EIF4G1

Summary

EIF4G1 (eukaryotic translation initiation factor 4 gamma 1, HGNC:3296) is a protein-coding gene on chromosome 3q27.1, encoding Eukaryotic translation initiation factor 4 gamma 1 (Q04637). Component of the protein complex eIF4F, which is involved in the recognition of the mRNA cap, ATP-dependent unwinding of 5’-terminal secondary structure and recruitment of mRNA to the ribosome. It is a selective cancer dependency (DepMap: 83.5% of cell lines).

The protein encoded by this gene is a component of the multi-subunit protein complex EIF4F. This complex facilitates the recruitment of mRNA to the ribosome, which is a rate-limiting step during the initiation phase of protein synthesis. The recognition of the mRNA cap and the ATP-dependent unwinding of 5’-terminal secondary structure is catalyzed by factors in this complex. The subunit encoded by this gene is a large scaffolding protein that contains binding sites for other members of the EIF4F complex. A domain at its N-terminus can also interact with the poly(A)-binding protein, which may mediate the circularization of mRNA during translation. Alternative splicing results in multiple transcript variants, some of which are derived from alternative promoter usage.

Source: NCBI Gene 1981 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Parkinson disease 18, autosomal dominant, susceptibility to (Moderate, GenCC)
• GWAS associations: 2
• Clinical variants (ClinVar): 304 total
• Phenotypes (HPO): 38
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 83.5% of screened cell lines
• MANE Select transcript: NM_198241

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3296
Approved symbol	EIF4G1
Name	eukaryotic translation initiation factor 4 gamma 1
Location	3q27.1
Locus type	gene with protein product
Status	Approved
Aliases	p220, PARK18
Ensembl gene	ENSG00000114867
Ensembl biotype	protein_coding
OMIM	600495
Entrez	1981

Gene structure

Transcript identifiers

Ensembl transcripts: 59 — 45 protein_coding, 9 retained_intron, 5 nonsense_mediated_decay

ENST00000342981, ENST00000346169, ENST00000350481, ENST00000352767, ENST00000382330, ENST00000392537, ENST00000411531, ENST00000413967, ENST00000414031, ENST00000421110, ENST00000422614, ENST00000424196, ENST00000426123, ENST00000427141, ENST00000427607, ENST00000427845, ENST00000428387, ENST00000434061, ENST00000435046, ENST00000440448, ENST00000441154, ENST00000442406, ENST00000444134, ENST00000444861, ENST00000448284, ENST00000450424, ENST00000455679, ENST00000456033, ENST00000457456, ENST00000460829, ENST00000464548, ENST00000466311, ENST00000475721, ENST00000478291, ENST00000482303, ENST00000484862, ENST00000485712, ENST00000493299, ENST00000676206, ENST00000676453, ENST00000891266, ENST00000891267, ENST00000891268, ENST00000891269, ENST00000891270, ENST00000891271, ENST00000915012, ENST00000915013, ENST00000915014, ENST00000915015, ENST00000915016, ENST00000915017, ENST00000915018, ENST00000915019, ENST00000915020, ENST00000915021, ENST00000915022, ENST00000915023, ENST00000947102

RefSeq mRNA: 8 — MANE Select: NM_198241 NM_001194946, NM_001194947, NM_001291157, NM_004953, NM_182917, NM_198241, NM_198242, NM_198244

CCDS: CCDS3259, CCDS3260, CCDS3261, CCDS46970, CCDS54687, CCDS54688, CCDS77866

Canonical transcript exons

ENST00000346169 — 33 exons

Exon	Start	End
ENSE00001364164	184315489	184315545
ENSE00002215687	184316132	184316218
ENSE00003471959	184322362	184322450
ENSE00003472737	184324201	184324347
ENSE00003480134	184321282	184322103
ENSE00003501050	184326527	184326629
ENSE00003506935	184331728	184331809
ENSE00003510956	184322821	184322954
ENSE00003514373	184327830	184328002
ENSE00003515005	184322544	184322730
ENSE00003522567	184323408	184323593
ENSE00003524294	184323780	184323977
ENSE00003548264	184327216	184327448
ENSE00003550892	184325851	184325951
ENSE00003553171	184325480	184325639
ENSE00003554055	184327586	184327704
ENSE00003567464	184324878	184325114
ENSE00003572420	184320927	184320993
ENSE00003583326	184331266	184331364
ENSE00003589203	184315763	184315856
ENSE00003611501	184326881	184326983
ENSE00003617655	184325269	184325373
ENSE00003627195	184323083	184323241
ENSE00003628073	184331472	184331606
ENSE00003629506	184328909	184328990
ENSE00003631707	184317717	184317816
ENSE00003656765	184331946	184332086
ENSE00003669953	184328631	184328756
ENSE00003696654	184317321	184317497
ENSE00003786062	184319689	184319801
ENSE00003788615	184320630	184320722
ENSE00003901474	184334727	184335353
ENSE00003903965	184314606	184314674

Expression profiles

Bgee: expression breadth ubiquitous, 294 present calls, max score 99.08.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 154.5931 / max 1177.2078, expressed in 1828 samples.

FANTOM5 promoters (20 alternative TSS)

Promoter ID	TPM avg	Samples expressed
40164	109.6394	1828
40167	21.2680	1768
40165	10.5546	1791
40168	3.2459	1092
40183	1.6098	935
40163	1.3647	926
40166	1.2212	730
40175	0.8247	369
40182	0.8010	538
203050	0.6919	381

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
gastrocnemius	UBERON:0001388	99.08	gold quality
skin of leg	UBERON:0001511	98.90	gold quality
skin of abdomen	UBERON:0001416	98.87	gold quality
lower esophagus mucosa	UBERON:0035834	98.85	gold quality
muscle of leg	UBERON:0001383	98.79	gold quality
stromal cell of endometrium	CL:0002255	98.78	gold quality
right lobe of liver	UBERON:0001114	98.77	gold quality
hindlimb stylopod muscle	UBERON:0004252	98.73	gold quality
right lobe of thyroid gland	UBERON:0001119	98.68	gold quality
adenohypophysis	UBERON:0002196	98.67	gold quality
apex of heart	UBERON:0002098	98.65	gold quality
right adrenal gland	UBERON:0001233	98.63	gold quality
lower esophagus muscularis layer	UBERON:0035833	98.62	gold quality
lower esophagus	UBERON:0013473	98.61	gold quality
body of pancreas	UBERON:0001150	98.59	gold quality
left adrenal gland cortex	UBERON:0035825	98.57	gold quality
right adrenal gland cortex	UBERON:0035827	98.57	gold quality
esophagus	UBERON:0001043	98.56	gold quality
left lobe of thyroid gland	UBERON:0001120	98.56	gold quality
left adrenal gland	UBERON:0001234	98.55	gold quality
esophagus mucosa	UBERON:0002469	98.52	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	98.52	gold quality
mucosa of transverse colon	UBERON:0004991	98.52	gold quality
body of stomach	UBERON:0001161	98.51	gold quality
muscle layer of sigmoid colon	UBERON:0035805	98.49	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	98.48	gold quality
adrenal cortex	UBERON:0001235	98.47	gold quality
minor salivary gland	UBERON:0001830	98.47	gold quality
upper lobe of left lung	UBERON:0008952	98.47	gold quality
body of tongue	UBERON:0011876	98.44	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-8060	no	622.08
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FOXO1, HINFP, MYC, PRKAA1, PRKAA2

miRNA regulators (miRDB)

