EIF4A2

Summary

EIF4A2 (eukaryotic translation initiation factor 4A2, HGNC:3284) is a protein-coding gene on chromosome 3q27.3, encoding Eukaryotic initiation factor 4A-II (Q14240). ATP-dependent RNA helicase which is a subunit of the eIF4F complex involved in cap recognition and is required for mRNA binding to ribosome.

Enables ATP hydrolysis activity. Involved in negative regulation of RNA-dependent RNA polymerase activity. Located in perinuclear region of cytoplasm. Implicated in neurodevelopmental disorder with hypotonia and speech delay.

Source: NCBI Gene 1974 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder with hypotonia and speech delay, with or without seizures (Strong, GenCC)
• Clinical variants (ClinVar): 118 total — 7 pathogenic, 10 likely-pathogenic
• Phenotypes (HPO): 77
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 1 cancer types
• MANE Select transcript: NM_001967

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3284
Approved symbol	EIF4A2
Name	eukaryotic translation initiation factor 4A2
Location	3q27.3
Locus type	gene with protein product
Status	Approved
Aliases	DDX2B, EIF4A, BM-010
Ensembl gene	ENSG00000156976
Ensembl biotype	protein_coding
OMIM	601102
Entrez	1974

Gene structure

Transcript identifiers

Ensembl transcripts: 40 — 18 protein_coding, 18 retained_intron, 4 nonsense_mediated_decay

ENST00000323963, ENST00000425053, ENST00000426808, ENST00000429589, ENST00000440191, ENST00000441007, ENST00000443963, ENST00000445596, ENST00000461021, ENST00000465032, ENST00000465222, ENST00000465267, ENST00000465792, ENST00000466362, ENST00000467585, ENST00000468362, ENST00000475409, ENST00000475653, ENST00000485101, ENST00000486805, ENST00000491473, ENST00000492144, ENST00000494445, ENST00000495049, ENST00000496382, ENST00000497177, ENST00000498746, ENST00000865627, ENST00000865628, ENST00000865629, ENST00000865630, ENST00000928247, ENST00000928248, ENST00000928249, ENST00000928250, ENST00000928251, ENST00000928252, ENST00000957080, ENST00000957081, ENST00000957082

RefSeq mRNA: 1 — MANE Select: NM_001967 NM_001967

CCDS: CCDS3282

Canonical transcript exons

ENST00000323963 — 11 exons

Exon	Start	End
ENSE00002462331	186784962	186785101
ENSE00003466757	186783577	186783639
ENSE00003469666	186784432	186784477
ENSE00003496146	186785883	186786051
ENSE00003497356	186787803	186787882
ENSE00003517413	186789125	186789897
ENSE00003611073	186784564	186784696
ENSE00003623292	186786502	186786645
ENSE00003633979	186787495	186787584
ENSE00003635471	186786164	186786273
ENSE00003675683	186787127	186787264

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 99.95.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 321.7889 / max 10348.9559, expressed in 1825 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
40306	319.4060	1825
40311	0.8289	485
40308	0.6251	340
40309	0.4687	204
40307	0.4602	221

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	99.95	gold quality
endothelial cell	CL:0000115	99.93	gold quality
cerebellar vermis	UBERON:0004720	99.91	gold quality
germinal epithelium of ovary	UBERON:0001304	99.88	gold quality
postcentral gyrus	UBERON:0002581	99.88	gold quality
adult organism	UBERON:0007023	99.87	gold quality
oocyte	CL:0000023	99.86	gold quality
superior frontal gyrus	UBERON:0002661	99.86	gold quality
lateral nuclear group of thalamus	UBERON:0002736	99.85	gold quality
parietal lobe	UBERON:0001872	99.83	gold quality
CA1 field of hippocampus	UBERON:0003881	99.83	gold quality
Brodmann (1909) area 23	UBERON:0013554	99.83	gold quality
pons	UBERON:0000988	99.81	gold quality
superficial temporal artery	UBERON:0001614	99.81	gold quality
pigmented layer of retina	UBERON:0001782	99.81	gold quality
primary visual cortex	UBERON:0002436	99.81	gold quality
middle temporal gyrus	UBERON:0002771	99.81	gold quality
jejunal mucosa	UBERON:0000399	99.80	gold quality
parotid gland	UBERON:0001831	99.80	gold quality
occipital lobe	UBERON:0002021	99.80	gold quality
parietal pleura	UBERON:0002400	99.80	gold quality
orbitofrontal cortex	UBERON:0004167	99.79	gold quality
pleura	UBERON:0000977	99.78	gold quality
biceps brachii	UBERON:0001507	99.78	gold quality
Brodmann (1909) area 46	UBERON:0006483	99.78	gold quality
prefrontal cortex	UBERON:0000451	99.77	gold quality
cauda epididymis	UBERON:0004360	99.77	gold quality
blood vessel layer	UBERON:0004797	99.77	gold quality
bronchial epithelial cell	CL:0002328	99.76	gold quality
epithelium of nasopharynx	UBERON:0001951	99.76	gold quality

