IARS1

Summary

IARS1 (isoleucyl-tRNA synthetase 1, HGNC:5330) is a protein-coding gene on chromosome 9q22.31, encoding Isoleucine–tRNA ligase, cytoplasmic (P41252). Catalyzes the specific attachment of an amino acid to its cognate tRNA in a 2 step reaction: the amino acid (AA) is first activated by ATP to form AA-AMP and then transferred to the acceptor end of the tRNA. It is a common-essential gene (DepMap: required in 99.9% of cancer cell lines).

Aminoacyl-tRNA synthetases catalyze the aminoacylation of tRNA by their cognate amino acid. Because of their central role in linking amino acids with nucleotide triplets contained in tRNAS, aminoacyl-tRNA synthetases are thought to be among the first proteins that appeared in evolution. Isoleucine-tRNA synthetase belongs to the class-I aminoacyl-tRNA synthetase family and has been identified as a target of autoantibodies in the autoimmune disease polymyositis/dermatomyositis. Alternatively spliced transcript variants have been found.

Source: NCBI Gene 3376 — RefSeq curated summary.

At a glance

• Gene–disease (curated): growth retardation, intellectual developmental disorder, hypotonia, and hepatopathy (Strong, GenCC)
• GWAS associations: 4
• Clinical variants (ClinVar): 529 total — 22 pathogenic, 12 likely-pathogenic
• Phenotypes (HPO): 55
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 99.9% of screened cell lines (common-essential)
• MANE Select transcript: NM_002161

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5330
Approved symbol	IARS1
Name	isoleucyl-tRNA synthetase 1
Location	9q22.31
Locus type	gene with protein product
Status	Approved
Aliases	ILRS
Ensembl gene	ENSG00000196305
Ensembl biotype	protein_coding
OMIM	600709
Entrez	3376

Gene structure

Transcript identifiers

Ensembl transcripts: 49 — 23 retained_intron, 14 protein_coding, 12 nonsense_mediated_decay

ENST00000375627, ENST00000375643, ENST00000443024, ENST00000447699, ENST00000467876, ENST00000472894, ENST00000473915, ENST00000474340, ENST00000490438, ENST00000498025, ENST00000627121, ENST00000682141, ENST00000682156, ENST00000682521, ENST00000682533, ENST00000682578, ENST00000682714, ENST00000682756, ENST00000682893, ENST00000683017, ENST00000683119, ENST00000683192, ENST00000683376, ENST00000683469, ENST00000683477, ENST00000683495, ENST00000683537, ENST00000683565, ENST00000683679, ENST00000683793, ENST00000683817, ENST00000684101, ENST00000684232, ENST00000684267, ENST00000684328, ENST00000684445, ENST00000684542, ENST00000684557, ENST00000684575, ENST00000684594, ENST00000684726, ENST00000684757, ENST00000909316, ENST00000909317, ENST00000909318, ENST00000909319, ENST00000909320, ENST00000935911, ENST00000935912

RefSeq mRNA: 21 — MANE Select: NM_002161 NM_001374299, NM_001374300, NM_001374301, NM_001378569, NM_001378571, NM_001378572, NM_001378573, NM_001378574, NM_001378575, NM_001378576, NM_001378577, NM_001378578, NM_001378579, NM_001378580, NM_001378582, NM_001378583, NM_001378584, NM_001378585, NM_001378586, NM_002161, NM_013417

CCDS: CCDS6694, CCDS94438, CCDS94439

Canonical transcript exons

ENST00000443024 — 34 exons

Exon	Start	End
ENSE00000711228	92240856	92240961
ENSE00001089616	92243216	92243311
ENSE00001776989	92293611	92293697
ENSE00001955221	92210207	92210889
ENSE00003466726	92251808	92251885
ENSE00003468130	92256680	92256800
ENSE00003476342	92262969	92263055
ENSE00003477176	92288126	92288282
ENSE00003484700	92286536	92286618
ENSE00003486825	92264929	92265123
ENSE00003502981	92222520	92222672
ENSE00003514759	92278199	92278286
ENSE00003517564	92287791	92287910
ENSE00003526845	92250187	92250289
ENSE00003527964	92260151	92260234
ENSE00003553280	92242154	92242330
ENSE00003562910	92289301	92289426
ENSE00003565411	92244959	92245071
ENSE00003585842	92247377	92247551
ENSE00003592740	92277863	92277923
ENSE00003598431	92249858	92249941
ENSE00003598811	92280746	92280893
ENSE00003615064	92258854	92258998
ENSE00003620242	92269885	92269983
ENSE00003623874	92250713	92250834
ENSE00003632621	92285722	92285839
ENSE00003633186	92270985	92271076
ENSE00003637379	92268174	92268300
ENSE00003656515	92223346	92223489
ENSE00003664556	92265480	92265553
ENSE00003676853	92271533	92271655
ENSE00003679114	92229001	92229126
ENSE00003680595	92253362	92253453
ENSE00003786105	92274426	92274521