45 targeting EIF4G1, 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-190A-3P	100.00	80.35	5520
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-362-3P	99.91	66.38	1267
HSA-MIR-329-3P	99.91	66.56	1234
HSA-MIR-8087	99.90	69.55	1351
HSA-MIR-8062	99.88	68.43	995
HSA-MIR-498-5P	99.76	69.64	1807
HSA-MIR-6516-3P	99.65	68.57	1238
HSA-MIR-10393-5P	99.65	68.01	1368
HSA-MIR-6715B-5P	99.64	69.63	1420
HSA-MIR-3942-3P	99.57	69.03	2854
HSA-MIR-4269	99.55	69.89	1373
HSA-MIR-4452	99.50	68.45	1493
HSA-MIR-6083	99.47	68.73	2393
HSA-MIR-183-3P	99.41	69.41	1598
HSA-MIR-520E-5P	99.27	68.90	1513
HSA-MIR-4254	99.11	65.15	1315
HSA-MIR-4651	99.06	67.57	2002
HSA-MIR-7151-3P	99.04	69.72	2370
HSA-MIR-608	98.93	67.83	2013
HSA-MIR-6889-3P	98.84	67.35	1198

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 83.5% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• mass spectrometric analysis of N terminus reveals novel isoforms (PMID:11821405)
• demonstrate that the expression of the amino-terminal one-third of eIF4G, which interacts with eIF4E and PABP, in Xenopus oocyte inhibits translation and progesterone-induced maturation (PMID:11866104)
• data suggest that expression of the eIF4GI isoforms is partly controlled by a complex translation strategy involving both cap-dependent and cap-independent mechanisms (PMID:12052860)
• X-ray structure of rotavirus NSP3-C bound to the 30 residue fragment of eIF4G that is also recognized by poly(A) binding protein (PABP) (PMID:12086624)
• Vesicular stomatitis virus infection alters the eIF4F translation initiation complex and causes dephosphorylation of the eIF4E binding protein 4E-BP1 (PMID:12239292)
• proteolytic activity of HIV-1 protease on eIF4GI and eIF4GII and its implications for the translation of mRNAs (PMID:12505164)
• Overexpression of EIF4G1 causes aberrant cell morphology and results in disruption of the localization of F-actin and the organization of microtubules. (PMID:12581158)
• cleavage of EIF4G by Coxsackievirus 2A protease enhances the translation efficiency of EV71 IRES activity (PMID:14592777)
• RoXaN is capable of interacting with NSP3 and eIF4G I in vivo and during rotavirus infection. Domains of interaction were mapped. (PMID:15047801)
• Expression of fragments of eIF4GI reveals a nuclear localization sequence within the N-terminal apoptotic cleavage fragment N-FAG. (PMID:15128869)
• eIF4F activation is an essential component of the malignant phenotype in breast carcinoma (PMID:15193258)
• Adenovirus 100K protein blocks cellular protein synthesis by coopting eIF4G and cap-initiation complexes and displacing or blocking binding by Mnk1, which occurs only on preassembled complexes, resulting in dephosphorylation of eIF4E. (PMID:15220445)
• eIF4G binding to Mnk is inhibted by Mnk1 phosphorylation by caspase-activated Pak2/gamma-PAK (PMID:15234964)
• role of binding to adenoviral mRNA in ribosome shunting (PMID:15314025)
• phoshorylation induced by human Cytomegalovirus infections is both mTOR and phosphatidylinositol kinase independent. (PMID:15452223)
• intact eIF4GI protein is not required for the de novo synthesis of eIF4GI, suggesting its expression can continue under stress or infection conditions where eIF4GI is cleaved (PMID:15755734)
• Results identify two conserved basic residues (K646 and R650) in human eukaryotic initiation factor 4GI (eIF4GI) that are important for foot-and-mouth disease virus leader proteinase binding. (PMID:15885108)
• FN has a role in controlling translation through beta1 integrin and eukaryotic initiation factors 4 and 2 coordinated pathways (PMID:15961545)
• The organization of the CBP80-CBP20 complex suggests how the activity of eIF4G in translation initiation could be regulated through a dynamic network of overlapping intra- and intermolecular interactions. (PMID:16156639)
• Citrullinated eIF4G1 was identified as a candidate citrullinated autoantigen in RA patients. (PMID:16412378)
• The X-ray structure of the C-terminal region of human eukaryotic translation initiation factor 4G (eIF4G) has been determined at 2.2 A resolution, revealing two atypical HEAT-repeat domains. (PMID:16698552)
• eIF3e binds to eIF4G during the process of cap-dependent translation initiation (PMID:16766523)
• We quantify the efficiency of eIF4GI promoter usage in mammalian cells and demonstrate that even though the longest isoform eIF4GIf was relatively poorly expressed when reintroduced, it was more efficient at promoting the translation of cellular mRNAs. (PMID:16982693)
• analysis of cells of eIF4GIf molecules lacking either the PABP-binding site, the eIF3-binding site, the middle domain eIF4A-binding site, or the C-terminal segment that includes the second eIF4A-binding site (PMID:17130132)
• Data show that coxsackievirus B3 proteases 2A and 3C induce apoptotic cell death through mitochondrial injury and cleavage of eIF4GI but not DAP5. (PMID:17195095)
• Results show that three genes, namely FXR1, CLAPM1 and EIF4G, are most frequently overexpressed in the center of the amplified domain in squamous cell carcinomas. (PMID:17290396)
• These results demonstrate that “pure” isoprenoids and genistein differentially impact cap-dependent translation in tumor cell lines. (PMID:17601486)
• subcellular distribution of eIF4F components may potentiate the complex assembly (PMID:18250159)
• the PDCD4 MA3 domains compete with the eIF4G MA3 domain and RNA for eIF4A binding. PDCD4 inhibits translation initiation by displacing eIF4G and RNA from eIF4A. (PMID:18296639)
• High levels of eIF4GI observed in many cancers might act to specifically increase proliferation, prevent autophagy, and release tumor cells from control by nutrient sensing. (PMID:18426977)
• A feedforward loop involving c-Myc and eIF4F that serves to link transcription and translation and that could contribute to the effects of c-Myc on cell proliferation and neoplastic growth. (PMID:18593934)
• kinetic analysis of assembly of the m7GpppG.eIF4E.eIF4G complex (PMID:18614538)
• nuclear localization of PABP-C1 not only is dependent on the capacity of rotavirus NSP3 to interact with eIF4G but also requires the interaction of NSP3 with a specific region in RoXaN (PMID:18799579)
• eIF4GI serves to anchor eIF4E to the mRNA and enhance its interaction with the cap structure. (PMID:19114555)
• Study reports the topology of the eIF4A/4G/4H helicase complex, which is built from multiple experimentally observed domain-domain contacts. (PMID:19203580)
• Data show that the unique pathogenic properties of IBC result in part from overexpression of the translation initiation factor eIF4GI in most inflammatory breast cancer. (PMID:19525934)
• eIF4GI does not colocalize with ribosomes in VSV-infected cells, while eIF2alpha locates at perinuclear sites coincident with ribosomes. (PMID:19769989)
• Hsp90 probably contributes to the correct localization of eIF4E and 4E-T to stress granules and also to the interaction between eIF4E and eIF4G, both of which may be needed for eIF4E to acquire the physiological functionality (PMID:19850929)
• HIV- 1 protease inhibits Cap- and poly(A)-dependent translation upon eIF4GI and PABP cleavage (PMID:19956697)
• findings assign NAD(P)H quinone-oxydoreductase 1 an original role in the regulation of mRNA translation via the control of eIF4GI stability by the proteasome. (PMID:20028737)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	eif4g1a	ENSDARG00000006200
		ENSDARG00000101256
danio_rerio		ENSDARG00000116712
mus_musculus	Eif4g1	ENSMUSG00000045983
rattus_norvegicus	Eif4g1	ENSRNOG00000001738
rattus_norvegicus	Eif4g1-ps1	ENSRNOG00000030704

