EIF3D

Summary

EIF3D (eukaryotic translation initiation factor 3 subunit D, HGNC:3278) is a protein-coding gene on chromosome 22q12.3, encoding Eukaryotic translation initiation factor 3 subunit D (O15371). mRNA cap-binding component of the eukaryotic translation initiation factor 3 (eIF-3) complex, a complex required for several steps in the initiation of protein synthesis of a specialized repertoire of mRNAs. It is a common-essential gene (DepMap: required in 99.7% of cancer cell lines).

Eukaryotic translation initiation factor-3 (eIF3), the largest of the eIFs, is a multiprotein complex composed of at least ten nonidentical subunits. The complex binds to the 40S ribosome and helps maintain the 40S and 60S ribosomal subunits in a dissociated state. It is also thought to play a role in the formation of the 40S initiation complex by interacting with the ternary complex of eIF2/GTP/methionyl-tRNA, and by promoting mRNA binding. The protein encoded by this gene is the major RNA binding subunit of the eIF3 complex.

Source: NCBI Gene 8664 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 50 total
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 99.7% of screened cell lines (common-essential)
• MANE Select transcript: NM_003753

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3278
Approved symbol	EIF3D
Name	eukaryotic translation initiation factor 3 subunit D
Location	22q12.3
Locus type	gene with protein product
Status	Approved
Aliases	eIF3-p66, eIF3-zeta
Ensembl gene	ENSG00000100353
Ensembl biotype	protein_coding
OMIM	603915
Entrez	8664

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 20 protein_coding, 5 retained_intron, 1 nonsense_mediated_decay

ENST00000216190, ENST00000402116, ENST00000405442, ENST00000426531, ENST00000432675, ENST00000455547, ENST00000457241, ENST00000458572, ENST00000462641, ENST00000462794, ENST00000478547, ENST00000496875, ENST00000886942, ENST00000886943, ENST00000886944, ENST00000933170, ENST00000933171, ENST00000933172, ENST00000933173, ENST00000933174, ENST00000933175, ENST00000933176, ENST00000933177, ENST00000958485, ENST00000958486, ENST00000958487

RefSeq mRNA: 1 — MANE Select: NM_003753 NM_003753

CCDS: CCDS13930

Canonical transcript exons

ENST00000216190 — 15 exons

Exon	Start	End
ENSE00000653658	36517301	36517431
ENSE00000653660	36519405	36519537
ENSE00000653661	36520576	36520688
ENSE00000653663	36523209	36523281
ENSE00000653664	36523895	36523980
ENSE00000653665	36524596	36524732
ENSE00000653666	36525664	36525709
ENSE00000880068	36510855	36511000
ENSE00001732057	36529076	36529166
ENSE00003590308	36511503	36511786
ENSE00003704372	36516478	36516607
ENSE00003707593	36518763	36518910
ENSE00003709904	36512460	36512602
ENSE00003710056	36516705	36516790
ENSE00003762723	36525999	36526131

Expression profiles

Bgee: expression breadth ubiquitous, 306 present calls, max score 99.03.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 147.4780 / max 637.6356, expressed in 1827 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
193961	126.1170	1826
193960	10.5581	1775
193962	5.9360	1697
209463	2.9659	1548
193958	0.8413	495
193956	0.6021	354
193959	0.4575	217

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
body of pancreas	UBERON:0001150	99.03	gold quality
left ovary	UBERON:0002119	98.83	gold quality
skin of abdomen	UBERON:0001416	98.76	gold quality
skin of leg	UBERON:0001511	98.74	gold quality
epithelium of nasopharynx	UBERON:0001951	98.68	gold quality
nasopharynx	UBERON:0001728	98.67	gold quality
parotid gland	UBERON:0001831	98.66	gold quality
right uterine tube	UBERON:0001302	98.63	gold quality
right ovary	UBERON:0002118	98.63	gold quality
zone of skin	UBERON:0000014	98.62	gold quality
spleen	UBERON:0002106	98.61	gold quality
body of stomach	UBERON:0001161	98.60	gold quality
lymph node	UBERON:0000029	98.59	gold quality
body of uterus	UBERON:0009853	98.59	gold quality
endocervix	UBERON:0000458	98.56	gold quality
pancreas	UBERON:0001264	98.54	gold quality
esophagus mucosa	UBERON:0002469	98.53	gold quality
granulocyte	CL:0000094	98.51	gold quality
ectocervix	UBERON:0012249	98.46	gold quality
ovary	UBERON:0000992	98.45	gold quality
rectum	UBERON:0001052	98.44	gold quality
urinary bladder	UBERON:0001255	98.42	gold quality
mammary duct	UBERON:0001765	98.42	gold quality
saliva-secreting gland	UBERON:0001044	98.36	gold quality
esophagus	UBERON:0001043	98.34	gold quality
minor salivary gland	UBERON:0001830	98.34	gold quality
mucosa of stomach	UBERON:0001199	98.32	gold quality
upper leg skin	UBERON:0004262	98.31	gold quality
islet of Langerhans	UBERON:0000006	98.30	gold quality
stomach	UBERON:0000945	98.28	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-125970	yes	12.73
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

