EIF2A

Summary

EIF2A (eukaryotic translation initiation factor 2A, HGNC:3254) is a protein-coding gene on chromosome 3q25.1, encoding Eukaryotic translation initiation factor 2A (Q9BY44). Functions in the early steps of protein synthesis of a small number of specific mRNAs.

This gene encodes a eukaryotic translation initiation factor that catalyzes the formation of puromycin-sensitive 80 S preinitiation complexes and the poly(U)-directed synthesis of polyphenylalanine at low concentrations of Mg2+. This gene should not be confused with eIF2-alpha (EIF2S1, Gene ID: 1965), the alpha subunit of the eIF2 translation initiation complex. Although both of these proteins function in binding initiator tRNA to the 40 S ribosomal subunit, the encoded protein does so in a codon-dependent manner, whereas eIF2 complex requires GTP. Alternative splicing of this gene results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 83939 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder (Moderate, GenCC)
• Clinical variants (ClinVar): 85 total
• Druggable target: yes
• MANE Select transcript: NM_032025

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3254
Approved symbol	EIF2A
Name	eukaryotic translation initiation factor 2A
Location	3q25.1
Locus type	gene with protein product
Status	Approved
Aliases	EIF-2A
Ensembl gene	ENSG00000144895
Ensembl biotype	protein_coding
OMIM	609234
Entrez	83939

Gene structure

Transcript identifiers

Ensembl transcripts: 22 — 12 protein_coding, 5 retained_intron, 4 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000273435, ENST00000406576, ENST00000460851, ENST00000462221, ENST00000463863, ENST00000465535, ENST00000469331, ENST00000472926, ENST00000473499, ENST00000474505, ENST00000477551, ENST00000482093, ENST00000482471, ENST00000487799, ENST00000490505, ENST00000494558, ENST00000873826, ENST00000932187, ENST00000932188, ENST00000952463, ENST00000952464, ENST00000952465

RefSeq mRNA: 5 — MANE Select: NM_032025 NM_001319043, NM_001319044, NM_001319045, NM_001319046, NM_032025

CCDS: CCDS46935, CCDS82859, CCDS82860, CCDS82861

Canonical transcript exons

ENST00000460851 — 14 exons

Exon	Start	End
ENSE00001551247	150546787	150546830
ENSE00003488643	150567902	150568046
ENSE00003493608	150558388	150558462
ENSE00003505932	150564299	150564381
ENSE00003522047	150552356	150552425
ENSE00003559912	150581618	150581746
ENSE00003565773	150568176	150568292
ENSE00003598056	150562542	150562660
ENSE00003600521	150563515	150563614
ENSE00003608505	150567693	150567766
ENSE00003626068	150583200	150583265
ENSE00003634647	150571958	150572529
ENSE00003671662	150575649	150575762
ENSE00003841784	150583846	150586016

Expression profiles

Bgee: expression breadth ubiquitous, 263 present calls, max score 99.23.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 57.0541 / max 579.6242, expressed in 1816 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
39200	56.4618	1816
39199	0.5923	330

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	99.23	gold quality
tibialis anterior	UBERON:0001385	98.96	gold quality
oocyte	CL:0000023	98.93	gold quality
epithelial cell of pancreas	CL:0000083	98.54	gold quality
upper arm skin	UBERON:0004263	98.50	gold quality
body of pancreas	UBERON:0001150	98.45	gold quality
calcaneal tendon	UBERON:0003701	98.32	gold quality
cortical plate	UBERON:0005343	98.28	gold quality
deltoid	UBERON:0001476	98.12	gold quality
left ventricle myocardium	UBERON:0006566	98.01	gold quality
pancreas	UBERON:0001264	97.96	gold quality
ileal mucosa	UBERON:0000331	97.93	gold quality
monocyte	CL:0000576	97.91	gold quality
islet of Langerhans	UBERON:0000006	97.90	gold quality
colonic epithelium	UBERON:0000397	97.89	gold quality
cardiac muscle of right atrium	UBERON:0003379	97.88	gold quality
myocardium	UBERON:0002349	97.85	gold quality
leukocyte	CL:0000738	97.83	gold quality
skin of hip	UBERON:0001554	97.80	gold quality
upper leg skin	UBERON:0004262	97.78	gold quality
smooth muscle tissue	UBERON:0001135	97.68	gold quality
rectum	UBERON:0001052	97.64	gold quality
gall bladder	UBERON:0002110	97.42	gold quality
bone marrow cell	CL:0002092	97.37	gold quality
embryo	UBERON:0000922	97.35	gold quality
ganglionic eminence	UBERON:0004023	97.35	gold quality
left ovary	UBERON:0002119	97.34	gold quality
kidney epithelium	UBERON:0004819	97.15	gold quality
ventricular zone	UBERON:0003053	97.12	gold quality
biceps brachii	UBERON:0001507	97.02	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-CURD-112	no	3.26
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