Paralogs (2): EIF4G3 (ENSG00000075151), EIF4G2 (ENSG00000110321)

Protein

Protein identifiers

Eukaryotic translation initiation factor 4 gamma 1 — Q04637 (reviewed: Q04637)

Alternative names: p220

All UniProt accessions (23): Q04637, A0A6Q8PFB2, A0A6Q8PG29, A0A7I2Y1C3, C9J2Z7, C9J556, C9J6B6, C9J987, C9JF13, C9JHW9, C9JIH5, C9JSU8, C9JWH7, C9JWH9, C9JWW9, C9K073, E7EUU4, E7EX73, E9PGM1, F8WB97, F8WCF2, H7C044, H7C0V6

UniProt curated annotations — full annotation on UniProt →

Function. Component of the protein complex eIF4F, which is involved in the recognition of the mRNA cap, ATP-dependent unwinding of 5’-terminal secondary structure and recruitment of mRNA to the ribosome. Exists in two complexes, either with EIF1 or with EIF4E (mutually exclusive). Together with EIF1, is required for leaky scanning, in particular for avoiding cap-proximal start codon. Together with EIF4E, antagonizes the scanning promoted by EIF1-EIF4G1 and locates the start codon (through a TISU element) without scanning. As a member of the eIF4F complex, required for endoplasmic reticulum stress-induced ATF4 mRNA translation.

Subunit / interactions. eIF4F is a multi-subunit complex, the composition of which varies with external and internal environmental conditions. It is composed of at least EIF4A, EIF4E (cap-binding) and EIF4G1/EIF4G3. Interacts with eIF3 complex, mutually exclusive with EIF4A1 or EIF4A2, EIF4E and through its N-terminus with PABPC1. Interacts with EIF4E or with EIF1 (mutually exclusive) through a common binding site. Interacts through its C-terminus with the serine/threonine kinases MKNK1, and with MKNK2. Appears to act as a scaffold protein, holding these enzymes in place to phosphorylate EIF4E. Non-phosphorylated EIF4EBP1 competes with EIF4G1/EIF4G3 to interact with EIF4E; insulin stimulated MAP-kinase (MAPK1 and MAPK3) phosphorylation of EIF4EBP1 causes dissociation of the complex allowing EIF4G1/EIF4G3 to bind and consequent initiation of translation. EIF4G1/EIF4G3 interacts with PABPC1 to bring about circularization of the mRNA. Interacts with EIF4E3. Interacts with CIRBP and MIF4GD. Interacts with RBM4. Interacts with HNRNPD/AUF1; the interaction requires RNA. Interacts with DDX3X; the interaction requires RNA. Interacts with DAZAP2. (Microbial infection) Interacts with rotavirus A NSP3; in this interaction, NSP3 takes the place of PABPC1 thereby inducing shutoff of host protein synthesis. (Microbial infection) Interacts with human adenovirus 5 protein 100K; this interaction promotes translational shunt in presence of polysomes containing viral tripartite leader mRNAs. (Microbial infection) Interacts with viral genome-linked protein (via c-terminus); this interaction plays a role in the translation of viral proteins.

Subcellular location. Cytoplasm. Nucleus. Stress granule.

Post-translational modifications. Phosphorylated at multiple sites in vivo. Phosphorylation at Ser-1185 by PRKCA induces binding to MKNK1. Following infection by certain enteroviruses, rhinoviruses and aphthoviruses, EIF4G1 is cleaved by the viral protease 2A, or the leader protease in the case of aphthoviruses. This shuts down the capped cellular mRNA transcription.

Disease relevance. Parkinson disease 18 (PARK18) [MIM:614251] An autosomal dominant, late-onset form of Parkinson disease. Parkinson disease is a complex neurodegenerative disorder characterized by bradykinesia, resting tremor, muscular rigidity and postural instability, as well as by a clinically significant response to treatment with levodopa. The pathology involves the loss of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies (intraneuronal accumulations of aggregated proteins), in surviving neurons in various areas of the brain. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. Produced by alternative initiation at Met-41 of isoform A. Produced by alternative initiation at Met-88 of isoform A. Produced by alternative initiation at Met-165 of isoform A. Produced by alternative initiation at Met-197 of isoform A. Produced by alternative splicing. Produced by alternative splicing. Produced by alternative splicing.