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 98.76.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 108.1961 / max 930.7114, expressed in 1824 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
101411	91.9293	1823
101410	14.2797	1733
101412	1.9590	1237
101409	0.0281	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cartilage tissue	UBERON:0002418	98.76	gold quality
corpus epididymis	UBERON:0004359	98.43	gold quality
middle temporal gyrus	UBERON:0002771	98.29	gold quality
cauda epididymis	UBERON:0004360	98.23	gold quality
caput epididymis	UBERON:0004358	97.90	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	97.90	gold quality
biceps brachii	UBERON:0001507	97.77	gold quality
cervix squamous epithelium	UBERON:0006922	97.74	gold quality
oral cavity	UBERON:0000167	97.67	gold quality
heart right ventricle	UBERON:0002080	97.67	gold quality
gluteal muscle	UBERON:0002000	97.65	gold quality
trabecular bone tissue	UBERON:0002483	97.59	gold quality
Brodmann (1909) area 23	UBERON:0013554	97.47	gold quality
stromal cell of endometrium	CL:0002255	97.43	gold quality
tibia	UBERON:0000979	97.37	gold quality
gingiva	UBERON:0001828	97.22	gold quality
renal glomerulus	UBERON:0000074	97.21	gold quality
gingival epithelium	UBERON:0001949	97.20	gold quality
metanephric glomerulus	UBERON:0004736	97.16	gold quality
Brodmann (1909) area 46	UBERON:0006483	97.15	gold quality
deltoid	UBERON:0001476	97.13	gold quality
mucosa of sigmoid colon	UBERON:0004993	97.09	gold quality
vastus lateralis	UBERON:0001379	97.02	gold quality
adrenal tissue	UBERON:0018303	96.94	gold quality
skin of hip	UBERON:0001554	96.90	gold quality
triceps brachii	UBERON:0001509	96.81	gold quality
diaphragm	UBERON:0001103	96.78	gold quality
endometrium epithelium	UBERON:0004811	96.76	gold quality
quadriceps femoris	UBERON:0001377	96.71	gold quality
mammalian vulva	UBERON:0000997	96.58	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-GEOD-98556	yes	1849.32
E-CURD-112	yes	14.39
E-ANND-3	yes	9.23
E-CURD-89	no	519.89
E-MTAB-7606	no	317.36

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ATF4, EPAS1, FOXM1, FOXO1, QRICH1, STAT6

miRNA regulators (miRDB)

76 targeting IARS1, 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-6867-5P	100.00	82.21	3464
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-362-3P	99.91	66.38	1267
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-4302	99.89	67.94	1187
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-3941	99.86	70.54	2735
HSA-MIR-26A-5P	99.78	73.52	2303
HSA-MIR-26B-5P	99.78	73.51	2305
HSA-MIR-4465	99.71	72.56	2096
HSA-MIR-4677-5P	99.70	70.09	1940

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 4)

• Biallelic IARS Mutations Cause Growth Retardation with Prenatal Onset, Intellectual Disability, Muscular Hypotonia, and Infantile Hepatopathy (PMID:27426735)
• bi-allelic mutations in cytosolic isoleucyl-tRNA synthetase (IARS) have been described in three individuals with growth delay, hepatic dysfunction, and neurodevelopmental disabilities. Here we report an additional subject with this condition identified by whole-exome sequencing. Our findings support the association between this disorder and neonatal cholestasis with distinct liver pathology (PMID:27891590)
• Our report presents new evidence that recessive mutations inIARSgene are associated with characteristic clinical phenotype suchas infantile hepatopathy, growth retardation, facial dysmorphism,hypotonia, intellectual disability with no speech . (PMID:29052218)
• Circular RNA IARS modulates the progression and ferroptosis of osteosarcoma via sponging miR-188-5p from RAB14. (PMID:38958715)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	iars1	ENSDARG00000007955
mus_musculus	Iars1	ENSMUSG00000037851
rattus_norvegicus	Iars1	ENSRNOG00000014616
drosophila_melanogaster	IleRS	FBGN0027086
caenorhabditis_elegans		WBGENE00002152

Paralogs (7): LARS2 (ENSG00000011376), IARS2 (ENSG00000067704), LARS1 (ENSG00000133706), VARS2 (ENSG00000137411), MARS1 (ENSG00000166986), VARS1 (ENSG00000204394), MARS2 (ENSG00000247626)

Protein

Protein identifiers

Isoleucine–tRNA ligase, cytoplasmic — P41252 (reviewed: P41252)

Alternative names: Isoleucyl-tRNA synthetase

All UniProt accessions (14): A0A0A0MSX9, A0A0D9SFC1, A0A804HHW9, A0A804HIG2, A0A804HIV9, A0A804HJ36, A0A804HJN6, A0A804HK69, A0A804HKU1, A0A804HKW6, A0A804HL54, A0A804HLB4, P41252, J3KR24

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the specific attachment of an amino acid to its cognate tRNA in a 2 step reaction: the amino acid (AA) is first activated by ATP to form AA-AMP and then transferred to the acceptor end of the tRNA.