Single-cell (SCXA)

Detected in 17 experiment(s), a significant marker in 8.

Experiment	Marker?	Max mean expression
E-HCAD-4	yes	41.30
E-HCAD-31	yes	31.34
E-GEOD-135922	yes	20.20
E-MTAB-5061	yes	17.74
E-MTAB-7316	yes	17.54
E-MTAB-8142	yes	12.07
E-CURD-112	yes	5.57
E-MTAB-6379	no	1957.65
E-MTAB-7606	no	1096.85
E-MTAB-8884	no	666.67
E-HCAD-5	no	48.19
E-HCAD-6	no	43.49
E-HCAD-10	no	34.01
E-GEOD-81608	no	19.62
E-CURD-122	no	10.14

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

110 targeting EIF4A2, 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-126-5P	100.00	72.71	3180
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-3162-3P	100.00	65.37	363
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4803	99.98	71.99	3117
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-300	99.92	71.76	2856

Literature-anchored findings (GeneRIF, showing 20)

• interacted with NS5B protein, and the two proteins were shown to be partially colocalized in the perinuclear region (PMID:11922617)
• Single nucleotide polymorphisms in two relevant candidate genes for glucose homeostasis, kininogen (KNG1), and eukaryotic translation initiation factor 4alpha2 (EIF4A2) linked to type 2 diabetes. (PMID:16567544)
• subcellular distribution of eIF4F components may potentiate the complex assembly (PMID:18250159)
• 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)
• This protein has been found differentially expressed in the temporal lobe from patients with schizophrenia. (PMID:19034380)
• Studies indicate that eIF4A (DDX2), together with its accessory proteins eIF4B and eIF4H, is thought to act as a helicase that unwinds secondary structures in the mRNA 5’ UTR. (PMID:21427765)
• A protein encoded by this locus was found to be differentially expressed in postmortem brains from patients with atypical frontotemporal lobar degeneration. (PMID:22360420)
• The results indicated that eIF4AI and eIF4AII expression are linked and that the two protein isoforms exhibit functional differences. (PMID:22589333)
• These data support a linear model for miRNA-mediated gene regulation in which translational repression via eIF4A2 is required first, followed by mRNA destabilization. (PMID:23559250)
• expression is an independent prognostic factor for patients with non-small-cell lung cancer for both overall survival and disease-free survival (PMID:23867391)
• Studies indicate a developing focus on targeting eukaryotic initiation factor 4A eIF4A1 and eIF4A2 as cancer therapy. (PMID:26614665)
• eIF4A2 is recruited to stress granules, suggesting sumoylation of eIF4A2 correlates with its recruitment to stress granules. (PMID:27160682)
• Eukaryotic translation initiation factor 4A2 (eIF4A2) is necessary for efficient HIV-1 replication in human lymphoid cell line. eIF4A2 depletion reduces the efficiency of viral cDNA synthesis with virion entry into target cells being unaffected. Depletion of eIF4A2 also inhibits HIV-1 spreading infection in a knockdown level-dependent manner. (PMID:29842983)
• high EIF4A2 expression predicts poor prognosis of CRC patients and is associated with distant metastasis and poor response to oxaliplatin. Knocking-down EIF4A2 inhibits sphere formation and experimental metastasis, as well as oxaliplatin resistance in CRC. (PMID:31088567)
• Data show that incorporation of ATP-dependent RNA helicase eIF4A-2 (eIF4A2) into the CCR4-NOT complex inhibits CCR4-NOT transcription complex subunit 7 (CNOT7) deadenylation activity. (PMID:31180491)
• EIF4A2 was confirmed as a potential target of miR-5195-3p. MicroRNA-5195-3p enhances the chemosensitivity of triple-negative breast cancer (TNBC) to paclitaxel (PTX) by downregulating EIF4A2. (PMID:31308851)
• exerts its repressive effect on translation initiation by binding purine-rich motifs which are enriched in the 5’UTR of target mRNAs directly upstream of the AUG start codon (PMID:31791371)
• Rare EIF4A2 variants are associated with a neurodevelopmental disorder characterized by intellectual disability, hypotonia, and epilepsy. (PMID:36528028)
• Monitoring RNA restructuring in a human cell-free extract reveals eIF4A-dependent and eIF4A-independent unwinding activity. (PMID:37331603)
• Dystonia Linked to EIF4A2 Haploinsufficiency: A Disorder of Protein Translation Dysfunction. (PMID:37485550)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	eif4a2	ENSDARG00000016477
mus_musculus	Eif4a2	ENSMUSG00000022884
rattus_norvegicus	Eif4a2	ENSRNOG00000001815

