8
TRNAILE2	0.0001–0.0004	6
TRNAILE	0.0001–0.0021	4
ILE	0.0036–1.3	3
L-NORVALINE	0.47–11	2
L-VALINE	0.82–7.9	2
AMP	—	0
ISOLEUCINE	—	0

Catalyzed reactions (Rhea), 1 shown:

• tRNA(Ile) + L-isoleucine + ATP = L-isoleucyl-tRNA(Ile) + AMP + diphosphate (RHEA:11060)

UniProt features (34 total): modified residue 14, sequence variant 12, short sequence motif 2, sequence conflict 2, binding site 2, transit peptide 1, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NSE4-F1	89.77	0.79

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 (2): 664; 667

Post-translational modifications (14): 233, 241, 241, 479, 500, 725, 775, 775, 781, 781, 74, 74, 189, 194

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-379726	Mitochondrial tRNA aminoacylation
R-HSA-9837999	Mitochondrial protein degradation
R-HSA-379724	tRNA Aminoacylation
R-HSA-392499	Metabolism of proteins
R-HSA-72766	Translation

MSigDB gene sets: 441 (showing top): BORCZUK_MALIGNANT_MESOTHELIOMA_UP, GOBP_AMINO_ACID_ACTIVATION, GOBP_TRNA_METABOLIC_PROCESS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_MITOCHONDRIAL_TRANSLATION, PUJANA_CHEK2_PCC_NETWORK, GOBP_TRANSLATION, APPIERTO_RESPONSE_TO_FENRETINIDE_DN, TIEN_INTESTINE_PROBIOTICS_24HR_UP, KEGG_AMINOACYL_TRNA_BIOSYNTHESIS, GOBP_REGULATION_OF_TRANSLATIONAL_FIDELITY, REACTOME_MITOCHONDRIAL_TRNA_AMINOACYLATION, MODULE_18, ACEVEDO_LIVER_CANCER_UP, GOCC_MITOCHONDRIAL_MATRIX

GO Biological Process (5): tRNA aminoacylation for protein translation (GO:0006418), isoleucyl-tRNA aminoacylation (GO:0006428), mitochondrial translation (GO:0032543), translation (GO:0006412), aminoacyl-tRNA metabolism involved in translational fidelity (GO:0106074)

GO Molecular Function (7): tRNA binding (GO:0000049), aminoacyl-tRNA deacylase activity (GO:0002161), isoleucine-tRNA ligase activity (GO:0004822), ATP binding (GO:0005524), nucleotide binding (GO:0000166), aminoacyl-tRNA ligase activity (GO:0004812), ligase activity (GO:0016874)

GO Cellular Component (2): mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Metabolism of proteins	2
tRNA Aminoacylation	1
Translation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
translation	2
mitochondrion	2
catalytic activity, acting on a tRNA	2
tRNA aminoacylation	1
tRNA aminoacylation for protein translation	1
mitochondrial gene expression	1
peptidyltransferase activity	1
translational initiation	1
translational elongation	1
translational termination	1
macromolecule biosynthetic process	1
protein metabolic process	1
protein biosynthetic process	1
tRNA metabolic process	1
regulation of translational fidelity	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
nucleoside phosphate binding	1
heterocyclic compound binding	1
ligase activity, forming carbon-oxygen bonds	1
catalytic activity	1
cytoplasm	1
intracellular membrane-bounded organelle	1
intracellular organelle lumen	1

Protein interactions and networks

STRING

2938 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IARS2	MARS1	P56192	994
IARS2	MARS2	Q96GW9	994
IARS2	LARS1	Q9P2J5	993
IARS2	KARS1	Q15046	987
IARS2	QARS1	P47897	982
IARS2	RARS2	Q5T160	974
IARS2	EPRS1	P07814	966
IARS2	LARS2	Q15031	965
IARS2	RARS1	P54136	959
IARS2	PARS2	Q7L3T8	956
IARS2	AARS1	P49588	904
IARS2	CARS2	Q9HA77	902
IARS2	CARS1	P49589	889
IARS2	SARS1	P49591	885
IARS2	TARS2	Q9BW92	882