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

Subcellular location. Cytoplasm. Cytosol.

Tissue specificity. Expressed in liver and muscle (at protein level).

Disease relevance. Growth retardation, impaired intellectual development, hypotonia, and hepatopathy (GRIDHH) [MIM:617093] An autosomal recessive disorder characterized by severe growth retardation with prenatal onset, intellectual disability, muscular hypotonia, and hepatic dysfunction. The disease is caused by variants affecting the gene represented in this entry.

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

RefSeq proteins (21): NP_001361228, NP_001361229, NP_001361230, NP_001365498, NP_001365500, NP_001365501, NP_001365502, NP_001365503, NP_001365504, NP_001365505, NP_001365506, NP_001365507, NP_001365508, NP_001365509, NP_001365511, NP_001365512, NP_001365513, NP_001365514, NP_001365515, NP_002152, NP_038203 (=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
IPR013155	M/V/L/I-tRNA-synth_anticd-bd	Domain
IPR014729	Rossmann-like_a/b/a_fold	Homologous_superfamily
IPR023586	Ile-tRNA-ligase_type2	Family
IPR033709	Anticodon_Ile_ABEc	Domain
IPR057033	Ubiquitin_IARS1	Domain

Pfam: PF00133, PF08264, PF19302, PF23567

Catalyzed reactions (Rhea), 1 shown:

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

UniProt features (18 total): sequence variant 9, modified residue 4, short sequence motif 2, chain 1, sequence conflict 1, binding site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P41252-F1	89.06	0.58

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 (1): 603

Post-translational modifications (4): 1, 1047, 1049, 1058

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: 405 (showing top): GNF2_CKS1B, MORF_DNMT1, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_AMINO_ACID_ACTIVATION, TSENG_IRS1_TARGETS_UP, MORF_BUB1, GOBP_TRNA_METABOLIC_PROCESS, MORF_RRM1, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_OSTEOBLAST_DIFFERENTIATION, MORF_HDAC2, GOMF_GTPASE_BINDING, LINDGREN_BLADDER_CANCER_CLUSTER_2A_DN, PATIL_LIVER_CANCER

GO Biological Process (5): osteoblast differentiation (GO:0001649), tRNA aminoacylation for protein translation (GO:0006418), isoleucyl-tRNA aminoacylation (GO:0006428), translation (GO:0006412), aminoacyl-tRNA metabolism involved in translational fidelity (GO:0106074)

GO Molecular Function (9): tRNA binding (GO:0000049), aminoacyl-tRNA deacylase activity (GO:0002161), isoleucine-tRNA ligase activity (GO:0004822), ATP binding (GO:0005524), GTPase binding (GO:0051020), nucleotide binding (GO:0000166), aminoacyl-tRNA ligase activity (GO:0004812), protein binding (GO:0005515), ligase activity (GO:0016874)

GO Cellular Component (6): nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), membrane (GO:0016020), aminoacyl-tRNA synthetase multienzyme complex (GO:0017101), extracellular exosome (GO:0070062)

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	4
catalytic activity, acting on a tRNA	2
ossification	1
cell differentiation	1
translation	1
tRNA aminoacylation	1
tRNA aminoacylation for protein translation	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
enzyme binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
ligase activity, forming carbon-oxygen bonds	1
binding	1
catalytic activity	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1
intracellular protein-containing complex	1
catalytic complex	1
extracellular vesicle	1

Protein interactions and networks

STRING

3210 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IARS1	LARS1	Q9P2J5	998
IARS1	MARS1	P56192	996
IARS1	MARS2	Q96GW9	995
IARS1	KARS1	Q15046	995
IARS1	EPRS1	P07814	993
IARS1	QARS1	P47897	991
IARS1	RARS2	Q5T160	982
IARS1	LARS2	Q15031	980
IARS1	RARS1	P54136	975
IARS1	PARS2	Q7L3T8	973
IARS1	CARS2	Q9HA77	883
IARS1	CARS1	P49589	882
IARS1	SARS1	P49591	880
IARS1	AARS1	P49588	875
IARS1	M0R2C6	M0R2C6	874

IntAct

195 interactions, top by confidence:

A	B	Type	Score
EPRS1	IARS1	psi-mi:“MI:0915”(physical association)	0.880
IARS1	EPRS1	psi-mi:“MI:0915”(physical association)	0.880
IARS1	EPRS1	psi-mi:“MI:0407”(direct interaction)	0.880
RNF146	TNKS	psi-mi:“MI:0914”(association)	0.790
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
NCBP2	KPNA3	psi-mi:“MI:0914”(association)	0.640
IARS1	ERBB2	psi-mi:“MI:0915”(physical association)	0.550
COMTD1	IFRD1	psi-mi:“MI:0914”(association)	0.530
QARS1	EEF1E1	psi-mi:“MI:0914”(association)	0.530
NME1	NME2P1	psi-mi:“MI:0914”(association)	0.530
SDCBP	TARS3	psi-mi:“MI:0914”(association)	0.530
EBNA-LP	HAX1	psi-mi:“MI:0914”(association)	0.530
FOXM1	PES1	psi-mi:“MI:0914”(association)	0.500
JUN	NKRF	psi-mi:“MI:0914”(association)	0.460
gag	SDCBP	psi-mi:“MI:0914”(association)	0.460

BioGRID (551): IARS (Affinity Capture-MS), IARS (Affinity Capture-MS), IARS (Affinity Capture-MS), IARS (Affinity Capture-MS), IARS (Affinity Capture-MS), ACACA (Co-fractionation), AIMP2 (Co-fractionation), EEF1E1 (Co-fractionation), EPRS (Co-fractionation), GFPT1 (Co-fractionation), IARS (Co-fractionation), IARS (Co-fractionation), IARS (Co-fractionation), IARS (Co-fractionation), IARS (Co-fractionation)

ESM2 similar proteins: A0M5I5, A6LIG7, A8EY49, A8GNE3, A8GPA1, A8GPJ3, A8GW18, B2RK53, C0R573, C3PLG3, C3PP60, C4K2T0, F4JLM5, O13651, P09436, P36422, P41252, Q1RIY1, Q21926, Q30SH2, Q3II73, Q3YRX3, Q3YT16, Q3ZY20, Q4UMD8, Q54YD4, Q5FF72, Q5FH91, Q5GRK0, Q5GSS3, Q5HB43, Q5HC99, Q5L5L0, Q5LGN1, Q5PAL9, Q64XH6, Q68WC2, Q6MDY1, Q6MKX0, Q73HW7

Diamond homologs: A0B7P3, A0Q3B0, A0RDG3, A1R0Q9, A2SPV6, A3CSI6, A5IML2, A5N3P1, A6UVK2, A7IAM2, A9BI29, B0B9C6, B0BB05, B0K2W1, B0K8R7, B2S1H8, B2S348, B2V9T1, B5RN32, B5RQH0, B7IGT1, B7J0S6, B8CWL4, B9K8X3, C0QP76, C3MVH6, C3N5S5, C5CHA1, O13651, O27428, O29622, O51773, O58792, O83466, O84022, P09436, P26499, P41252, P41368, P46213

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
QRICH1	“up-regulates quantity by expression”	IARS1	“transcriptional regulation”
ATF4	“up-regulates quantity by expression”	IARS1	“transcriptional regulation”
IARS1	“form complex”	“Multiaminoacyl-tRNA synthetase”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 201 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	21.6×	2e-05
Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants	5	18.3×	6e-04
tRNA Aminoacylation	7	14.1×	8e-05
Selenoamino acid metabolism	9	12.5×	2e-05
FCERI mediated MAPK activation	5	12.2×	2e-03
FLT3 Signaling	5	12.2×	2e-03
Transcriptional and post-translational regulation of MITF-M expression and activity	9	11.3×	2e-05
Signaling by FGFR1 in disease	5	10.3×	3e-03

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of miRNA transcription	7	11.8×	8e-04
cytoplasmic translation	10	10.7×	5e-05
positive regulation of fibroblast proliferation	6	10.2×	5e-03
negative regulation of translation	9	10.2×	2e-04
MAPK cascade	8	7.1×	4e-03
cell surface receptor protein tyrosine kinase signaling pathway	7	7.0×	9e-03
translation	10	5.9×	2e-03
negative regulation of apoptotic process	17	3.4×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	22
Likely pathogenic	12
Uncertain significance	247
Likely benign	155
Benign	30