88 targeting EIF2A, 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-6867-5P	100.00	82.21	3464
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-1229-3P	99.97	66.49	906
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-374B-5P	99.90	69.98	2734
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-7978	99.86	66.90	856
HSA-MIR-3941	99.86	70.54	2735
HSA-MIR-664B-3P	99.84	71.65	3590
HSA-MIR-5010-3P	99.83	70.60	2357
HSA-MIR-8080	99.82	67.52	1342
HSA-MIR-489-3P	99.80	66.46	839
HSA-MIR-4694-3P	99.79	69.53	2640
HSA-MIR-323A-3P	99.79	70.30	1739
HSA-MIR-7856-5P	99.75	69.99	2901
HSA-MIR-4524A-3P	99.72	66.85	2406

Literature-anchored findings (GeneRIF, showing 26)

• There was no statistically significant difference in IFN therapeutic effectiveness among the patients with different genotypes of eIF-2a-reg2. (PMID:17407708)
• Data suggest that neither eIF2A nor eIF2D are involved in the translation of this Sindbis virus subgenomic mRNA (sgmRNA) bearing non-AUG codons. (PMID:28240315)
• POSTN may function as a protective factor for osteoblasts during this process by inhibiting the eIF2alphaATF4 pathway. (PMID:29207036)
• HRD1 prevents apoptosis in renal tubular epithelial cells by mediating eIF-2a ubiquitylation and degradation. (PMID:29233968)
• findings indicate that MSI1 plays a leading role in stress granule formation that grants cancer stem cell properties and chemoresistant stress granules in GBM, in response to stressful conditions via the PKR/eIF2alpha signalling cascade. (PMID:29486283)
• The data also support a potential role for the PERK/eIF2a/ATF4 axis in modulating cell viability in irradiated glioblastoma multiforme (GBM). The dual function of PERK as a mediator of survival and death may be exploited to enhance the efficacy of radiation therapy. (PMID:29991528)
• Our studies suggested that chelerythrine (CHE) possibly induces apoptosis through the nuclear translocation of MLKL and *MLKL, which is promoted by a mutual regulation between MLKL and PERK-eIF2alpha pathway in response to ROS formation. The present study clarified the new function of MLKL in apoptosis. (PMID:30084053)
• the endogenously produced product of inflammation, 15-deoxy-Delta(12,14)-prostaglandin J2 (15-d-PGJ2), triggers eIF2alpha phosphorylation, thereby activating the ISR, repressing bulk translation, and triggering SG formation. (PMID:30723157)
• Data show that high level of pancreatic endoplasmic reticulum kinase (PERK) and eukaryotic translation initiation factor 2A (p-eIF2[alpha]) expression in patients with pancreatic ductal adenocarcinoma (PDAC) correlated with poor survival. (PMID:30747823)
• PERK activation augments respiratory SCs. The PERK-eIF2alpha-ATF4 axis increases supercomplex assembly factor 1 (SCAF1 or COX7A2L), promoting SCs and enhanced mitochondrial respiration. PERK activation is sufficient to rescue bioenergetic defects caused by complex I missense mutations derived from mitochondrial disease patients. (PMID:31023583)
• Study shows an anti-tumor function of the protein kinase PKR and its substrate eIF2alpha in a HER2+ breast cancer patient-derived xenograft mouse model. The anti-tumor function depends on the transcription factor ATF4, which upregulates the CDK inhibitor P21/CIP1 and activates JNK1/2. Also, the findings show that increased eIF2alpha-P is a surrogate biomarker of trastuzumab treatment. (PMID:31086176)