IntAct

145 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
RAF1	CALU	psi-mi:“MI:0914”(association)	0.640
NDUFS7	NDUFS8	psi-mi:“MI:0914”(association)	0.640
IARS2	GAK	psi-mi:“MI:0914”(association)	0.530
CELF5	CASC3	psi-mi:“MI:0914”(association)	0.530
YBEY	NME4	psi-mi:“MI:0914”(association)	0.530
ASB8	CUL5	psi-mi:“MI:0914”(association)	0.530
IARS2		psi-mi:“MI:0915”(physical association)	0.490
HSCB	NDUFS8	psi-mi:“MI:0914”(association)	0.460
sseJ	AGPS	psi-mi:“MI:0914”(association)	0.460
AIFM1	HAX1	psi-mi:“MI:0914”(association)	0.420
AIFM1	HAX1	psi-mi:“MI:2364”(proximity)	0.420
HTRA2	HAX1	psi-mi:“MI:2364”(proximity)	0.420
IARS2	FOXM1	psi-mi:“MI:0915”(physical association)	0.400
IARS2	SNRPA	psi-mi:“MI:0915”(physical association)	0.400
IARS2	HSPB1	psi-mi:“MI:0915”(physical association)	0.370
SIRT4	VWA8	psi-mi:“MI:0914”(association)	0.350
ECSIT	NDUFS2	psi-mi:“MI:0914”(association)	0.350
Papss1	TCOF1	psi-mi:“MI:0914”(association)	0.350
Bub1b	ASAH1	psi-mi:“MI:0914”(association)	0.350
CHORDC1	SSR3	psi-mi:“MI:0914”(association)	0.350
PARD6B	PARD3	psi-mi:“MI:0914”(association)	0.350
KLC4	PUF60	psi-mi:“MI:0914”(association)	0.350
Nek2	WDR46	psi-mi:“MI:0914”(association)	0.350
Cul1	GPS1	psi-mi:“MI:0914”(association)	0.350

BioGRID (359): IARS2 (Affinity Capture-MS), IARS2 (Two-hybrid), GRSF1 (Co-fractionation), HNRNPH1 (Co-fractionation), HNRNPH2 (Co-fractionation), HNRNPH3 (Co-fractionation), HYAL4 (Co-fractionation), IARS2 (Affinity Capture-MS), IARS2 (Synthetic Lethality), IARS2 (Proximity Label-MS), IARS2 (Affinity Capture-MS), IARS2 (Affinity Capture-MS), IARS2 (Affinity Capture-MS), IARS2 (Affinity Capture-MS), IARS2 (Affinity Capture-MS)

ESM2 similar proteins: A0A1D6LAG9, A2YQ56, A6H7E1, B3LFA4, B8B4H5, B9FK36, B9FSH5, F4I1L3, F4IPY2, F4KE63, O23247, O24357, O75005, P49589, P49696, P93736, Q0IZQ2, Q2KIF8, Q2QMG2, Q43727, Q43768, Q43794, Q43839, Q499X9, Q4R646, Q5M7N8, Q5ZKA2, Q69UZ3, Q6DJ95, Q6GQJ7, Q6PA41, Q7T0Z0, Q8BIJ6, Q8BYM8, Q8L743, Q8L785, Q8RXE9, Q8RXK8, Q8S6N5, Q90YI3

Diamond homologs: A2BP36, A2BUL8, A2C071, A3PAV8, A4IM25, A4XKR2, A5IML2, A6LK77, A6Q4I1, A6QB84, A7GRM0, A7HMY6, A7I1S7, A8G2P6, A8YUP7, A8Z6P6, A9BDK6, A9BI29, A9VTD5, B0C872, B0JSP4, B0K2W1, B0K8R7, B0SBW4, B0STE5, B1WVA3, B2G6L2, B2IZP5, B2V9T1, B3DYQ6, B4U8K1, B7H6N1, B7HLM9, B7IGT1, B7IUQ5, B7JJY2, B7K5H5, B7KFT1, B8CWL4, B8FT35

SIGNOR signaling

0 interactions.