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1030524	NM_002161.6(IARS1):c.213T>G (p.Tyr71Ter)	Pathogenic
2016884	NM_002161.6(IARS1):c.773dup (p.Leu258fs)	Pathogenic
2028285	NM_002161.6(IARS1):c.2202T>A (p.Tyr734Ter)	Pathogenic
2104398	NM_002161.6(IARS1):c.986del (p.Gly329fs)	Pathogenic
253317	NM_002161.6(IARS1):c.1252C>T (p.Arg418Ter)	Pathogenic
253318	NM_002161.6(IARS1):c.3521T>A (p.Ile1174Asn)	Pathogenic
253319	NM_002161.6(IARS1):c.1310C>T (p.Pro437Leu)	Pathogenic
253320	NM_002161.6(IARS1):c.760C>T (p.Arg254Ter)	Pathogenic
253321	NM_002161.6(IARS1):c.1109T>G (p.Val370Gly)	Pathogenic
253322	NM_002161.6(IARS1):c.2974A>G (p.Asn992Asp)	Pathogenic
2627366	NM_002161.6(IARS1):c.632del (p.Pro211fs)	Pathogenic
2746671	NM_002161.6(IARS1):c.1924G>T (p.Glu642Ter)	Pathogenic
2782366	NM_002161.6(IARS1):c.2108_2109del (p.Leu703fs)	Pathogenic
2875559	NM_002161.6(IARS1):c.2939C>G (p.Ser980Ter)	Pathogenic
2902124	NM_002161.6(IARS1):c.1043_1044del (p.Pro348fs)	Pathogenic
2987089	NM_002161.6(IARS1):c.26_27del (p.Ile9fs)	Pathogenic
3234592	NM_002161.6(IARS1):c.1156C>T (p.Arg386Ter)	Pathogenic
4691244	NM_002161.6(IARS1):c.423G>A (p.Trp141Ter)	Pathogenic
4700160	NM_002161.6(IARS1):c.128_153dup (p.Gly52fs)	Pathogenic
559509	NM_002161.6(IARS1):c.1667T>C (p.Phe556Ser)	Pathogenic
559510	NM_002161.6(IARS1):c.2215C>T (p.Arg739Cys)	Pathogenic
872023	NM_002161.6(IARS1):c.2752C>T (p.Gln918Ter)	Pathogenic
1299497	NM_002161.6(IARS1):c.578delinsTT (p.Glu193fs)	Likely pathogenic
2020593	NM_002161.6(IARS1):c.3553+1G>A	Likely pathogenic
2418160	NM_002161.6(IARS1):c.276+1G>A	Likely pathogenic
3779752	NM_002161.6(IARS1):c.3355del (p.Thr1119fs)	Likely pathogenic
4081860	NM_002161.6(IARS1):c.1658C>A (p.Pro553His)	Likely pathogenic
4690939	NM_002161.6(IARS1):c.2137+1G>C	Likely pathogenic
4701914	NM_002161.6(IARS1):c.2430-2A>G	Likely pathogenic
4704699	NM_002161.6(IARS1):c.3410-2A>G	Likely pathogenic

SpliceAI

5837 predictions. Top by Δscore:

Variant	Effect	Δscore
9:92222518:AC:A	donor_gain	1.0000
9:92222519:CC:C	donor_gain	1.0000
9:92222556:T:TA	donor_gain	1.0000
9:92222669:CACT:C	acceptor_gain	1.0000
9:92222671:CT:C	acceptor_gain	1.0000
9:92222673:C:CC	acceptor_gain	1.0000
9:92242149:CTCA:C	donor_loss	1.0000
9:92242150:TCACC:T	donor_loss	1.0000
9:92242151:CACCT:C	donor_loss	1.0000
9:92242153:C:A	donor_loss	1.0000
9:92242326:TTGCA:T	acceptor_gain	1.0000
9:92242327:TGCA:T	acceptor_gain	1.0000
9:92242328:GCA:G	acceptor_gain	1.0000
9:92242329:CA:C	acceptor_gain	1.0000
9:92242329:CAC:C	acceptor_gain	1.0000
9:92242330:AC:A	acceptor_loss	1.0000
9:92242331:C:CC	acceptor_gain	1.0000
9:92242331:CTGAA:C	acceptor_loss	1.0000
9:92242332:T:A	acceptor_loss	1.0000
9:92243202:A:C	donor_gain	1.0000
9:92243214:A:AC	donor_gain	1.0000
9:92243215:C:CC	donor_gain	1.0000
9:92243307:AAAGC:A	acceptor_gain	1.0000
9:92243308:AAGC:A	acceptor_gain	1.0000
9:92243309:AGC:A	acceptor_gain	1.0000
9:92243310:GC:G	acceptor_gain	1.0000
9:92243311:CC:C	acceptor_gain	1.0000
9:92243311:CCTG:C	acceptor_loss	1.0000
9:92243312:C:CC	acceptor_gain	1.0000
9:92244955:ATAC:A	donor_loss	1.0000