Similarity. Belongs to the eukaryotic initiation factor 4G family.

Isoforms (8)

UniProt ID	Names	Canonical?
Q04637-1	A	yes
Q04637-3	B
Q04637-4	C
Q04637-5	D
Q04637-6	E
Q04637-7	7
Q04637-8	8
Q04637-9	9

RefSeq proteins (8): NP_001181875, NP_001181876, NP_001278086, NP_004944, NP_886553, NP_937884, NP_937885, NP_937887 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003307	W2_domain	Domain
IPR003890	MIF4G-like_typ-3	Domain
IPR003891	Initiation_fac_eIF4g_MI	Domain
IPR016024	ARM-type_fold	Homologous_superfamily

Pfam: PF02020, PF02847, PF02854

UniProt features (167 total): modified residue 33, helix 27, mutagenesis site 21, sequence conflict 20, compositionally biased region 17, sequence variant 17, region of interest 12, splice variant 6, turn 5, domain 3, strand 2, site 2, chain 1, initiator methionine 1

Structure

Experimental structures (PDB)

14 structures.

PDB	Method	Resolution (Å)
5T46	X-RAY DIFFRACTION	1.53
5EI3	X-RAY DIFFRACTION	1.71
4F02	X-RAY DIFFRACTION	2
4AZA	X-RAY DIFFRACTION	2.16
1UG3	X-RAY DIFFRACTION	2.24
5ZK5	X-RAY DIFFRACTION	2.25
2W97	X-RAY DIFFRACTION	2.29
1LJ2	X-RAY DIFFRACTION	2.38
5EHC	X-RAY DIFFRACTION	2.4
5EIR	X-RAY DIFFRACTION	2.69
8OZ0	ELECTRON MICROSCOPY	3.5
6ZMW	ELECTRON MICROSCOPY	3.7
8J7R	ELECTRON MICROSCOPY	3.7
8HUJ	ELECTRON MICROSCOPY	3.76

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q04637-F1	56.06	0.13

Functional residue map

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

Catalytic / active sites (2): 674–675 (cleavage; by foot-and-mouth disease virus leader protease); 681–682 (cleavage; by enterovirus/rhinovirus protease 2a)

Post-translational modifications (33): 2, 489, 498, 509, 685, 694, 705, 15, 73, 110, 207, 223, 314, 602, 647, 685, 694, 1028, 1032, 1042 …

Mutagenesis-validated functional residues (21):

Position	Phenotype
905	abolishes binding to eif4a; when associated with a-895 and a-92.
974	abolishes binding to eif4a; when associated with a-976.
977	abolishes binding to eif4a; when associated with a-973.
985	slightly reduced binding to eif4a; when associated with a-989.
990	slightly reduced binding to eif4a; when associated with a-984.
174–178	loss of pabpc1 binding; when associated with 184-aaaa-187.
180	loss of pabpc1 binding.
182	loss of pabpc1 binding.
184–187	loss of pabpc1 binding; when associated with 174-aaaaa-178.
192	loss of pabpc1 binding.
196	loss of pabpc1 binding.
612	abolishes binding to eif4e.
617–618	abolishes binding to eif4e.
682	reduced cleavage by protease 2a from human rhinovirus 2.
768	abolishes binding to eif4a; when associated with a-770 and a-775.
771	abolishes binding to eif4a; when associated with a-767 and a-775.
776	abolishes binding to eif4a; when associated with a-767 and a-770.
842–843	abolishes binding to eif4a; when associated with a-850 and k-851.
851–852	abolishes binding to eif4a; when associated with a-841 and a-842.
896	abolishes binding to eif4a; when associated with a-92 and a-95.
902	abolishes binding to eif4a; when associated with a-895 and a-95.

Function

Pathways and Gene Ontology

Reactome pathways

15 pathways

ID	Pathway
R-HSA-1169408	ISG15 antiviral mechanism
R-HSA-156827	L13a-mediated translational silencing of Ceruloplasmin expression
R-HSA-166208	mTORC1-mediated signalling
R-HSA-429947	Deadenylation of mRNA
R-HSA-450408	AUF1 (hnRNP D0) binds and destabilizes mRNA
R-HSA-72649	Translation initiation complex formation
R-HSA-72662	Activation of the mRNA upon binding of the cap-binding complex and eIFs, and subsequent binding to 43S
R-HSA-72702	Ribosomal scanning and start codon recognition
R-HSA-72706	GTP hydrolysis and joining of the 60S ribosomal subunit
R-HSA-9010553	Regulation of expression of SLITs and ROBOs
R-HSA-975956	Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC)
R-HSA-975957	Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC)
R-HSA-9820841	M-decay: degradation of maternal mRNAs by maternally stored factors
R-HSA-9820865	Z-decay: degradation of maternal mRNAs by zygotically expressed factors
R-HSA-9918487	Dengue Virus Genome Translation and Replication

MSigDB gene sets: 466 (showing top): GOBP_CYTOPLASMIC_TRANSLATION, CREL_01, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_REGULATION_OF_AUTOPHAGY, GGTGTGT_MIR329, GOBP_REGULATION_OF_TRANSLATION_IN_RESPONSE_TO_STRESS, GOBP_BEHAVIOR, LU_IL4_SIGNALING, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, BASSO_B_LYMPHOCYTE_NETWORK, GOBP_SYNAPSE_ASSEMBLY, SP3_Q3, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GOBP_POSITIVE_REGULATION_OF_NEURON_DIFFERENTIATION, GOBP_CELL_CYCLE_PHASE_TRANSITION

GO Biological Process (20): behavioral fear response (GO:0001662), cap-dependent translational initiation (GO:0002191), translation (GO:0006412), translational initiation (GO:0006413), regulation of translational initiation (GO:0006446), negative regulation of autophagy (GO:0010507), neuron differentiation (GO:0030182), positive regulation of cell growth (GO:0030307), cellular response to nutrient levels (GO:0031669), miRNA-mediated gene silencing by inhibition of translation (GO:0035278), positive regulation of translation in response to endoplasmic reticulum stress (GO:0036493), positive regulation of neuron differentiation (GO:0045666), positive regulation of protein metabolic process (GO:0051247), regulation of cellular response to stress (GO:0080135), energy homeostasis (GO:0097009), positive regulation of G1/S transition of mitotic cell cycle (GO:1900087), positive regulation of protein localization to cell periphery (GO:1904377), positive regulation of eukaryotic translation initiation factor 4F complex assembly (GO:1905537), regulation of presynapse assembly (GO:1905606), regulation of translation (GO:0006417)