Paralogs (38): DDX20 (ENSG00000064703), DDX3Y (ENSG00000067048), DDX1 (ENSG00000079785), DDX43 (ENSG00000080007), DDX18 (ENSG00000088205), DDX24 (ENSG00000089737), DDX17 (ENSG00000100201), DDX49 (ENSG00000105671), DDX50 (ENSG00000107625), DDX5 (ENSG00000108654), DDX25 (ENSG00000109832), DDX6 (ENSG00000110367), DDX55 (ENSG00000111364), DDX59 (ENSG00000118197), DDX54 (ENSG00000123064), DDX39A (ENSG00000123136), DDX27 (ENSG00000124228), DDX31 (ENSG00000125485), DDX56 (ENSG00000136271), EIF4A3 (ENSG00000141543), DDX46 (ENSG00000145833), DDX4 (ENSG00000152670), DDX19B (ENSG00000157349), EIF4A1 (ENSG00000161960), DDX21 (ENSG00000165732), DDX19A (ENSG00000168872), TDRD12 (ENSG00000173809), DDX23 (ENSG00000174243), DDX10 (ENSG00000178105), DDX28 (ENSG00000182810), DDX41 (ENSG00000183258), DDX53 (ENSG00000184735), DDX51 (ENSG00000185163), DDX42 (ENSG00000198231), DDX39B (ENSG00000198563), DDX47 (ENSG00000213782), DDX3X (ENSG00000215301), DDX52 (ENSG00000278053)

Protein

Protein identifiers

Eukaryotic initiation factor 4A-II — Q14240 (reviewed: Q14240)

Alternative names: ATP-dependent RNA helicase eIF4A-2

All UniProt accessions (7): Q14240, C9JUF0, E7EMV8, E7EQG2, E9PBH4, F8WE11, J3KSN7

UniProt curated annotations — full annotation on UniProt →

Function. ATP-dependent RNA helicase which is a subunit of the eIF4F complex involved in cap recognition and is required for mRNA binding to ribosome. In the current model of translation initiation, eIF4A unwinds RNA secondary structures in the 5’-UTR of mRNAs which is necessary to allow efficient binding of the small ribosomal subunit, and subsequent scanning for the initiator codon.

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 and EIF4G1/EIFFG3. Interacts with EIF4E. May interact with NOM1. (Microbial infection) Interacts with herpes simplex virus 1/HHV-1 protein Vhs.