Enriched among interaction partners

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

GO biological processes:

GO term	Partners	Fold	FDR
mitochondrion organization	8	7.5×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	16
Likely pathogenic	10
Uncertain significance	269
Likely benign	238
Benign	60

Top pathogenic / likely-pathogenic (26)

Variant ID	HGVS	Classification
1468343	NM_018060.4(IARS2):c.351T>G (p.Tyr117Ter)	Pathogenic
1524256	NM_018060.4(IARS2):c.2062G>T (p.Glu688Ter)	Pathogenic
1925086	NM_018060.4(IARS2):c.288_289del (p.Tyr97fs)	Pathogenic
2158656	NM_018060.4(IARS2):c.314_318del (p.Val105fs)	Pathogenic
2831739	NM_018060.4(IARS2):c.419del (p.His140fs)	Pathogenic
2881068	NM_018060.4(IARS2):c.2775del (p.Ser926fs)	Pathogenic
3248006	NC_000001.10:g.(?220307724)(220307872_?)del	Pathogenic
3248008	NC_000001.10:g.(?220267559)(220269588_?)del	Pathogenic
3768372	NM_018060.4(IARS2):c.280dup (p.Ser94fs)	Pathogenic
4621906	NM_018060.4(IARS2):c.2043dup (p.Gly682fs)	Pathogenic
4705467	NM_018060.4(IARS2):c.1729dup (p.Glu577fs)	Pathogenic
4719770	NM_018060.4(IARS2):c.330C>A (p.Cys110Ter)	Pathogenic
4778519	NM_018060.4(IARS2):c.2758C>T (p.Gln920Ter)	Pathogenic
638569	NM_018060.4(IARS2):c.680T>C (p.Phe227Ser)	Pathogenic
638571	NM_018060.4(IARS2):c.2725C>T (p.Pro909Ser)	Pathogenic
638572	NM_018060.4(IARS2):c.2282A>G (p.His761Arg)	Pathogenic
1371228	NM_018060.4(IARS2):c.267+2T>A	Likely pathogenic
1675405	NM_018060.4(IARS2):c.1774_1777del (p.Pro592fs)	Likely pathogenic
1710798	NM_018060.4(IARS2):c.2446C>T (p.Arg816Ter)	Likely pathogenic
2503287	NM_018060.4(IARS2):c.2350C>T (p.Arg784Trp)	Likely pathogenic
4716816	NM_018060.4(IARS2):c.860-1G>A	Likely pathogenic
4734907	NM_018060.4(IARS2):c.1066+1G>T	Likely pathogenic
4813835	NM_018060.4(IARS2):c.890G>A (p.Trp297Ter)	Likely pathogenic
488929	NM_018060.4(IARS2):c.55C>T (p.Arg19Ter)	Likely pathogenic
504356	NM_018060.4(IARS2):c.1342C>T (p.Gln448Ter)	Likely pathogenic
638568	NM_018060.4(IARS2):c.2620G>A (p.Gly874Arg)	Likely pathogenic

SpliceAI

3256 predictions. Top by Δscore:

Variant	Effect	Δscore
1:220094480:GCAG:G	donor_gain	1.0000
1:220094481:CAGGT:C	donor_loss	1.0000
1:220094482:AGG:A	donor_loss	1.0000
1:220094483:GGTAC:G	donor_loss	1.0000
1:220094484:G:GA	donor_loss	1.0000
1:220094484:G:GG	donor_gain	1.0000
1:220095664:G:T	donor_gain	1.0000
1:220096097:A:AG	acceptor_gain	1.0000
1:220096098:A:G	acceptor_gain	1.0000
1:220096102:A:AG	acceptor_gain	1.0000
1:220096102:AGAA:A	acceptor_loss	1.0000
1:220096103:G:GA	acceptor_gain	1.0000
1:220096103:GA:G	acceptor_gain	1.0000
1:220096103:GAA:G	acceptor_gain	1.0000
1:220096103:GAAA:G	acceptor_gain	1.0000
1:220096103:GAAAT:G	acceptor_gain	1.0000
1:220096222:ATAAG:A	donor_loss	1.0000
1:220096227:GTAA:G	donor_loss	1.0000
1:220096228:T:A	donor_loss	1.0000
1:220100485:TGCA:T	acceptor_loss	1.0000
1:220100486:GCA:G	acceptor_loss	1.0000
1:220100487:CAG:C	acceptor_loss	1.0000
1:220100488:A:AG	acceptor_gain	1.0000
1:220100488:A:T	acceptor_loss	1.0000
1:220100489:G:GA	acceptor_gain	1.0000
1:220100489:GA:G	acceptor_gain	1.0000
1:220100489:GAT:G	acceptor_gain	1.0000
1:220100489:GATT:G	acceptor_gain	1.0000
1:220100489:GATTT:G	acceptor_gain	1.0000
1:220100645:GAAAG:G	donor_gain	1.0000