• A MYC-GCN2-eIF2alpha negative feedback loop limits protein synthesis to prevent MYC-dependent apoptosis in colorectal cancer. (PMID:31685988)
• GADD45alpha is a key mediator of ER stress-induced growth arrest via regulation of the G2/M transition and cell death through the eIF2alpha signaling pathway. (PMID:31847234)
• miR195 promotes LPSmediated intestinal epithelial cell apoptosis via targeting SIRT1/eIF2a. (PMID:31894250)
• This review summarizes the canonical roles of each branch of the integrated stress response (ISR_ and follow up with consideration and evidence of their implications in neurodegenerative pathologies. The maladaptive outcomes of ISR kinase activation and eIF2alpha phosphorylation, which might play mechanistic roles in neurodegeneration were also examined. [Review] (PMID:31913484)
• Translation Regulation by eIF2alpha Phosphorylation and mTORC1 Signaling Pathways in Non-Communicable Diseases (NCDs). (PMID:32722591)
• The eIF2alpha kinase HRI in innate immunity, proteostasis, and mitochondrial stress. (PMID:32892501)
• MARK2 phosphorylates eIF2alpha in response to proteotoxic stress. (PMID:33705388)
• CCCP-induced mitochondrial dysfunction - characterization and analysis of integrated stress response to cellular signaling and homeostasis. (PMID:33837631)
• The alternative initiation factor eIF2A plays key role in RAN translation of myotonic dystrophy type 2 CCUG*CAGG repeats. (PMID:33856033)
• Downregulation of PHLPP induced by endoplasmic reticulum stress promotes eIF2alpha phosphorylation and chemoresistance in colon cancer. (PMID:34663797)
• PKR-Mediated Phosphorylation of eIF2a and CHK1 Is Associated with Doxorubicin-Mediated Apoptosis in HCC1143 Triple-Negative Breast Cancer Cells. (PMID:36555509)
• The enterovirus genome can be translated in an IRES-independent manner that requires the initiation factors eIF2A/eIF2D. (PMID:36689548)
• Genome-wide CRISPR screens identify noncanonical translation factor eIF2A as an enhancer of SARS-CoV-2 programmed -1 ribosomal frameshifting. (PMID:37581984)
• Increased levels of eIF2A inhibit translation by sequestering 40S ribosomal subunits. (PMID:37602404)
• To initiate or not to initiate: A critical assessment of eIF2A, eIF2D, and MCT-1.DENR to deliver initiator tRNA to ribosomes. (PMID:38433101)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	eif2a	ENSDARG00000101061
mus_musculus	Eif2a	ENSMUSG00000027810
rattus_norvegicus	Eif2a	ENSRNOG00000013393
drosophila_melanogaster	eIF2A	FBGN0037135
caenorhabditis_elegans		WBGENE00008480

Protein

Protein identifiers

Eukaryotic translation initiation factor 2A — Q9BY44 (reviewed: Q9BY44)

Alternative names: 65 kDa eukaryotic translation initiation factor 2A

All UniProt accessions (8): Q9BY44, C9IZE1, F8WAE5, F8WAT3, F8WF18, H7C5Q3, H7C5Q4, H7C5R5

UniProt curated annotations — full annotation on UniProt →

Function. Functions in the early steps of protein synthesis of a small number of specific mRNAs. Acts by directing the binding of methionyl-tRNAi to 40S ribosomal subunits. In contrast to the eIF-2 complex, it binds methionyl-tRNAi to 40S subunits in a codon-dependent manner, whereas the eIF-2 complex binds methionyl-tRNAi to 40S subunits in a GTP-dependent manner.

Tissue specificity. Widely expressed. Expressed at higher level in pancreas, heart, brain and placenta.