GO Molecular Function (9): RNA binding (GO:0003723), mRNA binding (GO:0003729), translation initiation factor activity (GO:0003743), ATP binding (GO:0005524), translation factor activity, RNA binding (GO:0008135), eukaryotic initiation factor 4E binding (GO:0008190), translation initiation factor binding (GO:0031369), molecular adaptor activity (GO:0060090), protein binding (GO:0005515)

GO Cellular Component (7): nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829), ribosome (GO:0005840), cytoplasmic stress granule (GO:0010494), membrane (GO:0016020), eukaryotic translation initiation factor 4F complex (GO:0016281)

Reactome top-level categories

Rollup of top-11 pathways:

Category	Pathways
Cap-dependent Translation Initiation	3
Nonsense-Mediated Decay (NMD)	2
Maternal to zygotic transition (MZT)	2
Antimicrobial mechanism of IFN-stimulated genes	1
Eukaryotic Translation Initiation	1
MTOR signalling	1
Deadenylation-dependent mRNA decay	1
Regulation of mRNA stability by proteins that bind AU-rich elements	1
Activation of the mRNA upon binding of the cap-binding complex and eIFs, and subsequent binding to 43S	1
Signaling by ROBO receptors	1
Dengue Virus Infection	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
translation	4
translational initiation	3
cellular anatomical structure	3
protein metabolic process	2
regulation of protein metabolic process	2
RNA binding	2
translation factor activity	2
binding	2
cytoplasm	2
behavioral defense response	1
fear response	1
cytoplasmic translational initiation	1
cap-dependent translation initiation factor activity	1
peptidyltransferase activity	1
translational elongation	1
translational termination	1
macromolecule biosynthetic process	1
protein biosynthetic process	1
formation of translation initiation ternary complex	1
metabolic process	1
regulation of translation	1
autophagy	1
negative regulation of catabolic process	1
regulation of autophagy	1
cell differentiation	1
generation of neurons	1
regulation of cell growth	1
cell growth	1
positive regulation of growth	1
positive regulation of cellular process	1
response to nutrient levels	1
cellular response to stimulus	1
negative regulation of translation	1
miRNA-mediated post-transcriptional gene silencing	1
positive regulation of translation in response to stress	1
response to endoplasmic reticulum stress	1
regulation of translation in response to endoplasmic reticulum stress	1
neuron differentiation	1
positive regulation of cell differentiation	1
regulation of neuron differentiation	1

Protein interactions and networks

STRING

3956 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EIF4G1	EIF4A1	P04765	999
EIF4G1	PABPC1	P11940	999
EIF4G1	EIF4A2	Q14240	999
EIF4G1	EIF4E	P06730	999
EIF4G1	EIF4B	P23588	998
EIF4G1	ATP7A	Q04656	989
EIF4G1	SH2D3C	Q8N5H7	984
EIF4G1	MKNK1	Q9BUB5	984
EIF4G1	EIF4EBP1	Q13541	980
EIF4G1	G3BP1	Q13283	978
EIF4G1	EIF4A3	P38919	974
EIF4G1	EIF5	P55010	973
EIF4G1	EIF1	P41567	972
EIF4G1	EIF4H	Q15056	969
EIF4G1	EIF3E	P60228	968

IntAct

272 interactions, top by confidence:

A	B	Type	Score
EIF4A1	EIF4G1	psi-mi:“MI:0407”(direct interaction)	0.970
EIF4G1	EIF4A1	psi-mi:“MI:0407”(direct interaction)	0.970
EIF4E	EIF4G1	psi-mi:“MI:0915”(physical association)	0.940
EIF4E	EIF4G1	psi-mi:“MI:0407”(direct interaction)	0.940
EIF4G1	EIF4E	psi-mi:“MI:0407”(direct interaction)	0.940
EIF4G1	EIF4E	psi-mi:“MI:0914”(association)	0.940
RACGAP1	KIF23	psi-mi:“MI:0914”(association)	0.920
	EIF4E	psi-mi:“MI:0914”(association)	0.880
EIF4G1	PABPC1	psi-mi:“MI:0407”(direct interaction)	0.840
PABPC1	EIF4G1	psi-mi:“MI:0915”(physical association)	0.840
EIF4E	EIF4G3	psi-mi:“MI:0914”(association)	0.810
EIF4A1	EIF4G3	psi-mi:“MI:0914”(association)	0.800
CEP350	CEP43	psi-mi:“MI:0914”(association)	0.770
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
YWHAG	BLTP3B	psi-mi:“MI:0914”(association)	0.640
CDC26	BUB1B	psi-mi:“MI:0914”(association)	0.640
IFT22	IFT56	psi-mi:“MI:0914”(association)	0.640
EIF3I	EIF3CL	psi-mi:“MI:0914”(association)	0.640
RBM4	EIF4G1	psi-mi:“MI:0407”(direct interaction)	0.590

BioGRID (673): EIF4G1 (Affinity Capture-Western), EIF4G1 (Affinity Capture-Western), EIF4G1 (Affinity Capture-Western), EIF4G1 (Affinity Capture-Western), EIF4G1 (Affinity Capture-MS), EIF4G1 (Affinity Capture-MS), EIF4G1 (Affinity Capture-MS), EIF4G1 (Affinity Capture-MS), EIF4G1 (Affinity Capture-MS), EIF4G1 (Affinity Capture-MS), EIF4G1 (Affinity Capture-RNA), EIF4A1 (Co-fractionation), EIF4A2 (Co-fractionation), EIF4G1 (Co-fractionation), EIF4G1 (Co-fractionation)

ESM2 similar proteins: A0A0R4IZ84, A0JMU8, A1L1K8, A5D7H5, B2RRE7, O15234, O60293, O75420, P48634, P61129, P61406, Q04637, Q14444, Q1ECZ4, Q1LZB6, Q3TLH4, Q5CZI8, Q5JSZ5, Q5JVS0, Q5M9G3, Q5RAK6, Q5TM26, Q5U236, Q5VK71, Q5XJD3, Q60865, Q6IMN6, Q6MG48, Q6NZJ6, Q7TPM1, Q7TQG1, Q7TQH0, Q7TSC1, Q80XI3, Q86US8, Q8BWW4, Q8BXJ2, Q8BYK8, Q8K3W3, Q8K3X0