AlphaMissense

6623 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:220114405:G:T	R524M	0.998
1:220100499:G:C	D134H	0.997
1:220100512:G:C	R138P	0.997
1:220100556:T:A	W153R	0.997
1:220100556:T:C	W153R	0.997
1:220110899:T:A	W481R	0.997
1:220110899:T:C	W481R	0.997
1:220110902:T:C	F482L	0.997
1:220110904:T:A	F482L	0.997
1:220110904:T:G	F482L	0.997
1:220114405:G:C	R524T	0.997
1:220134455:T:A	W631R	0.997
1:220134455:T:C	W631R	0.997
1:220140283:A:T	K803I	0.997
1:220100500:A:C	D134A	0.996
1:220102731:T:A	W302R	0.996
1:220102731:T:C	W302R	0.996
1:220126804:T:A	W600R	0.996
1:220126804:T:C	W600R	0.996
1:220140284:A:C	K803N	0.996
1:220140284:A:T	K803N	0.996
1:220100497:A:T	K133I	0.995
1:220100498:A:C	K133N	0.995
1:220100498:A:T	K133N	0.995
1:220102518:T:C	L258P	0.995
1:220106025:G:C	D401H	0.995
1:220114397:T:G	C521W	0.995
1:220114399:T:A	I522K	0.995
1:220114406:G:C	R524S	0.995
1:220114406:G:T	R524S	0.995

dbSNP variants (sampled 300 via entrez): RS1000011318 (1:220125656 T>G), RS1000136136 (1:220095791 G>A), RS1000175374 (1:220121703 C>G), RS1000260667 (1:220133182 C>T), RS1000313241 (1:220129033 C>A,T), RS1000422151 (1:220134772 T>G), RS1000423312 (1:220114407 C>G), RS1000424660 (1:220127236 G>A,T), RS1000510918 (1:220119793 G>A), RS1000683753 (1:220128575 A>G), RS1000721951 (1:220132948 C>G), RS1000791145 (1:220107269 GT>G), RS1000884466 (1:220107566 C>T), RS1000934206 (1:220095065 C>G), RS1000973286 (1:220139987 A>G,T)

Disease associations

OMIM: gene MIM:612801 | disease phenotypes: MIM:616007, MIM:256000, MIM:116200, MIM:614225, MIM:212720

GenCC curated gene-disease

Disease	Classification	Inheritance
cataract-growth hormone deficiency-sensory neuropathy-sensorineural hearing loss-skeletal dysplasia syndrome	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
mitochondrial disease	Definitive	AR
Leigh syndrome	Limited	AR

Mondo (6): cataract-growth hormone deficiency-sensory neuropathy-sensorineural hearing loss-skeletal dysplasia syndrome (MONDO:0014455), Leigh syndrome (MONDO:0009723), cataract (MONDO:0005129), peripheral neuropathy (MONDO:0005244), Warburg micro syndrome 2 (MONDO:0013641), Martsolf syndrome (MONDO:0023910)

Orphanet (4): Cataract-growth hormone deficiency-sensory neuropathy-sensorineural hearing loss-skeletal dysplasia syndrome (Orphanet:436174), Leigh syndrome (Orphanet:506), Cataract-intellectual disability-hypogonadism syndrome (Orphanet:1387), Micro syndrome (Orphanet:2510)

HPO phenotypes

167 total (30 of 167 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000100	Nephrotic syndrome
HP:0000124	Renal tubular dysfunction
HP:0000160	Narrow mouth
HP:0000233	Thin vermilion border
HP:0000238	Hydrocephalus
HP:0000303	Mandibular prognathia
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000348	High forehead
HP:0000399	Prelingual sensorineural hearing impairment
HP:0000400	Macrotia
HP:0000407	Sensorineural hearing impairment
HP:0000408	Progressive sensorineural hearing impairment
HP:0000430	Underdeveloped nasal alae
HP:0000486	Strabismus
HP:0000490	Deeply set eye
HP:0000508	Ptosis
HP:0000518	Cataract
HP:0000519	Developmental cataract
HP:0000540	Hypermetropia
HP:0000565	Esotropia
HP:0000574	Thick eyebrow
HP:0000587	Abnormal optic nerve morphology
HP:0000602	Ophthalmoplegia
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000666	Horizontal nystagmus
HP:0000763	Sensory neuropathy
HP:0000824	Decreased response to growth hormone stimulation test