Disease relevance. Neurodevelopmental disorder with hypotonia and speech delay, with or without seizures (NEDHSS) [MIM:620455] A disorder characterized by global developmental delay, intellectual disability, poor or absent speech, hypotonia, epilepsy, and structural brain anomalies. Inheritance is autosomal dominant or autosomal recessive. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the DEAD box helicase family. eIF4A subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q14240-1	1	yes
Q14240-2	2

RefSeq proteins (1): NP_001958* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000629	RNA-helicase_DEAD-box_CS	Conserved_site
IPR001650	Helicase_C-like	Domain
IPR011545	DEAD/DEAH_box_helicase_dom	Domain
IPR014001	Helicase_ATP-bd	Domain
IPR014014	RNA_helicase_DEAD_Q_motif	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR044728	EIF4A_DEADc	Domain

Pfam: PF00270, PF00271

Catalyzed reactions (Rhea), 1 shown:

• ATP + H2O = ADP + phosphate + H(+) (RHEA:13065)

UniProt features (43 total): sequence variant 15, helix 9, strand 7, domain 2, sequence conflict 2, short sequence motif 2, chain 1, region of interest 1, turn 1, binding site 1, modified residue 1, splice variant 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
3BOR	X-RAY DIFFRACTION	1.85

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q14240-F1	86.94	0.62

Functional residue map

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

Ligand- & substrate-binding residues (1): 77–84

Post-translational modifications (1): 159

Function

Pathways and Gene Ontology

Reactome pathways

10 pathways

ID	Pathway
R-HSA-1169408	ISG15 antiviral mechanism
R-HSA-156827	L13a-mediated translational silencing of Ceruloplasmin expression
R-HSA-429947	Deadenylation of 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-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: 510 (showing top): AHRARNT_01, GOBP_CYTOPLASMIC_TRANSLATION, CREL_01, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, AAGCAAT_MIR137, TAATAAT_MIR126, TGCGCANK_UNKNOWN, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_RESPONSE_TO_PEPTIDE, GCANCTGNY_MYOD_Q6, MORF_SNRP70, MORF_UBE2I, RIZ_ERYTHROID_DIFFERENTIATION_CCNE1, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN

GO Biological Process (7): cytoplasmic translational initiation (GO:0002183), translational initiation (GO:0006413), regulation of translational initiation (GO:0006446), negative regulation of RNA-dependent RNA polymerase activity (GO:1900260), cellular response to leukemia inhibitory factor (GO:1990830), RNA processing (GO:0006396), translation (GO:0006412)

GO Molecular Function (10): RNA binding (GO:0003723), RNA helicase activity (GO:0003724), translation initiation factor activity (GO:0003743), helicase activity (GO:0004386), ATP binding (GO:0005524), ATP hydrolysis activity (GO:0016887), nucleotide binding (GO:0000166), nucleic acid binding (GO:0003676), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (4): cytosol (GO:0005829), eukaryotic translation initiation factor 4F complex (GO:0016281), perinuclear region of cytoplasm (GO:0048471), nucleolus (GO:0005730)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
Cap-dependent Translation Initiation	3
Maternal to zygotic transition (MZT)	2
Antimicrobial mechanism of IFN-stimulated genes	1
Eukaryotic Translation Initiation	1
Deadenylation-dependent mRNA decay	1
Activation of the mRNA upon binding of the cap-binding complex and eIFs, and subsequent binding to 43S	1
Dengue Virus Infection	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
translational initiation	4
cytoplasm	3
ATP-dependent activity	2
binding	2
cellular anatomical structure	2
cytoplasmic translation	1
formation of translation initiation ternary complex	1
translation	1
metabolic process	1
regulation of translation	1
RNA-directed RNA polymerase activity	1
negative regulation of catalytic activity	1
regulation of transferase activity	1
cellular response to cytokine stimulus	1
response to leukemia inhibitory factor	1
gene expression	1
RNA biosynthetic process	1
primary metabolic process	1
peptidyltransferase activity	1
translational elongation	1
translational termination	1
macromolecule biosynthetic process	1
protein metabolic process	1
protein biosynthetic process	1
nucleic acid binding	1
helicase activity	1
ATP-dependent activity, acting on RNA	1
catalytic activity, acting on RNA	1
translation factor activity	1
nucleic acid conformation isomerase activity	1
catalytic activity, acting on a nucleic acid	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
ribonucleoside triphosphate phosphatase activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
catalytic activity	1
RNA cap binding complex	1
nuclear lumen	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