AlphaMissense

8180 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:92243238:C:G	R993P	1.000
9:92287794:C:A	W131C	1.000
9:92287794:C:G	W131C	1.000
9:92287796:A:G	W131R	1.000
9:92287796:A:T	W131R	1.000
9:92243223:C:G	R998P	0.999
9:92243224:G:T	R998S	0.999
9:92243253:C:G	R988P	0.999
9:92250206:C:G	R838P	0.999
9:92250211:T:A	R836S	0.999
9:92250211:T:G	R836S	0.999
9:92258888:C:G	R661P	0.999
9:92258990:A:G	L627P	0.999
9:92260151:C:G	R624T	0.999
9:92260213:T:A	K603N	0.999
9:92260213:T:G	K603N	0.999
9:92286594:A:G	W141R	0.999
9:92286594:A:T	W141R	0.999
9:92286596:C:G	R140P	0.999
9:92287795:C:G	W131S	0.999
9:92288149:A:G	W85R	0.999
9:92288149:A:T	W85R	0.999
9:92288166:A:T	V79D	0.999
9:92288205:T:A	D66V	0.999
9:92288205:T:G	D66A	0.999
9:92288206:C:G	D66H	0.999
9:92288207:T:A	K65N	0.999
9:92288207:T:G	K65N	0.999
9:92288208:T:A	K65I	0.999
9:92288229:T:C	H58R	0.999

dbSNP variants (sampled 300 via entrez): RS1000005816 (9:92248527 T>G), RS1000073068 (9:92290943 C>A,T), RS1000096922 (9:92248398 T>C), RS1000114717 (9:92285648 C>A,T), RS1000173776 (9:92235846 A>G), RS1000231311 (9:92285218 T>C), RS1000349417 (9:92229413 G>A), RS1000352487 (9:92218953 C>T), RS1000367911 (9:92254831 G>A), RS1000372942 (9:92236090 C>T), RS1000375596 (9:92261604 C>T), RS1000437688 (9:92279584 T>A), RS1000438252 (9:92241675 C>A,T), RS1000509210 (9:92244087 A>C), RS1000515597 (9:92286033 T>A)

Disease associations

OMIM: gene MIM:600709 | disease phenotypes: MIM:617093

GenCC curated gene-disease

Disease	Classification	Inheritance
growth retardation, intellectual developmental disorder, hypotonia, and hepatopathy	Strong	Autosomal recessive

Mondo (2): growth retardation, intellectual developmental disorder, hypotonia, and hepatopathy (MONDO:0014911), microcephaly (MONDO:0001149)

Orphanet (1): Growth delay-intellectual disability-hepatopathy syndrome (Orphanet:541423)

HPO phenotypes

55 total (30 of 55 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000081	Duplicated collecting system
HP:0000126	Hydronephrosis
HP:0000252	Microcephaly
HP:0000293	Full cheeks
HP:0000311	Round face
HP:0000407	Sensorineural hearing impairment
HP:0000729	Autistic behavior
HP:0000819	Diabetes mellitus
HP:0000952	Jaundice
HP:0000974	Hyperextensible skin
HP:0001027	Soft, doughy skin
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001344	Absent speech
HP:0001382	Joint hypermobility
HP:0001395	Hepatic fibrosis
HP:0001396	Cholestasis
HP:0001397	Hepatic steatosis
HP:0001399	Hepatic failure
HP:0001406	Intrahepatic cholestasis
HP:0001410	Decreased liver function
HP:0001433	Hepatosplenomegaly
HP:0001508	Failure to thrive
HP:0001510	Growth delay
HP:0001511	Intrauterine growth retardation
HP:0001518	Small for gestational age

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST009356_7	Nonsyndromic cleft palate	2.000000e-06
GCST010725_16	Malaria	9.000000e-06
GCST010725_28	Malaria	6.000000e-06
GCST010725_95	Malaria	6.000000e-06

MeSH disease descriptors (1)

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

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3235 (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: 24,662 (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
CHEMBL719	MUPIROCIN	4	24,662

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

ChEMBL bioactivities

33 potent at pChembl≥5 of 48 total, top 32 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.10	IC50	0.8	nM	MUPIROCIN
7.85	IC50	14	nM	CHEMBL605376
7.82	IC50	15	nM	CHEMBL125075
7.70	IC50	20	nM	CHEMBL340359
7.52	IC50	30	nM	CHEMBL538163
7.52	IC50	30	nM	CHEMBL125820
7.47	IC50	34	nM	CHEMBL125075
7.41	IC50	39	nM	CHEMBL605592
7.35	IC50	45	nM	CHEMBL125221
7.03	Kd	94.41	nM	CHEMBL3752910
7.03	ED50	94.41	nM	CHEMBL3752910
7.01	IC50	98	nM	CHEMBL1163069
7.00	IC50	100	nM	CHEMBL538163
7.00	IC50	100	nM	CHEMBL333001
7.00	IC50	100	nM	CHEMBL264002
7.00	IC50	100	nM	CHEMBL94318
6.96	IC50	110	nM	CHEMBL126515
6.92	IC50	120	nM	CHEMBL123796
6.70	IC50	200	nM	CHEMBL333001
6.52	IC50	300	nM	CHEMBL125820
6.52	IC50	300	nM	CHEMBL95037
6.52	IC50	300	nM	CHEMBL98732
6.48	IC50	330	nM	CHEMBL264002
6.43	IC50	370	nM	CHEMBL125221
6.40	IC50	400	nM	CHEMBL340359
5.99	IC50	1020	nM	CHEMBL126515
5.96	IC50	1100	nM	CHEMBL605809
5.52	IC50	3000	nM	CHEMBL94590
5.35	IC50	4500	nM	CHEMBL1161570
5.34	Kd	4574	nM	CHEMBL5653589
5.34	ED50	4574	nM	CHEMBL5653589
5.26	IC50	5500	nM	CHEMBL605380