Diamond homologs: A0A1S3C4H6, B9FXV5, C7G046, G5CEW6, P39935, P39936, Q04637, Q10475, Q553R3, Q5Z5Q3, Q6K641, Q6NZJ6, Q76E23, Q80XI3, Q84PB3, A9Z1V5, O43432, P41110, Q03387, Q41583, Q54DU5, Q54DV3, Q54MG1, Q54MG4, Q5TIE3, O73777, P78344, P79398, Q5R7J9, Q62448, Q95L46, Q8SVP8, O82233, Q8W4Q4, Q93ZT6, Q94BR1, Q9STL9, A3CEM4, Q0DBW8, Q2QT65

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
EIF4G1	“form complex”	eIF4F_complex	binding
4E2RCat	“down-regulates activity”	EIF4G1	“chemical inhibition”
EIF3_complex	“up-regulates activity”	EIF4G1	stabilization
PRKCA	“up-regulates activity”	EIF4G1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 193 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
Deadenylation of mRNA	6	19.2×	2e-05
Dengue Virus Genome Translation and Replication	8	18.5×	9e-07
Translation initiation complex formation	13	18.1×	7e-11
Ribosomal scanning and start codon recognition	13	18.1×	7e-11
M-decay: degradation of maternal mRNAs by maternally stored factors	7	16.7×	9e-06
Activation of the mRNA upon binding of the cap-binding complex and eIFs, and subsequent binding to 43S	8	15.9×	2e-06
Formation of the ternary complex, and subsequently, the 43S complex	9	14.2×	1e-06
mRNA 3’-end processing	8	11.5×	2e-05

GO biological processes:

GO term	Partners	Fold	FDR
formation of cytoplasmic translation initiation complex	6	38.3×	1e-06
translational initiation	12	24.4×	5e-11
stress granule assembly	5	17.1×	1e-03
nuclear-transcribed mRNA catabolic process, nonsense-mediated decay	6	16.0×	2e-04
regulation of translational initiation	6	16.0×	2e-04
positive regulation of translation	11	14.2×	1e-07
negative regulation of translation	12	13.4×	6e-08
mRNA transport	8	12.0×	7e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	175
Likely benign	37
Benign	32

Top pathogenic / likely-pathogenic (0)

SpliceAI

3725 predictions. Top by Δscore:

Variant	Effect	Δscore
3:184314675:GTA:G	donor_loss	1.0000
3:184314676:T:G	donor_loss	1.0000
3:184316130:A:AG	acceptor_gain	1.0000
3:184316131:G:GG	acceptor_gain	1.0000
3:184316131:GCCA:G	acceptor_gain	1.0000
3:184316219:G:A	donor_loss	1.0000
3:184316220:T:A	donor_loss	1.0000
3:184317712:ACCAG:A	acceptor_gain	1.0000
3:184317715:A:AG	acceptor_gain	1.0000
3:184317715:AG:A	acceptor_gain	1.0000
3:184317715:AGG:A	acceptor_gain	1.0000
3:184317715:AGGG:A	acceptor_gain	1.0000
3:184317716:G:GC	acceptor_gain	1.0000
3:184317716:GG:G	acceptor_gain	1.0000
3:184317716:GGG:G	acceptor_gain	1.0000
3:184317716:GGGG:G	acceptor_gain	1.0000
3:184317716:GGGGC:G	acceptor_gain	1.0000
3:184319671:C:A	acceptor_gain	1.0000
3:184319684:CCAAG:C	acceptor_loss	1.0000
3:184319686:A:AG	acceptor_gain	1.0000
3:184319686:AAGCT:A	acceptor_gain	1.0000
3:184319687:A:G	acceptor_gain	1.0000
3:184319687:AGCT:A	acceptor_gain	1.0000
3:184319688:G:A	acceptor_loss	1.0000
3:184319688:G:GG	acceptor_gain	1.0000
3:184319688:GCT:G	acceptor_gain	1.0000
3:184319688:GCTG:G	acceptor_gain	1.0000
3:184319798:GACG:G	donor_gain	1.0000
3:184319799:ACGGT:A	donor_loss	1.0000
3:184319800:CGGTG:C	donor_loss	1.0000

AlphaMissense

10357 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:184320637:T:A	I182N	1.000
3:184320637:T:C	I182T	1.000
3:184320637:T:G	I182S	1.000
3:184323519:T:A	W734R	1.000
3:184323519:T:C	W734R	1.000
3:184323521:G:C	W734C	1.000
3:184323521:G:T	W734C	1.000
3:184323808:T:C	L768P	1.000
3:184323813:A:G	K770E	1.000
3:184323815:A:C	K770N	1.000
3:184323815:A:T	K770N	1.000
3:184323817:T:A	L771Q	1.000
3:184323817:T:C	L771P	1.000
3:184323831:T:C	F776L	1.000
3:184323832:T:C	F776S	1.000
3:184323833:C:A	F776L	1.000
3:184323833:C:G	F776L	1.000
3:184323841:T:C	L779P	1.000
3:184323886:T:A	L794H	1.000
3:184323886:T:C	L794P	1.000
3:184323904:T:C	L800P	1.000
3:184323909:T:C	F802L	1.000
3:184323911:T:A	F802L	1.000
3:184323911:T:G	F802L	1.000
3:184323936:T:C	F811L	1.000
3:184323937:T:C	F811S	1.000
3:184323937:T:G	F811C	1.000
3:184323938:C:A	F811L	1.000
3:184323938:C:G	F811L	1.000
3:184323960:T:C	C819R	1.000

dbSNP variants (sampled 300 via entrez): RS1000138684 (3:184315933 A>G), RS1000417291 (3:184324626 AT>A,ATT), RS1000533938 (3:184313181 G>A,C,T), RS1000596102 (3:184312996 C>T), RS1000803956 (3:184318603 A>G), RS1000982715 (3:184316372 T>A), RS1001128405 (3:184321929 A>G), RS1001152099 (3:184318989 G>A), RS1001214278 (3:184319262 C>A,G), RS1001406159 (3:184324737 T>C), RS1001607656 (3:184330561 G>T), RS1001942991 (3:184329357 G>C,T), RS1001974107 (3:184329136 G>A), RS1002136274 (3:184323313 G>A,C,T), RS1002241869 (3:184335348 A>C,G)

Disease associations

OMIM: gene MIM:600495 | disease phenotypes: MIM:614251, MIM:168600

GenCC curated gene-disease

Disease	Classification	Inheritance
Parkinson disease 18, autosomal dominant, susceptibility to	Moderate	Autosomal dominant

Mondo (2): Parkinson disease 18, autosomal dominant, susceptibility to (MONDO:0013653), late-onset Parkinson disease (MONDO:0008199)

Orphanet (1): Hereditary late-onset Parkinson disease (Orphanet:411602)