Similarity. Belongs to the WD repeat EIF2A family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q9BY44-1	1	yes
Q9BY44-2	2
Q9BY44-3	3
Q9BY44-4	4

RefSeq proteins (5): NP_001305972, NP_001305973, NP_001305974, NP_001305975, NP_114414* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011387	TIF2A	Family
IPR013979	TIF_beta_prop-like	Domain
IPR015943	WD40/YVTN_repeat-like_dom_sf	Homologous_superfamily
IPR036322	WD40_repeat_dom_sf	Homologous_superfamily

Pfam: PF08662

UniProt features (80 total): strand 35, sequence conflict 11, modified residue 8, repeat 7, turn 5, splice variant 4, chain 2, compositionally biased region 2, sequence variant 2, initiator methionine 1, region of interest 1, coiled-coil region 1, helix 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
8DYS	X-RAY DIFFRACTION	1.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BY44-F1	85.97	0.60

Functional residue map

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

Post-translational modifications (8): 1, 2, 5, 503, 506, 517, 518, 526

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 129 (showing top): GOBP_RIBOSOME_BIOGENESIS, CAIRO_PML_TARGETS_BOUND_BY_MYC_UP, GOBP_TRANSLATIONAL_INITIATION, GOBP_RIBOSOME_ASSEMBLY, GOMF_TRANSLATION_INITIATION_FACTOR_ACTIVITY, GOBP_TRANSLATION, GOBP_POST_TRANSCRIPTIONAL_REGULATION_OF_GENE_EXPRESSION, GOBP_ER_NUCLEUS_SIGNALING_PATHWAY, MILI_PSEUDOPODIA_HAPTOTAXIS_UP, NF1_Q6_01, CAFFAREL_RESPONSE_TO_THC_24HR_5_UP, GOBP_ORGANELLE_ASSEMBLY, TGGNNNNNNKCCAR_UNKNOWN, MILI_PSEUDOPODIA_CHEMOTAXIS_UP, GOBP_RIBONUCLEOPROTEIN_COMPLEX_BIOGENESIS

GO Biological Process (9): translational initiation (GO:0006413), regulation of translation (GO:0006417), positive regulation of signal transduction (GO:0009967), SREBP signaling pathway (GO:0032933), ribosome assembly (GO:0042255), intrinsic apoptotic signaling pathway (GO:0097193), response to amino acid starvation (GO:1990928), negative regulation of intrinsic apoptotic signaling pathway (GO:2001243), translation (GO:0006412)

GO Molecular Function (6): tRNA binding (GO:0000049), mRNA binding (GO:0003729), translation initiation factor activity (GO:0003743), ribosome binding (GO:0043022), cadherin binding (GO:0045296), protein binding (GO:0005515)

GO Cellular Component (4): obsolete extracellular space (GO:0005615), cytoplasm (GO:0005737), eukaryotic translation initiation factor 2 complex (GO:0005850), blood microparticle (GO:0072562)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
translation	2
translational initiation	2
RNA binding	2
cellular anatomical structure	2
formation of translation initiation ternary complex	1
metabolic process	1
post-transcriptional regulation of gene expression	1
regulation of protein metabolic process	1
signal transduction	1
regulation of signal transduction	1
positive regulation of cell communication	1
positive regulation of signaling	1
positive regulation of response to stimulus	1
ER-nucleus signaling pathway	1
cellular response to sterol depletion	1
ribosome biogenesis	1
membraneless organelle assembly	1
intracellular signal transduction	1
apoptotic signaling pathway	1
response to starvation	1
intrinsic apoptotic signaling pathway	1
negative regulation of intracellular signal transduction	1
negative regulation of apoptotic signaling pathway	1
regulation of intrinsic apoptotic signaling pathway	1
peptidyltransferase activity	1
translational elongation	1
translational termination	1
macromolecule biosynthetic process	1
protein metabolic process	1
protein biosynthetic process	1
translation factor activity	1
ribonucleoprotein complex binding	1
cell adhesion molecule binding	1
binding	1
intracellular anatomical structure	1
cytoplasm	1
protein-containing complex	1
extracellular region	1

Protein interactions and networks

STRING

1475 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EIF2A	EIF5B	O60841	769
EIF2A	EIF2S1	P05198	759
EIF2A	XBP1	P17861	689
EIF2A	ATF6	P18850	646
EIF2A	EIF2AK4	Q9P2K8	625
EIF2A	EIF4E	P06730	588
EIF2A	DDIT3	P35638	574
EIF2A	ATF4	P18848	564
EIF2A	HSPA5	P11021	554
EIF2A	ERN1	O75460	553
EIF2A	EIF2AK3	Q9NZJ5	504
EIF2A	EIF2AK2	P19525	498
EIF2A	TDRD3	Q9H7E2	411
EIF2A	DELE1	Q14154	391
EIF2A	EIF2AK1	Q9BQI3	385