PubChem BioAssay actives

26 with measured affinity, of 97 total; 17 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
[(2R,3S,4R)-5-(6-amino-2-iodopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl N-[(2S,3S)-2-amino-3-methylpentanoyl]sulfamate	91616: Inhibitory activity against Escherichia coli Isoleucyl-tRNA synthetase was determined	ic50	0.0140	uM
[(2R,3S,4R,5R)-3,4-dihydroxy-5-[4-(3-methoxyphenyl)-1,3-thiazol-2-yl]oxolan-2-yl]methyl N-[(2S)-2-amino-3-methylpentanoyl]sulfamate	91614: Inhibition of Escherichia coli isoleucyl-tRNA synthetase	ic50	0.0150	uM
[(2R,3S,4R,5R)-3,4-dihydroxy-5-[4-(6-methoxynaphthalen-2-yl)-1,3-thiazol-2-yl]oxolan-2-yl]methyl N-[(2S)-2-amino-3-methylpentanoyl]sulfamate	91614: Inhibition of Escherichia coli isoleucyl-tRNA synthetase	ic50	0.0200	uM
[(2R,3S,4R,5R)-3,4-dihydroxy-5-[4-(2-methoxyphenyl)-1,3-thiazol-2-yl]oxolan-2-yl]methyl N-[(2S)-2-amino-3-methylpentanoyl]sulfamate	91614: Inhibition of Escherichia coli isoleucyl-tRNA synthetase	ic50	0.0300	uM
[(2R,3S,4R,5R)-3,4-dihydroxy-5-[4-(2-phenylethyl)-1,3-thiazol-2-yl]oxolan-2-yl]methyl N-[(2S)-2-amino-3-methylpentanoyl]sulfamate	91614: Inhibition of Escherichia coli isoleucyl-tRNA synthetase	ic50	0.0300	uM
[(2R,3S,4R)-5-(6-amino-2-ethynylpurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl N-[(2S,3S)-2-amino-3-methylpentanoyl]sulfamate	91616: Inhibitory activity against Escherichia coli Isoleucyl-tRNA synthetase was determined	ic50	0.0390	uM
[(2R,3S,4R,5R)-3,4-dihydroxy-5-[4-(4-phenoxyphenyl)-1,3-thiazol-2-yl]oxolan-2-yl]methyl N-[(2S)-2-amino-3-methylpentanoyl]sulfamate	91614: Inhibition of Escherichia coli isoleucyl-tRNA synthetase	ic50	0.0450	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148565: Binding affinity to human IARS incubated for 45 mins by Kinobead based pull down assay	kd	0.0944	uM
[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl N-[(2S,3S)-2-amino-3-methylpentanoyl]sulfamate	91616: Inhibitory activity against Escherichia coli Isoleucyl-tRNA synthetase was determined	ic50	0.0980	uM
[(2R,3S,4R,5R)-3,4-dihydroxy-5-(4-phenyl-1,3-thiazol-2-yl)oxolan-2-yl]methyl N-[(2S,3S)-2-amino-3-methylpentanoyl]sulfamate	91614: Inhibition of Escherichia coli isoleucyl-tRNA synthetase	ic50	0.1000	uM
[(2R,3S,4R,5R)-3,4-dihydroxy-5-[4-(4-methoxyphenyl)-1,3-thiazol-2-yl]oxolan-2-yl]methyl N-[(2S)-2-amino-3-methylpentanoyl]sulfamate	91614: Inhibition of Escherichia coli isoleucyl-tRNA synthetase	ic50	0.1000	uM
[(2R,3S,4R,5R)-3,4-dihydroxy-5-[4-[2-(4-phenoxyphenyl)ethyl]-1,3-thiazol-2-yl]oxolan-2-yl]methyl N-[(2S)-2-amino-3-methylpentanoyl]sulfamate	91614: Inhibition of Escherichia coli isoleucyl-tRNA synthetase	ic50	0.1100	uM
[(2R,3S,4R,5R)-5-[4-(4-cyanofuran-2-yl)-1,3-thiazol-2-yl]-3,4-dihydroxyoxolan-2-yl]methyl N-[(2S)-2-amino-3-methylpentanoyl]sulfamate	91614: Inhibition of Escherichia coli isoleucyl-tRNA synthetase	ic50	0.1200	uM
[(2R,3S,4R)-5-(6-amino-2-hex-1-ynylpurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl N-[(2S,3S)-2-amino-3-methylpentanoyl]sulfamate	91616: Inhibitory activity against Escherichia coli Isoleucyl-tRNA synthetase was determined	ic50	1.1000	uM
2-[hydroxy-(3-hydroxy-4-methoxybenzoyl)amino]ethyl (2S)-2-amino-3-methylpentanoate	223426: Inhibitory concentration against isoleucyl-tRNA synthetase was determined by measuring decrease of the aminoacylation product [3H]- isoleucyl tRNA of Escherichia coli	ic50	4.5000	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148565: Binding affinity to human IARS incubated for 45 mins by Kinobead based pull down assay	kd	4.5735	uM
[(2R,3S,4R)-5-(6-amino-2-chloropurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl N-[(2S,3S)-2-amino-3-methylpentanoyl]sulfamate	91616: Inhibitory activity against Escherichia coli Isoleucyl-tRNA synthetase was determined	ic50	5.5000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases methylation, decreases expression, increases expression, affects expression, affects cotreatment	5
Cyclosporine	affects expression, increases expression	4
arsenite	affects binding, decreases reaction, decreases methylation	2
sodium arsenite	decreases expression	2
Arsenic Trioxide	decreases expression, increases expression	2
Tobacco Smoke Pollution	decreases expression, increases expression	2
Tunicamycin	increases expression	2
Cadmium Chloride	increases expression	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
bisphenol F	increases expression	1
chloroacetaldehyde	affects expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, decreases expression	1
methylparaben	increases expression	1
cobaltous chloride	decreases expression	1
1-nitropyrene	increases expression	1
perfluorooctane sulfonic acid	increases expression	1
CGP 52608	affects binding, increases reaction	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
ICG 001	increases expression	1
LDN 193189	affects cotreatment, decreases expression	1
(+)-JQ1 compound	decreases expression	1
bisphenol AF	increases expression	1
Rosiglitazone	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	increases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Cidofovir	increases expression	1
Acetaminophen	increases expression	1