HPO phenotypes

38 total (30 of 38 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000338	Hypomimic face
HP:0000651	Diplopia
HP:0000713	Agitation
HP:0000716	Depression
HP:0000726	Dementia
HP:0000741	Apathy
HP:0000744	Low frustration tolerance
HP:0001268	Mental deterioration
HP:0001300	Parkinsonism
HP:0001332	Dystonia
HP:0001824	Weight loss
HP:0002015	Dysphagia
HP:0002063	Rigidity
HP:0002067	Bradykinesia
HP:0002120	Cerebral cortical atrophy
HP:0002171	Gliosis
HP:0002172	Postural instability
HP:0002304	Akinesia
HP:0002322	Resting tremor
HP:0002359	Frequent falls
HP:0002360	Sleep disturbance
HP:0002362	Shuffling gait
HP:0002367	Visual hallucination
HP:0002548	Parkinsonism with favorable response to dopaminergic medication
HP:0003394	Muscle spasm
HP:0003584	Late onset
HP:0003587	Insidious onset
HP:0003596	Middle age onset
HP:0004409	Hyposmia

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST002541_6	Menarche (age at onset)	3.000000e-12
GCST90002403_558	Red blood cell count	5.000000e-09

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004703	age at menarche
EFO:0004305	erythrocyte count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL1741197 (SINGLE PROTEIN), CHEMBL4523621 (PROTEIN COMPLEX)

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

Binding affinities (BindingDB)

506 measured of 518 human assays (534 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
HEXACHLOROPHENE	IC50	98.3 nM
2,5-bis(chloranyl)-3-(4-methylpiperazin-1-yl)-6-(2-piperidin-1-yl-1,3-thiazol-5-yl)cyclohexa-2,5-diene-1,4-dione	EC50	160 nM
2,5-bis(chloranyl)-3-[2-(dimethylamino)-1,3-thiazol-5-yl]-6-pyrrolidin-1-yl-cyclohexa-2,5-diene-1,4-dione	EC50	210 nM
1-[2,3-bis(2-furanyl)-6-quinoxalinyl]-3-(2-methoxyethyl)urea	IC50	492 nM
3-(2-{(E)-[1-(4-chlorophenyl)-2,5-dioxoimidazolidin-4-ylidene]methyl}-1H-pyrrol-1-yl)benzoic acid	IC50	1230 nM
MLS000392355	IC50	1490 nM
1-(3,4-Dichloro-phenyl)-3-(5-pyridin-4-yl-[1,3,4]thiadiazol-2-yl)-urea	IC50	1560 nM
2-(5,7-dichloro-2-methylquinolin-8-yl)oxy-N-(furan-2-ylmethyl)acetamide	IC50	1560 nM
(4E)-4-[(2-methyl-3-nitro-phenyl)hydrazinylidene]-3-(4-nitrophenyl)-5-oxidanylidene-pyrazole-1-carbothioamide	IC50	1710 nM
(4E)-4-[[[4-(2-furanyl)-2-(2-methoxyethylimino)-3-thiazolyl]amino]methylidene]-2,3-dihydroxy-1-cyclohexa-2,5-dienone	EC50	1810 nM
(5Z)-3-(3-chlorophenyl)-5-(4-hydroxy-3-methoxy-5-nitro-benzylidene)thiazolidine-2,4-quinone	IC50	2210 nM
(6E)-2-(2-furanyl)-5-imino-6-[[1-(4-methoxyphenyl)-2-pyrrolyl]methylidene]-[1,3,4]thiadiazolo[3,2-a]pyrimidin-7-one	IC50	2270 nM
(5Z)-3-(4-chlorophenyl)-5-(4-hydroxy-3-methoxy-5-nitro-benzylidene)thiazolidine-2,4-quinone	IC50	2300 nM
2,5-bis(chloranyl)-3-piperidin-1-yl-6-(2-piperidin-1-yl-1,3-thiazol-5-yl)cyclohexa-2,5-diene-1,4-dione	EC50	2320 nM
7-[8-formyl-1,6,7-trihydroxy-3-methyl-5-(propan-2-yl)naphthalen-2-yl]-2,3,8-trihydroxy-6-methyl-4-(propan-2-yl)naphthalene-1-carbaldehyde	IC50	2550 nM
7-[[4-(2-hydroxyethyl)-1-piperazinyl]-thiophen-2-ylmethyl]-8-quinolinol	IC50	2820 nM
(5Z)-3-(4-chlorobenzyl)-5-(4-hydroxy-3-methoxy-5-nitro-benzylidene)thiazolidine-2,4-quinone	IC50	3540 nM
2,6,7-Trihydroxy-9-methyl-xanthen-3-one	IC50	3600 nM
4-((3E)-3-{[5-(4-nitrophenyl)-2-furyl]methylene}-2-oxo-5-phenyl-2,3-dihydro-1H-pyrrol-1-yl)benzoic acid	IC50	3930 nM
4-[({[2-(4-fluorophenyl)-5H-chromeno[2,3-d]pyrimidin-4-yl]thio}acetyl)amino]benzoic acid	IC50	4040 nM
2-(2-furanyl)-4-quinolinecarboxylic acid [2-(diethylamino)-2-oxoethyl] ester	EC50	4950 nM
(2E,5E)-2,5-bis(4-hydroxy-3,5-dimethoxy-benzylidene)cyclopentanone	EC50	5130 nM
1-cetylquinolin-1-ium;iodide	IC50	5710 nM
2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one	IC50	6200 nM
5-amino-1-benzoyl-4-pyrazolecarboxylic acid ethyl ester	IC50	6280 nM
1-[[2,3-bis(2-furyl)quinoxalin-6-yl]carbamoyl]isonipecotic acid ethyl ester	EC50	6650 nM
MLS-0266887.0001	IC50	8130 nM
2-(4-bromophenyl)-4,6-dinitro-1,2-benzothiazol-3-one	IC50	8140 nM
MLS000534769	EC50	8540 nM
(Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(E,3S)-3-hydroxyoct-1-enyl]cyclopentyl]-5-heptenoic acid methyl ester	IC50	8700 nM
9,10-dimethoxy-2-(2-pyridinylmethylamino)-6,7-dihydropyrimido[6,1-a]isoquinolin-4-one	IC50	9210 nM
1-[2,3-bis(2-furanyl)-6-quinoxalinyl]-3-(3-hydroxypropyl)urea	IC50	9250 nM
1-Cyclopropyl-3-(2,3-di-furan-2-yl-quinoxalin-6-yl)-urea	EC50	9260 nM
(5Z)-1-(2-furanylmethyl)-2-sulfanylidene-5-(thiophen-2-ylmethylidene)-1,3-diazinane-4,6-dione	IC50	9490 nM
4-[2-[(E)-[1-[2-(4-methylanilino)-2-oxoethyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1-pyrrolyl]benzoic acid	IC50	9540 nM
7-(3,4-dimethylanilino)-6-(2-methylphenyl)-7H-pyrrolo[3,4-b]pyridin-5-one	IC50	9590 nM
1-(3-cetylimidazol-1-ium-1-yl)acetone;bromide	IC50	10100 nM
2-methyl-5,8-bis(oxidanyl)naphthalene-1,4-dione	IC50	10300 nM
4-[(8-hydroxy-7-quinolinyl)-(3-pyridinyl)methyl]-1-piperazinecarboxylic acid ethyl ester	IC50	10600 nM
(2E)-1-ethyl-2-[(1-ethyl-2-quinolin-1-iumyl)methylidene]quinoline;chloride	IC50	10600 nM
(4Z)-2-nitro-4-[(2-thiazolylhydrazo)methylidene]-1-cyclohexa-2,5-dienone	IC50	10800 nM
Icosa‐5,8,11,14‐tetraynoic acid (D3)	IC50	12100 nM
(1-cetyl-4-pyridylidene)methyl-keto-ammonium;bromide	IC50	12700 nM
1-cetyl-3-methyl-imidazol-3-ium;bromide	IC50	13000 nM
3-(3-keto-1,2-benzothiazol-2-yl)-N,N-dimethyl-benzenesulfonamide	IC50	13000 nM
MLS000334839	IC50	13100 nM
2,5-bis(azanyl)benzoic acid;hydrochloride	IC50	13400 nM
2-(1,3-thiazol-2-yl)-1,2-benzothiazol-3-one	IC50	13500 nM
(3-methyl-4-pyrrolidino-phenyl)amine;hydrochloride	EC50	13700 nM
2-tert-butyl-3-chloranyl-6-oxidanyl-1,5-diphenyl-pyridin-4-one	IC50	14100 nM