5 targeting EIF3D, 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-6739-5P	99.80	67.87	2806
HSA-MIR-6733-5P	99.74	67.94	2759
HSA-MIR-3153	99.55	67.59	2337
HSA-MIR-452-3P	99.01	66.25	1241

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 99.7% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 23)

• eukaryotic initiation factor 4G (eIF4G) protein binds to eIF3c, -d, and -e to promote mRNA recruitment to the ribosome. (PMID:24092755)
• the critical involvement of EIF3D in the survival and progression of melanoma cells (PMID:25322666)
• Findings suggest that eukaryotic translation initiation factor 3 subunit D (eIF3D) might play an important role in colon cancer progression. (PMID:25370813)
• EIF3D plays an important role in modulating glioma cell growth and migration. (PMID:25682860)
• Knockdown of eIF3D inhibited breast cancer cell proliferation and invasion. (PMID:26617750)
• Results provide evidences that EIF3D may function as a potential proto-oncogene that participates in the occurrence and progression of renal cell carcinoma. (PMID:27035563)
• eIF3d makes specific contacts with the RNA cap, as exemplified by cap analogue competition, and these interactions are essential for assembly of translation initiation complexes on eIF3-specialized mRNAs such as the cell proliferation regulator c-Jun (PMID:27462815)
• A transcript-specific eIF3 complex mediates global translational control of energy metabolism. (PMID:27477275)
• eIF3d promotes gallbladder cancer (GBC) progression mainly via eIF3d-GRK2-AKT axis and it may be used as a prognostic factor. The therapeutic targeting of eIF3d-GRK2 axis may be a potential treatment approach for GBC. (PMID:28594409)
• results indicate that eIF3D plays a key role in the proliferation of AML cells, and suggest that eIF3D silencing might be a potential therapeutic strategy for leukemia. (PMID:28801778)
• The current data highlight the importance of eIF3d in HIV infection by inhibiting CD8+ T cell function and promoting viral replication. (PMID:31118081)
• EIF3D is a novel substrate of CUL3/KCTD10 ubiquitin ligase. The ubiquitin code of EIF3D is K27-polyubiquitination at the lysine 153 and 275 residues. (PMID:31280863)
• Mechanistical study demonstrated that EIF3D interacted with GRP78 and enhanced protein stability through blocking the ubiquitin-mediated-proteasome degradation of GRP78. (PMID:31669222)
• Results demonstrated that the overexpression of eIF3D could independently predict poor prognosis for patients with lung adenocarcinoma (LUAD). In silico analysis demonstrated that the altered expression of eIF3D was at least regulated by both copy number alterations (CNAs) and the hypomethylation of cg14297023 site. (PMID:31885740)
• Systematic Investigation of mRNA N (6)-Methyladenosine Machinery in Primary Prostate Cancer. (PMID:33273988)
• EIF3D promotes the progression of preeclampsia by inhibiting of MAPK/ERK1/2 pathway. (PMID:34520790)
• A DAP5/eIF3d alternate mRNA translation mechanism promotes differentiation and immune suppression by human regulatory T cells. (PMID:34848685)
• Overexpression of Eukaryotic translation initiation factor 3D induces stem cell-like properties and metastasis in cervix cancer by activating FAK through inhibiting degradation of GRP78. (PMID:35104170)
• EIF3D promoted cervical carcinoma through Warburg effect by interacting with GRP78. (PMID:36264610)
• eIF3d: A driver of noncanonical cap-dependent translation of specific mRNAs and a trigger of biological/pathological processes. (PMID:36997088)
• Translational fidelity screens in mammalian cells reveal eIF3 and eIF4G2 as regulators of start codon selectivity. (PMID:37144468)
• Breast cancer cell mesenchymal transition and metastasis directed by DAP5/eIF3d-mediated selective mRNA translation. (PMID:37314929)
• eIF3d controls the persistent integrated stress response. (PMID:37683648)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	eif3d	ENSDARG00000021257
mus_musculus	Eif3d	ENSMUSG00000016554
rattus_norvegicus	Eif3d	ENSRNOG00000005804
drosophila_melanogaster	eIF3d2	FBGN0037994
drosophila_melanogaster	eIF3d1	FBGN0040227
caenorhabditis_elegans		WBGENE00001227

Protein

Protein identifiers

Eukaryotic translation initiation factor 3 subunit D — O15371 (reviewed: O15371)

Alternative names: Eukaryotic translation initiation factor 3 subunit 7, eIF-3-zeta, eIF3 p66