IntAct

89 interactions, top by confidence:

A	B	Type	Score
CCT2	TXNDC9	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CCT5	TXNDC9	psi-mi:“MI:0914”(association)	0.640
SNRNP27	UBA6	psi-mi:“MI:0914”(association)	0.530
CYP1A1	SNX3	psi-mi:“MI:0914”(association)	0.530
SERPINB5	ALDH2	psi-mi:“MI:0914”(association)	0.530
FGF9	PPID	psi-mi:“MI:0914”(association)	0.530
ZNRD2	MYO9A	psi-mi:“MI:0914”(association)	0.530
PTGES3	AIP	psi-mi:“MI:0914”(association)	0.530
CCT7	PEX7	psi-mi:“MI:0914”(association)	0.530
DNAJA1	DNAJA2	psi-mi:“MI:0914”(association)	0.530
RPS3	ZNF316	psi-mi:“MI:0914”(association)	0.530
ESR2	FBLL1	psi-mi:“MI:0914”(association)	0.460
EIF2AK3	EIF2A	psi-mi:“MI:0915”(physical association)	0.400
EIF2A	EIF2AK4	psi-mi:“MI:0915”(physical association)	0.400
EIF2AK1	EIF2A	psi-mi:“MI:0915”(physical association)	0.400
EIF2A	EIF2AK2	psi-mi:“MI:0915”(physical association)	0.400
EIF2A	MLH1	psi-mi:“MI:0915”(physical association)	0.370
ABL1	RPLP1	psi-mi:“MI:0914”(association)	0.350
MAST3	PPP6C	psi-mi:“MI:0914”(association)	0.350
JUN	TPM3	psi-mi:“MI:0914”(association)	0.350
KIE-1	GTPBP10	psi-mi:“MI:0914”(association)	0.350
RBM4	EIF4E	psi-mi:“MI:0914”(association)	0.350
RBM4	PABPC1	psi-mi:“MI:0914”(association)	0.350
UPF1	EIF2S2	psi-mi:“MI:0914”(association)	0.350
MAPT	C11orf98	psi-mi:“MI:0914”(association)	0.350
Prdm16	ESYT2	psi-mi:“MI:0914”(association)	0.350

BioGRID (188): EIF2A (Affinity Capture-MS), EIF2A (Affinity Capture-MS), EIF2A (Reconstituted Complex), RPS6 (Co-fractionation), EIF2A (Affinity Capture-MS), EIF2A (Affinity Capture-MS), CHORDC1 (Co-fractionation), EIF2A (Co-fractionation), EIF2A (Co-fractionation), EIF2A (Co-fractionation), EIF2A (Co-fractionation), EIF2A (Co-fractionation), EIF2A (Co-fractionation), EIF2A (Co-fractionation), EIF2A (Co-fractionation)

ESM2 similar proteins: A1CS92, A1D558, A2Q908, A3LY29, A4QZL9, A5DR43, A5E5Y8, A6SFQ6, A7EHM8, B0W562, B0XRG7, B3ME25, B3NMI5, B4GAY7, B4HMV9, B4J6D5, B4KNN9, B4LM71, B4MQL8, B4P5F7, B4QB88, B5E081, P0CN44, P0CN45, P56821, Q0CN46, Q0E940, Q0IEY3, Q10425, Q19052, Q1DI97, Q1HDZ5, Q2GM53, Q2URB7, Q4P6G4, Q4WKL7, Q5AGV4, Q5BGH1, Q5ZKC1, Q6BLY5

Diamond homologs: O74965, P53235, Q19052, Q4QRJ7, Q54PV7, Q5ZKC1, Q7ZY11, Q8BJW6, Q9BY44, Q9VNX8, Q8CHP5, B1WB17, A6QPH1, B0WII7, B4NSP6, B5XDD3, B5XG19, P82804, Q16LW2, Q2F5J3, Q640E9, Q6PH11, Q7Q6B5, Q9BRP8