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
7.62	Kd	23.81	nM	CHEMBL3752910
7.62	ED50	23.81	nM	CHEMBL3752910
7.11	Kd	77.79	nM	CHEMBL5653589
7.11	ED50	77.79	nM	CHEMBL5653589

PubChem BioAssay actives

2 with measured affinity, of 12 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
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148308: Binding affinity to human EIF4G1 incubated for 45 mins by Kinobead based pull down assay	kd	0.0238	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148308: Binding affinity to human EIF4G1 incubated for 45 mins by Kinobead based pull down assay	kd	0.0778	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects cotreatment, decreases methylation, decreases expression, increases expression	4
sodium arsenite	affects cotreatment, increases abundance, increases expression, decreases expression, increases activity	4
bisphenol S	increases expression, decreases expression, affects cotreatment, decreases methylation	3
Valproic Acid	affects expression, decreases methylation, increases expression	3
bisphenol F	increases expression, affects cotreatment, decreases expression	2
methylmercuric chloride	increases expression	2
arsenite	increases reaction, affects reaction, affects binding	2
Arsenic Trioxide	decreases expression, increases expression, affects cotreatment	2
Arsenic	affects expression, increases abundance, affects cotreatment, decreases expression, increases expression	2
Benzo(a)pyrene	increases methylation, increases mutagenesis	2
Aflatoxin B1	decreases methylation, increases methylation	2
Cadmium Chloride	increases expression	2
Particulate Matter	increases expression, affects expression, increases abundance	2
FR900359	affects phosphorylation	1
dicrotophos	increases expression	1
testosterone enanthate	affects expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	increases abundance, affects cotreatment, decreases expression, increases oxidation	1
deoxynivalenol	increases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, decreases expression, increases expression	1
decabromobiphenyl ether	increases expression	1
beta-lapachone	increases expression	1
7-methylguanosine triphosphate	affects binding, decreases reaction	1
cobaltous chloride	decreases expression	1
bleomycetin	increases expression	1
butylbenzyl phthalate	affects expression	1
nickel sulfate	increases expression	1
coumarin	affects phosphorylation	1
methacrylaldehyde	affects cotreatment, decreases expression, increases oxidation, increases abundance	1
beta-methylcholine	affects expression	1

ChEMBL screening assays

8 unique, capped per target: 8 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651350	Binding	Binding affinity to human EIF4G1 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

3 cell lines: 3 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_E7KV	KOLF2.1J EIF4G1 A502V SNV/SNV	Induced pluripotent stem cell	Male
CVCL_E7KW	KOLF2.1J EIF4G1 A502V SNV/WT	Induced pluripotent stem cell	Male
CVCL_E7NH	KOLF2.1J EIF4G1 9kbdel DEL/WT	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00455143	PHASE4	TERMINATED	Cognitive Protection - Dexmedetomidine and Cognitive Reserve
NCT00561678	PHASE4	COMPLETED	Perioperative Cognitive Function - Dexmedetomidine and Cognitive Reserve
NCT01807481	PHASE4	UNKNOWN	Phase IV Study to Evaluate the Efficacy and Safety of Mircera in PD
NCT07015671	PHASE3	COMPLETED	Bioavailability and Bioequivalence Study of ER Torsemide and Spironolactone FDC Tablet in Healthy Subjects
NCT03942458	PHASE1	COMPLETED	Pharmacokinetics and Pharmacodynamics of Vicagrel in Healthy Adult Subjects of Different CYP2C19
NCT07195825	PHASE1	RECRUITING	A Clinical Study to Evaluate the Safety, and Tolerability of BBM-P002 in the Treatment of Parkinson’s Disease
NCT04093349	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	A Gene Transfer Study for Late-Onset Pompe Disease (RESOLUTE)
NCT07282847	PHASE1/PHASE2	RECRUITING	A Study to Evaluate Safety, Tolerability, and Efficacy of AB-1009 Gene Therapy (GAA Gene) in Adult Participants With Late Onset Pompe Disease (PROGRESS-GT LOPD)
NCT00105131	Not specified	COMPLETED	Genetic Characterization of Parkinson’s Disease
NCT03021408	Not specified	UNKNOWN	Effectiveness of Different Approaches for the Rehabilitation of Gait in Patients With Parkinson’s Disease
NCT03893240	Not specified	COMPLETED	Neutralizing Antibody Seroprevalence Study With a Retrospective Component in Participants With Late-Onset Pompe Disease
NCT05810454	Not specified	NOT_YET_RECRUITING	iPACES v3 MCI NIA Protocol Copied for iPACES v4 PD NINDS