4460 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EIF4A2	EIF4E	P06730	999
EIF4A2	EIF4B	P23588	999
EIF4A2	EIF4G1	Q04637	999
EIF4A2	PABPC1	P11940	998
EIF4A2	EIF4G3	O43432	998
EIF4A2	PDCD4	Q53EL6	997
EIF4A2	EIF4G2	P78344	987
EIF4A2	EIF4H	Q15056	986
EIF4A2	EIF1	P41567	985
EIF4A2	EIF5	P55010	970
EIF4A2	MKNK1	Q9BUB5	929
EIF4A2	PAIP1	Q9H074	925
EIF4A2	EIF5B	O60841	919
EIF4A2	DHX29	Q7Z478	901
EIF4A2	EIF4E2	O60573	875

IntAct

139 interactions, top by confidence:

A	B	Type	Score
EIF4A1	EIF4G3	psi-mi:“MI:0914”(association)	0.800
EIF4A2	PDCD4	psi-mi:“MI:0915”(physical association)	0.680
PDCD4	EIF4A2	psi-mi:“MI:0915”(physical association)	0.680
TRIM39	EIF4A2	psi-mi:“MI:0915”(physical association)	0.670
EIF4A2	TRIM39	psi-mi:“MI:0915”(physical association)	0.670
EIF4G1	EIF4A2	psi-mi:“MI:0915”(physical association)	0.660
EIF4A2	EIF4G1	psi-mi:“MI:0915”(physical association)	0.660
EIF4A2		psi-mi:“MI:0915”(physical association)	0.660
	EIF4A2	psi-mi:“MI:0915”(physical association)	0.660
	EIF4A2	psi-mi:“MI:0403”(colocalization)	0.660
EIF4G2	EIF4A2	psi-mi:“MI:0915”(physical association)	0.590
DPPA4	EIF4A2	psi-mi:“MI:0915”(physical association)	0.560
EIF4A2	SLC16A9	psi-mi:“MI:0915”(physical association)	0.560
TRIM36	EIF4A2	psi-mi:“MI:0915”(physical association)	0.560
EIF4A2	SSX2IP	psi-mi:“MI:0915”(physical association)	0.560
EIF4A2	IPO11	psi-mi:“MI:0915”(physical association)	0.560
EIF4A2	DPPA4	psi-mi:“MI:0915”(physical association)	0.560
SLC16A9	EIF4A2	psi-mi:“MI:0915”(physical association)	0.560
EIF4A2	TRIM36	psi-mi:“MI:0915”(physical association)	0.560
SSX2IP	EIF4A2	psi-mi:“MI:0915”(physical association)	0.560
IPO11	EIF4A2	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (243): EIF4A2 (Two-hybrid), MDFI (Two-hybrid), PDCD4 (Two-hybrid), IPO11 (Two-hybrid), DPPA4 (Two-hybrid), TRIM36 (Two-hybrid), TRIM39 (Two-hybrid), SSX2IP (Two-hybrid), PIH1D2 (Two-hybrid), SLC16A9 (Two-hybrid), EIF4A2 (Affinity Capture-MS), EIF4A2 (Two-hybrid), EIF4A2 (Affinity Capture-Western), EIF4A2 (Affinity Capture-RNA), AIMP1 (Co-fractionation)

ESM2 similar proteins: A1CJT5, A1D7N3, A2QEN5, A4QU31, A4QVP2, A5A6N4, A6M931, A6R3R5, A6RJ45, A7EGL7, A7EM88, B5DG42, B5FZY7, P0CQ72, P0CQ73, P10630, P29562, P38919, P47943, P60842, P60843, Q0CXD0, Q0UU86, Q10055, Q10I26, Q14240, Q1DQ20, Q2HFP1, Q2NL22, Q2UPY3, Q3B8Q2, Q3SZ54, Q3SZ65, Q4IAA0, Q4P184, Q4P331, Q4R3Q1, Q4R8K5, Q4WX43, Q5B948