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST011369_4	Iron status biomarkers (ferritin levels)	1.000000e-13

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004459	ferritin measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D002386	Cataract	C11.510.245
D007888	Leigh Disease	C10.228.140.163.100.412; C16.320.565.189.412; C16.320.565.202.810.444; C18.452.132.100.412; C18.452.648.189.412; C18.452.648.202.810.444; C18.452.660.520

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4105821 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 3,452 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL2107832	PIMASERTIB	2	3,452

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

ChEMBL bioactivities

3 potent at pChembl≥5 of 3 total, top 3 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.96	Kd	11	nM	PIMASERTIB
6.11	Kd	778.5	nM	CHEMBL5653589
6.11	ED50	778.5	nM	CHEMBL5653589

PubChem BioAssay actives

2 with measured affinity, of 134 total; 2 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
N-[(2S)-2,3-dihydroxypropyl]-3-(2-fluoro-4-iodoanilino)pyridine-4-carboxamide	1425020: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.0110	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148566: Binding affinity to human IARS2 incubated for 45 mins by Kinobead based pull down assay	kd	0.7785	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Acetaminophen	decreases expression	4
bisphenol A	affects expression, increases expression	2
sodium arsenite	decreases expression, increases expression	2
aristolochic acid I	decreases expression	1
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
bisphenol F	affects cotreatment, decreases expression	1
triphenyl phosphate	affects expression	1
uranyl acetate	affects expression	1
sodium arsenate	decreases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, increases expression	1
cobaltous chloride	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
azoxystrobin	increases expression	1
chloropicrin	decreases expression	1
nutlin 3	affects cotreatment, increases secretion	1
abrine	decreases expression	1
2-amino-14,16-dimethyloctadecan-3-ol	increases expression	1
bisphenol S	increases expression	1
picoxystrobin	increases expression	1
bisphenol AF	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Dactinomycin	affects cotreatment, increases secretion	1
Dexamethasone	affects cotreatment, decreases expression	1
Doxorubicin	increases expression	1
Furaldehyde	decreases expression, affects cotreatment	1
Indomethacin	affects cotreatment, decreases expression	1
Ivermectin	decreases expression	1
Methyl Methanesulfonate	decreases expression	1
Phthalic Acids	decreases methylation	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
CHEMBL3991733	Binding	Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by ma	The target landscape of clinical kinase drugs. — Science