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
EIF2AK4	“down-regulates activity”	EIF2A	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 122 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	5	11.2×	8e-03
ESR-mediated signaling	6	9.1×	7e-03
L13a-mediated translational silencing of Ceruloplasmin expression	7	8.3×	7e-03

GO biological processes:

GO term	Partners	Fold	FDR
protein folding	11	10.3×	1e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	64
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1409 predictions. Top by Δscore:

Variant	Effect	Δscore
3:150546826:GACAG:G	donor_gain	1.0000
3:150546831:G:GG	donor_gain	1.0000
3:150552341:A:AG	acceptor_gain	1.0000
3:150552342:T:G	acceptor_gain	1.0000
3:150552346:A:AG	acceptor_gain	1.0000
3:150552347:C:G	acceptor_gain	1.0000
3:150552354:A:AG	acceptor_gain	1.0000
3:150552354:A:C	acceptor_loss	1.0000
3:150552354:AGTCC:A	acceptor_gain	1.0000
3:150552355:G:GG	acceptor_gain	1.0000
3:150552355:GT:G	acceptor_gain	1.0000
3:150552355:GTC:G	acceptor_gain	1.0000
3:150552355:GTCC:G	acceptor_gain	1.0000
3:150552355:GTCCG:G	acceptor_gain	1.0000
3:150552421:CCAAG:C	donor_loss	1.0000
3:150552422:CAAGG:C	donor_loss	1.0000
3:150552424:AGGTA:A	donor_loss	1.0000
3:150552425:GGTA:G	donor_loss	1.0000
3:150552426:GTATG:G	donor_loss	1.0000
3:150552427:T:G	donor_loss	1.0000
3:150558458:GAAAA:G	donor_gain	1.0000
3:150558463:G:GG	donor_gain	1.0000
3:150558464:T:G	donor_gain	1.0000
3:150562541:GA:G	acceptor_gain	1.0000
3:150564351:G:GT	donor_gain	1.0000
3:150564382:G:GG	donor_gain	1.0000
3:150564388:A:T	donor_gain	1.0000
3:150567691:A:AG	acceptor_gain	1.0000
3:150567692:G:GG	acceptor_gain	1.0000
3:150567896:TCTTA:T	acceptor_loss	1.0000

AlphaMissense

3840 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:150567945:T:A	V198D	1.000
3:150568236:G:A	G252E	1.000
3:150571987:T:A	W281R	1.000
3:150571987:T:C	W281R	1.000
3:150563548:T:C	L109P	0.999
3:150568001:A:C	S217R	0.999
3:150568003:T:A	S217R	0.999
3:150568003:T:G	S217R	0.999
3:150568007:T:C	F219L	0.999
3:150568009:T:A	F219L	0.999
3:150568009:T:G	F219L	0.999
3:150568034:T:A	W228R	0.999
3:150568034:T:C	W228R	0.999
3:150568229:T:C	Y250H	0.999
3:150568235:G:A	G252R	0.999
3:150568235:G:C	G252R	0.999
3:150568236:G:T	G252V	0.999
3:150568248:T:C	L256P	0.999
3:150572023:G:C	G293R	0.999
3:150572024:G:A	G293D	0.999
3:150572024:G:T	G293V	0.999
3:150572036:C:A	A297D	0.999
3:150572100:T:A	N318K	0.999
3:150572100:T:G	N318K	0.999
3:150572144:G:A	G333E	0.999
3:150572150:G:A	G335E	0.999
3:150572154:T:A	N336K	0.999
3:150572154:T:G	N336K	0.999
3:150572156:T:C	L337P	0.999
3:150572239:T:A	W365R	0.999

dbSNP variants (sampled 300 via entrez): RS1000031954 (3:150554140 C>T), RS1000178655 (3:150576738 T>C,G), RS1000193747 (3:150575587 TTTG>T), RS1000305073 (3:150582801 T>C), RS1000311511 (3:150569012 T>C), RS1000413088 (3:150544825 C>A,G), RS1000413936 (3:150575915 CCT>C), RS1000441344 (3:150569956 T>G), RS1000543847 (3:150574856 A>G), RS1000628701 (3:150581301 A>T), RS1000645471 (3:150567179 A>G), RS1000684712 (3:150566897 G>A,T), RS1000705121 (3:150581869 G>A,T), RS1000799812 (3:150574104 C>G,T), RS1000928135 (3:150546844 A>G)