ChEMBL screening assays

14 unique, capped per target: 10 binding, 4 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4118951	Binding	Binding affinity to IARS in human NCI-H358 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — Bioorg Med Chem
CHEMBL841257	Functional	In vitro antibacterial activity against isoleucyl-tRNA synthetase from Streptococcus pneumoniae PU7	Synthesis and antibacterial properties of beta-diketone acrylate bioisosteres of pseudomonic acid A. — Bioorg Med Chem Lett

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05518188	PHASE1/PHASE2	RECRUITING	Melpida: Recombinant Adeno-associated Virus (serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)
NCT00001639	Not specified	COMPLETED	Evaluation of Patients With Unresolved Chromosome Abnormalities
NCT01151462	Not specified	WITHDRAWN	Postnatal HCMV Infection in Very Preterm Infants. Implications, Morbidity, Growth and Neurodevelopmental Outcomes.
NCT01565005	Not specified	COMPLETED	Microcephaly Genetic Deficiency in Neural Progenitors
NCT02510170	Not specified	COMPLETED	Fetal and Maternal Head Circumference During Pregnancy in Israeli Population
NCT02741882	Not specified	COMPLETED	Zika and Microcephaly: Case-control Study
NCT02943304	Not specified	COMPLETED	Neurodevelopment Outcome of Newborns Exposed to Zika Virus (ZIKV) in Utero
NCT03255369	Not specified	UNKNOWN	Vertical Exposure to Zika Virus and Its Consequences for Child Neurodevelopment (ZIKVIRUSIFF)
NCT03325946	Not specified	RECRUITING	The FBRI VTC Neuromotor Research Clinic
NCT03330600	Not specified	COMPLETED	Efficacy of Aquatic Physiotherapy in Children With Microcephaly by Zika Virus Congenital Syndrome
NCT03548779	Not specified	COMPLETED	North Carolina Genomic Evaluation by Next-generation Exome Sequencing, 2
NCT03651687	Not specified	COMPLETED	Guangzhou Surveillance and Clinical Study in Microcephaly (GSCSM)
NCT03922594	Not specified	TERMINATED	Surveillance of Zika-related Microcephaly in Sub-Saharan Africa and Asia
NCT04816175	Not specified	COMPLETED	Intensive Therapy for Children With Microcephaly, Hyperkinetic Movements, or Global Developmental Delay
NCT05322980	Not specified	COMPLETED	Summary of Infants Weighing 500 Grams or Less
NCT06019182	Not specified	RECRUITING	MEHMO Natural History and Biomarkers
NCT06566066	Not specified	RECRUITING	Register for Patients With Thyroid Hormone Resistance.