Diamond homologs: A1C595, A1CJT5, A1D071, A1D7N3, A2QEN5, A3GFV3, A4QU31, A4QVP2, A5A6N4, A5AAE5, A5DE68, A5DWJ1, A6M931, A6QSQ0, A6R3R5, A6RJ45, A6S4N4, A6ZXY5, A7EGL7, A7EM88, A7TEF4, B5DG42, B5FZY7, B7ZTW1, O42226, P0CQ70, P0CQ71, P0CQ72, P0CQ73, P10630, P27639, P29562, P35683, P38919, P41376, P41377, P41378, P41379, P41380, P41382

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
EIF4A2	“form complex”	eIF4F_complex	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 113 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
Translation initiation complex formation	16	36.7×	6e-19
Ribosomal scanning and start codon recognition	15	34.4×	2e-17
Formation of the ternary complex, and subsequently, the 43S complex	12	31.1×	2e-13
Activation of the mRNA upon binding of the cap-binding complex and eIFs, and subsequent binding to 43S	7	22.9×	1e-06
Dengue Virus Genome Translation and Replication	6	22.9×	9e-06
L13a-mediated translational silencing of Ceruloplasmin expression	16	19.5×	1e-14
GTP hydrolysis and joining of the 60S ribosomal subunit	15	18.1×	2e-13
Nonsense-Mediated Decay (NMD)	6	16.9×	5e-05

GO biological processes:

GO term	Partners	Fold	FDR
formation of cytoplasmic translation initiation complex	9	100.1×	1e-14
translational initiation	16	56.8×	8e-22
regulation of translational initiation	6	27.8×	1e-05
cytoplasmic translation	6	11.0×	2e-03
mRNA splicing, via spliceosome	8	7.2×	2e-03

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 1 cancer types — BRCA.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	7
Likely pathogenic	10
Uncertain significance	64
Likely benign	9
Benign	3

Top pathogenic / likely-pathogenic (17)

Variant ID	HGVS	Classification
1712519	NM_001967.4(EIF4A2):c.646A>G (p.Thr216Ala)	Pathogenic
1712520	NM_001967.4(EIF4A2):c.647C>T (p.Thr216Ile)	Pathogenic
1722504	NM_001967.4(EIF4A2):c.186_187del (p.Arg62fs)	Pathogenic
1722505	NM_001967.4(EIF4A2):c.1161_1166del (p.Asp387_Ile388del)	Pathogenic
3507609	NM_001967.4(EIF4A2):c.1084G>A (p.Gly362Ser)	Pathogenic
4819733	NM_001967.4(EIF4A2):c.431_435del (p.Glu144fs)	Pathogenic
531899	NC_000003.11:g.(?186256465)(186980528_?)del	Pathogenic
1712247	NM_001967.4(EIF4A2):c.481G>T (p.Gly161Trp)	Likely pathogenic
1712514	NM_001967.4(EIF4A2):c.5C>G (p.Ser2Cys)	Likely pathogenic
1712515	NM_001967.4(EIF4A2):c.106GAT[1] (p.Asp37del)	Likely pathogenic
1712516	NM_001967.4(EIF4A2):c.131_132del (p.Leu44fs)	Likely pathogenic
1712518	NM_001967.4(EIF4A2):c.641C>A (p.Ser214Tyr)	Likely pathogenic
1712521	NM_001967.4(EIF4A2):c.945_947del (p.Ile315del)	Likely pathogenic
2691878	NM_001967.4(EIF4A2):c.517+1G>T	Likely pathogenic
3772177	NM_001967.4(EIF4A2):c.481G>A (p.Gly161Arg)	Likely pathogenic
3844150	NM_001967.4(EIF4A2):c.1012G>T (p.Asp338Tyr)	Likely pathogenic
4292981	NM_001967.4(EIF4A2):c.235_238del (p.Ser79fs)	Likely pathogenic

SpliceAI

1298 predictions. Top by Δscore:

Variant	Effect	Δscore
3:186784692:TAAAG:T	donor_loss	1.0000
3:186784693:AAAGG:A	donor_loss	1.0000
3:186784694:AAG:A	donor_loss	1.0000
3:186784695:AG:A	donor_loss	1.0000
3:186784696:GGTAA:G	donor_loss	1.0000
3:186784698:T:A	donor_loss	1.0000
3:186784960:AG:A	acceptor_gain	1.0000
3:186784961:GG:G	acceptor_gain	1.0000
3:186786052:G:GG	donor_gain	1.0000
3:186786159:A:AG	acceptor_gain	1.0000
3:186786160:A:G	acceptor_gain	1.0000
3:186786160:ACAGC:A	acceptor_loss	1.0000
3:186786161:CAG:C	acceptor_loss	1.0000
3:186786162:A:AC	acceptor_loss	1.0000
3:186786162:A:AG	acceptor_gain	1.0000
3:186786163:G:GA	acceptor_gain	1.0000
3:186786163:GC:G	acceptor_gain	1.0000
3:186786163:GCT:G	acceptor_gain	1.0000
3:186786163:GCTC:G	acceptor_gain	1.0000
3:186786163:GCTCC:G	acceptor_gain	1.0000
3:186786191:T:TA	acceptor_gain	1.0000
3:186786269:TTCAG:T	donor_gain	1.0000
3:186786272:AGG:A	donor_loss	1.0000
3:186786273:GGTA:G	donor_loss	1.0000
3:186786274:G:GG	donor_gain	1.0000
3:186786274:G:T	donor_loss	1.0000
3:186786275:T:G	donor_loss	1.0000
3:186786497:TTAA:T	acceptor_loss	1.0000
3:186786500:A:G	acceptor_gain	1.0000
3:186786501:G:GC	acceptor_loss	1.0000

AlphaMissense

2707 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:186784591:T:C	F35L	1.000
3:186784592:T:C	F35S	1.000
3:186784592:T:G	F35C	1.000
3:186784593:T:A	F35L	1.000
3:186784593:T:G	F35L	1.000
3:186784607:T:C	L40S	1.000
3:186784622:T:C	L45P	1.000
3:186784627:G:C	G47R	1.000
3:186784628:G:A	G47D	1.000
3:186784628:G:T	G47V	1.000
3:186784643:G:A	G52D	1.000
3:186784645:T:C	F53L	1.000
3:186784646:T:C	F53S	1.000
3:186784646:T:G	F53C	1.000
3:186784647:T:A	F53L	1.000
3:186784647:T:G	F53L	1.000
3:186784655:C:A	P56H	1.000
3:186784655:C:G	P56R	1.000
3:186784664:T:A	I59N	1.000
3:186784668:G:C	Q60H	1.000
3:186784668:G:T	Q60H	1.000
3:186784670:A:C	Q61P	1.000
3:186784675:G:C	A63P	1.000
3:186784676:C:A	A63D	1.000
3:186784968:A:T	D72V	1.000
3:186784977:C:A	A75D	1.000
3:186784981:A:C	Q76H	1.000
3:186784981:A:T	Q76H	1.000
3:186784982:G:C	A77P	1.000
3:186784991:G:C	G80R	1.000

dbSNP variants (sampled 300 via entrez): RS1000181570 (3:186783198 G>A,T), RS1000369195 (3:186786981 T>C,G), RS1000742171 (3:186786795 G>C), RS1001137050 (3:186785598 C>G,T), RS1001320650 (3:186782732 T>A,C), RS1001537937 (3:186782420 T>C), RS1001803516 (3:186783760 C>G,T), RS1002198857 (3:186788089 T>A,C,G), RS1003074956 (3:186790004 C>T), RS1003188684 (3:186787055 C>G,T), RS1003226118 (3:186785568 A>C,G), RS1003727296 (3:186783205 G>T), RS1003830971 (3:186783229 C>G), RS1004351293 (3:186783557 G>A,C), RS1004555557 (3:186787430 A>G,T)