Disease associations

OMIM: gene MIM:609234 | disease phenotypes: MIM:248800, MIM:619687

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder	Moderate	Autosomal recessive

Mondo (3): Marinesco-Sjogren syndrome (MONDO:0009567), dystonia 33 (MONDO:0030513), neurodevelopmental disorder (MONDO:0700092)

Orphanet (1): Marinesco-Sjögren syndrome (Orphanet:559)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

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): CHEMBL4295938 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 4 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.46	Kd	35.1	nM	CHEMBL5653589
7.41	ED50	38.65	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 5 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
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148295: Binding affinity to human EIF2A incubated for 45 mins by Kinobead based pull down assay	kd	0.0351	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases reaction, affects cotreatment, decreases expression, affects binding, increases activity (+5 more)	8
Thapsigargin	increases phosphorylation, increases reaction, decreases reaction, increases expression	6
salubrinal	decreases reaction, increases phosphorylation, decreases response to substance, increases expression	4
Valproic Acid	decreases methylation, affects expression, decreases expression	4
bisphenol A	decreases reaction, increases phosphorylation, affects expression, decreases expression	3
Sorafenib	affects cotreatment, increases phosphorylation, increases reaction	3
Vorinostat	increases reaction, affects cotreatment, increases phosphorylation	3
Cyclosporine	increases expression	3
Orlistat	decreases reaction, increases phosphorylation	2
Acetylcysteine	increases phosphorylation, decreases reaction	2
Arsenic	decreases expression, affects cotreatment, increases abundance, increases expression	2
Cycloheximide	decreases reaction, increases phosphorylation	2
Doxorubicin	increases phosphorylation, increases reaction, decreases expression	2
Manganese	increases expression, affects cotreatment, increases abundance	2
Quercetin	increases phosphorylation, decreases phosphorylation, decreases reaction	2
Tretinoin	decreases expression	2
Tunicamycin	increases expression, increases phosphorylation	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
bisphenol F	increases expression	1
epimedokoreanin B	decreases reaction, increases phosphorylation	1
celastrol methyl ester	decreases reaction, increases phosphorylation	1
dicrotophos	decreases expression	1
fusarenon-X	increases phosphorylation	1
borrelidin	increases phosphorylation	1
deoxynivalenol	increases phosphorylation	1
lead acetate	affects cotreatment, decreases expression	1
methylselenic acid	decreases reaction, increases phosphorylation	1
sodium arsenate	decreases expression	1
titanium dioxide	increases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4118709	Binding	Binding affinity to EIF2A in human NCI-H23 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — Bioorg Med Chem

Cellosaurus cell lines

3 cell lines: 2 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D9E5	Ubigene HEK293 EIF2A KO	Transformed cell line	Female
CVCL_E0CG	Ubigene HeLa EIF2A KO	Cancer cell line	Female
CVCL_SL62	HAP1 EIF2A (-)	Cancer cell line	Male

Clinical trials (associated diseases)