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00273221	PHASE4	UNKNOWN	Combined Phacotube vs Phacotrabeculectomy:A Randomized Controlled Trial
NCT00312299	PHASE4	COMPLETED	Posterior Capsule Opacification Study
NCT00345046	PHASE4	COMPLETED	A Comparison of Three Different Formulations of Prednisolone Acetate 1%
NCT00347243	PHASE4	COMPLETED	Wavefront Analisys and Contrast Sensitivity of Spherical and Aspherical Intraocular Lenses
NCT00347503	PHASE4	COMPLETED	Aqueous Concentrations and PGE2 Inhibition of Ketorolac 0.4% vs. Bromfenac 0.09% in Cataract Patients
NCT00348244	PHASE4	COMPLETED	Ketorolac vs. Steroid in the Prevention of CME
NCT00348270	PHASE4	COMPLETED	Comparison of the Quality of Vision Provided by AMO Tecnis Z9000 and Alcon Laboratories MA60 Acrysof Posterior Chamber Intraocular Lenses
NCT00348582	PHASE4	COMPLETED	Acular LS vs. Nevanac in Post op Inflammation Following Cataract Surgery
NCT00348621	PHASE4	COMPLETED	A Study of Interventions to Reduce Disability From Visual Loss in Nursing Home Residents
NCT00349583	PHASE4	COMPLETED	Efficacy of Topical Cyclosporine Versus Tears for Improving Visual Outcomes Following Multifocal IOL Implantation
NCT00355446	PHASE4	COMPLETED	Bioavailability of Bimatoprost Ophthalmic Solution in Human Aqueous.
NCT00386438	PHASE4	COMPLETED	Efficacy of Honan Balloon in Intraocular Pressure Reduction Before Phacoemulsification
NCT00392275	PHASE4	COMPLETED	Penetrance of Third Generation Fluoroquinolones in Eyes With Functioning Filtering Blebs
NCT00428363	PHASE4	COMPLETED	Effect of Optic Edge Design in a Silicone Intraocular Lens on Posterior Capsule Opacification
NCT00449267	PHASE4	COMPLETED	Aurolab Hydrophobic Foldable Intraocular Lens Study
NCT00459303	PHASE4	COMPLETED	Comparison of Functional Vision Provided by AMO Tecnis Z9000 and Alcon SA60AT Acrysof
NCT00469690	PHASE4	COMPLETED	Aqueous Concentrations and PGE2 Inhibition of Ketorolac 0.4% vs. Bromfenac 0.09% in Cataract Patients: Trough Drug Effects
NCT00576485	PHASE4	COMPLETED	Spherical Aberration and Contrast Sensitivity in IOLs
NCT00612729	PHASE4	COMPLETED	Light Filters in Intraocular Lenses (IOLs) and Its Influence on Colour and Contrast Vision.
NCT00612781	PHASE4	COMPLETED	Yellow Versus White Study
NCT00630019	PHASE4	COMPLETED	Ocular Tissue Levels of 1.5% Levofloxacin Ophthalmic Solution Compared to an Active Comparator
NCT00673803	PHASE4	COMPLETED	Influence of Two Different Preloaded Intraocular Lens (IOLs) on Posterior Capsule Opacification
NCT00684138	PHASE4	COMPLETED	ACRYSOF® ReSTOR® Aspheric +3.0 D Add Power Intraocular Lens (IOL)
NCT00698724	PHASE4	COMPLETED	Comparing Optical Coherence Tomography (OCT) and Visual Acuity Outcomes in Subjects Undergoing Cataract Surgery, Who Receive Xibrom Ophthalmic Solution and Standard Presurgical Care vs. Xibrom Ophthalmic Solution Plus Prednisolone Acetate 1% and Standard Presurgical Care
NCT00710905	PHASE4	TERMINATED	Visual Function With Contralateral AcrySof® ReSTOR® Aspheric SN6AD1 and SN6AD3
NCT00710931	PHASE4	COMPLETED	Visual Function With Bilateral AcrySof® ReSTOR® Aspheric SN6AD1
NCT00711347	PHASE4	COMPLETED	Intraoperative Floppy Iris Syndrome
NCT00712244	PHASE4	COMPLETED	DisCoVisc Versus DuoVisc, Healon5 and AmVisc Plus
NCT00717080	PHASE4	COMPLETED	The Role of Capsular Tension Ring (CTR) in Anterior Capsular Contraction
NCT00719732	PHASE4	COMPLETED	Visual Function After Implantation of Bilateral AcrySof ReSTOR Aspheric +3
NCT00721253	PHASE4	COMPLETED	Visual Outcomes of Subjects Bilaterally Implanted With ReSTOR Aspheric +4 vs. Tecnis or Acri.LISA
NCT00731640	PHASE4	COMPLETED	Contralateral ReSTOR / Monofocal or Phakic Eye
NCT00732030	PHASE4	COMPLETED	Low Cylinder Toric
NCT00758199	PHASE4	COMPLETED	Determination of Optimum Duration of Treatment With Bromfenac (Xibrom) Eyedrops Following Cataract Surgery
NCT00760058	PHASE4	WITHDRAWN	Visual Outcome and Visual Quality After Bilateral Implantation of the AcrySof® IQ IOL Compared to MI60® and Tecnis® IOL
NCT00760487	PHASE4	COMPLETED	Visual Function After Implantation of Bilateral AcrySof® Toric Natural Intraocular Lens
NCT00761488	PHASE4	WITHDRAWN	Recommendations for Monitoring Clinical Experience Following Implantation of the AcrySof® Toric
NCT00763360	PHASE4	COMPLETED	To Compare the Ability of DiscoVisc® OVD to Protect the Corneal Endothelium and Maintain Anterior Chamber Space With Healon® and Amvisc® PLUS During Cataract Surgery.
NCT00786370	PHASE4	COMPLETED	Dexmedetomidine vs. Propofol for Cataract Surgery
NCT00786565	PHASE4	COMPLETED	Clinical Evaluation of a New Aspheric Intraocular Lens.