Disease associations

OMIM: gene MIM:601102 | disease phenotypes: MIM:620455, MIM:621010, MIM:257920

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder with hypotonia and speech delay, with or without seizures	Strong	Autosomal dominant

Mondo (4): neurodevelopmental disorder with hypotonia and speech delay, with or without seizures (MONDO:0957541), neurodevelopmental disorder (MONDO:0700092), Morimoto-Ryu-Malicdan neuromuscular syndrome (MONDO:0975848), 3MC syndrome 1 (MONDO:0009770)

Orphanet (2): 3MC syndrome (Orphanet:293843), Michels syndrome (Orphanet:2506)

HPO phenotypes

77 total (30 of 77 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000041	Chordee
HP:0000160	Narrow mouth
HP:0000252	Microcephaly
HP:0000256	Macrocephaly
HP:0000286	Epicanthus
HP:0000322	Short philtrum
HP:0000347	Micrognathia
HP:0000365	Hearing impairment
HP:0000431	Wide nasal bridge
HP:0000463	Anteverted nares
HP:0000505	Visual impairment
HP:0000577	Exotropia
HP:0000582	Upslanted palpebral fissure
HP:0000609	Optic nerve hypoplasia
HP:0000618	Blindness
HP:0000637	Long palpebral fissure
HP:0000664	Synophrys
HP:0000717	Autism
HP:0000750	Delayed speech and language development
HP:0001007	Hirsutism
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001256	Mild intellectual disability
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001276	Hypertonia
HP:0001285	Spastic tetraparesis

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4105952 (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: 1,538 (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
CHEMBL1232461	MOLIBRESIB	2	1,538

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

ChEMBL bioactivities

1 potent at pChembl≥5 of 2 total, top 1 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.33	IC50	4670	nM	MOLIBRESIB

PubChem BioAssay actives

1 with measured affinity, of 16 total; 1 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
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2178748: Inhibition of EIF4A2 (unknown origin) incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	ic50	4.6700	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, decreases methylation	5
sodium arsenite	affects binding, increases reaction, decreases expression, increases expression	3
bisphenol A	affects expression, increases expression	2
Resveratrol	affects cotreatment, increases expression, decreases expression	2
Carbamazepine	affects expression	2
Tretinoin	decreases expression, increases expression	2
aristolochic acid I	decreases expression	1
dicrotophos	decreases expression	1
alpha-pinene	affects cotreatment, decreases expression, increases oxidation, increases abundance	1
2-methyl-4-isothiazolin-3-one	increases expression	1
tetrahydropalmatine	decreases expression	1
beta-lapachone	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
cobaltous chloride	increases expression	1
zinc chromate	increases abundance, increases expression	1
potassium chromate(VI)	affects cotreatment, increases expression	1
ferrous chloride	increases expression	1
methacrylaldehyde	affects cotreatment, decreases expression, increases oxidation, increases abundance	1
beta-methylcholine	affects expression	1
epigallocatechin gallate	affects cotreatment, increases expression	1
tamibarotene	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
chromium hexavalent ion	increases abundance, increases expression	1
CD 437	decreases expression	1
chloropicrin	affects expression	1
corosolic acid	increases expression	1
K 7174	increases expression	1
3-(4’-hydroxy-3’-adamantylbiphenyl-4-yl)acrylic acid	decreases expression	1
nutlin 3	affects cotreatment, increases secretion	1
ICG 001	decreases expression	1

ChEMBL screening assays

10 unique, capped per target: 10 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4007298	Binding	Inhibition of eIF4G-induced eIF4A2 (unknown origin) RNA dependent ATPase activity expressed in Escherichia coli BL21(DE3) using single stranded poly(U) RNA as substrate after 40 mins by ADP-Glo luminescence assay	Discovery of selective ATP-competitive eIF4A3 inhibitors. — Bioorg Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism
NCT03229928	Not specified	COMPLETED	Clinical Testing of a Real-Time Behavior Measurement Tool: Measuring Outcomes for CHAnge
NCT03232489	Not specified	UNKNOWN	Study for the Evaluation of the Feasibility of Applying Advanced MRI Scanning in Pediatric Clinical Practice