231 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,
NCT02887365	PHASE4	UNKNOWN	A Phase II Study of Tegafur-Uracil as Maintenance Chemotherapy in Patients With Stage II of Colon Cancer
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
NCT07549399	PHASE3	NOT_YET_RECRUITING	SCRT + Chemo Targeted Immuno-neoadjuvant Therapy for High-risk pMMR/MSS RC
NCT07551479	PHASE3	NOT_YET_RECRUITING	SCRT Based iTNT vs. LCRT Based TNT for MSS Locally Advanced Rectal Cancer
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
NCT03271047	PHASE2	COMPLETED	Study of Binimetinib + Nivolumab Plus or Minus Ipilimumab in Patients With Previously Treated Microsatellite-stable (MSS) Metastatic Colorectal Cancer With RAS Mutation
NCT04030260	PHASE2	UNKNOWN	Regorafenib and PD-1 Antibody in Combination With Radiotherapy for pMMR/MSS Metastatic Colorectal Cancer
NCT04098068	PHASE2	COMPLETED	Study of MK-3475 (Pembrolizumab) in Patients With Microsatellite Unstable (MSI) Tumors (Cohort D)
NCT04483219	PHASE2	UNKNOWN	Tyrosine Kinase Inhibitor (TKI) + Anti-PD-1 Antibody in TKI-responded Microsatellite Stability/Proficient Mismatch Repair (MSS/pMMR) Metastatic Colorectal Adenocarcinoma.
NCT04527068	PHASE2	UNKNOWN	QL1101 in Combination With JS001 in Patients With pMMR/MSS Refractory Metastatic Colorectal Cancer
NCT04659382	PHASE2	UNKNOWN	Study to Evaluate Efficacy and Safety of Selective Internal Radiation Therapy Plus Xelox, Bevacizumab and Atezolizumab (Immune Chekpoint Inhibitor) in Patients With Liver-dominant Metastatic Colorectal Cancer
NCT05731726	PHASE2	RECRUITING	Serplulimab Combined With CAPEOX + Celecoxib as Neoadjuvant Treatment for Locally Advanced Rectal Cancer
NCT05733611	PHASE2	TERMINATED	RP2/RP3 in Combination With Atezolizumab and Bevacizumab for the Treatment of Patients With CRC
NCT05815303	PHASE2	UNKNOWN	XELOX Combined With Cadonilimab Versus XELOX as Neoadjuvant Treatment for Locally Advanced, pMMR Rectal Cancer
NCT05933980	PHASE2	UNKNOWN	Toripalimab,Celecoxib and Regorafenib in the Treatment of Refractory Advanced Colorectal Cancer
NCT05970302	PHASE2	RECRUITING	XELOX +Bev +Tislelizumab for First-line Treatment of MSS/pMMR RAS-mutated mCRC
NCT06321081	PHASE2	RECRUITING	ICE Study: Combination of Irinotecan Plus Cetuximab and Envafolimab as a Rechallenge Regimen in mCRC
NCT06415851	PHASE2	NOT_YET_RECRUITING	Chemotherapy Plus Bevacizumab and Anti-PD-1 Followed by Induction Therapy of Chemotherapy Plus Bevacizumab
NCT06593548	PHASE2	NOT_YET_RECRUITING	Lvosidenib (AK112) Combined With CapeOX and Radiotherapy in Patients With Unresectable Metastatic MSS-type Colorectal Cancer
NCT06850103	PHASE2	RECRUITING	SCRT-CAPEOX-Serplulimab for MSS/pMMR Rectal Cancer With Oligometastases
NCT06908031	PHASE2	RECRUITING	SCRT + mFOLFOX6 + PD-1 Antibody + Targeted Therapy for HIgh-Risk pMMR/MSS Rectal Cancer
NCT07156682	PHASE2	NOT_YET_RECRUITING	QL1706 Plus XELOX as Neoadjuvant Therapy for MSS/pMMR Clinical Stage III Colon Cancer
NCT07506109	PHASE2	RECRUITING	A Phase II Study of Sintilimab Combined With Ipilimumab N01, Cetuximab and Dabrafenib in Patients With Microsatellite-Stable, BRAF V600E-Mutated Metastatic Colorectal Cancer
NCT07527520	PHASE2	NOT_YET_RECRUITING	Neoadjuvant Moderately Hypofractionated Radiotherapy Combined With Chemotherapy and Immunotherapy for High-risk pMMR/MSS Locally Advanced Rectal Cancer: A Prospective, Multi-center Randomized Control Phase II Trial
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
NCT03274804	PHASE1	COMPLETED	Combined PD-1 and CCR5 Inhibition for the Treatment of Refractory Microsatellite Stable mCRC
NCT04046445	PHASE1	ACTIVE_NOT_RECRUITING	Phase 1b Study to Evaluate ATP128, VSV-GP128 and BI 754091, in Patients With Stage IV Colorectal Cancer
NCT07001592	PHASE1	RECRUITING	Intra-tumoral (IT) Injection of vvDD-hIL2-2-RG-1 for Metastatic Gastrointestinal and Peritoneal Tumors
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