All UniProt accessions (6): O15371, A0A0D9SGB5, B0QYA4, B0QYA5, B0QYA6, B0QYA8

UniProt curated annotations — full annotation on UniProt →

Function. mRNA cap-binding component of the eukaryotic translation initiation factor 3 (eIF-3) complex, a complex required for several steps in the initiation of protein synthesis of a specialized repertoire of mRNAs. The eIF-3 complex associates with the 40S ribosome and facilitates the recruitment of eIF-1, eIF-1A, eIF-2:GTP:methionyl-tRNAi and eIF-5 to form the 43S pre-initiation complex (43S PIC). The eIF-3 complex stimulates mRNA recruitment to the 43S PIC and scanning of the mRNA for AUG recognition. The eIF-3 complex is also required for disassembly and recycling of post-termination ribosomal complexes and subsequently prevents premature joining of the 40S and 60S ribosomal subunits prior to initiation. The eIF-3 complex specifically targets and initiates translation of a subset of mRNAs involved in cell proliferation, including cell cycling, differentiation and apoptosis, and uses different modes of RNA stem-loop binding to exert either translational activation or repression. In the eIF-3 complex, EIF3D specifically recognizes and binds the 7-methylguanosine cap of a subset of mRNAs. (Microbial infection) In case of FCV infection, plays a role in the ribosomal termination-reinitiation event leading to the translation of VP2.

Subunit / interactions. Component of the eukaryotic translation initiation factor 3 (eIF-3) complex, which is composed of 13 subunits: EIF3A, EIF3B, EIF3C, EIF3D, EIF3E, EIF3F, EIF3G, EIF3H, EIF3I, EIF3J, EIF3K, EIF3L and EIF3M. The eIF-3 complex appears to include 3 stable modules: module A is composed of EIF3A, EIF3B, EIF3G and EIF3I; module B is composed of EIF3F, EIF3H, and EIF3M; and module C is composed of EIF3C, EIF3D, EIF3E, EIF3K and EIF3L. EIF3C of module C binds EIF3B of module A and EIF3H of module B, thereby linking the three modules. EIF3J is a labile subunit that binds to the eIF-3 complex via EIF3B. The eIF-3 complex interacts with RPS6KB1 under conditions of nutrient depletion. Mitogenic stimulation leads to binding and activation of a complex composed of MTOR and RPTOR, leading to phosphorylation and release of RPS6KB1 and binding of EIF4B to eIF-3. (Microbial infection) Interacts with Norwalk virus VPg protein.

Subcellular location. Cytoplasm.

Disease relevance. Defects in EIF3D are associated with some cancers, such as prostate, breast and colon cancers. Disease susceptibility may be associated with variants affecting the gene represented in this entry. Down-regulation inhibits proliferation of cancers.

Domain organisation. The RNA gate region regulates mRNA cap recognition to prevent promiscuous mRNA-binding before assembly of EIF3D into the full eukaryotic translation initiation factor 3 (eIF-3) complex.

Similarity. Belongs to the eIF-3 subunit D family.

Isoforms (3)

UniProt ID	Names	Canonical?
O15371-1	1	yes
O15371-2	2
O15371-3	3

RefSeq proteins (1): NP_003744* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007783	eIF3d	Family

Pfam: PF05091

UniProt features (47 total): strand 14, helix 10, turn 9, modified residue 4, mutagenesis site 3, region of interest 2, splice variant 2, chain 1, sequence variant 1, compositionally biased region 1

Structure

Experimental structures (PDB)

26 structures.

PDB	Method	Resolution (Å)
8PPL	ELECTRON MICROSCOPY	2.65
6ZP4	ELECTRON MICROSCOPY	2.9
8PJ5	ELECTRON MICROSCOPY	2.9
8PJ6	ELECTRON MICROSCOPY	2.9
6ZON	ELECTRON MICROSCOPY	3
9KZU	ELECTRON MICROSCOPY	3
6YBS	ELECTRON MICROSCOPY	3.1
8PJ4	ELECTRON MICROSCOPY	3.2
9KN5	ELECTRON MICROSCOPY	3.2
9KRP	ELECTRON MICROSCOPY	3.2
6YBD	ELECTRON MICROSCOPY	3.3
9KKF	ELECTRON MICROSCOPY	3.3
9KN6	ELECTRON MICROSCOPY	3.3
9KZX	ELECTRON MICROSCOPY	3.3
8PJ1	ELECTRON MICROSCOPY	3.4
8PJ2	ELECTRON MICROSCOPY	3.4
8RG0	ELECTRON MICROSCOPY	3.4
7A09	ELECTRON MICROSCOPY	3.5
8OZ0	ELECTRON MICROSCOPY	3.5
8XXN	ELECTRON MICROSCOPY	3.6
6ZMW	ELECTRON MICROSCOPY	3.7
7QP7	ELECTRON MICROSCOPY	3.7
8PJ3	ELECTRON MICROSCOPY	3.7
6ZVJ	ELECTRON MICROSCOPY	3.8
9BLN	ELECTRON MICROSCOPY	3.9
7QP6	ELECTRON MICROSCOPY	4.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O15371-F1	82.36	0.58

Functional residue map

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

Post-translational modifications (4): 53, 161, 528, 529

Mutagenesis-validated functional residues (3):

Position	Phenotype
249	reduced binding to jun mrna; when associated with 262-i-a-263.
262–263	reduced binding to jun mrna; when associated with q-249.
317–321	reduced binding to jun mrna.

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-156827	L13a-mediated translational silencing of Ceruloplasmin expression
R-HSA-72649	Translation initiation complex formation
R-HSA-72689	Formation of a pool of free 40S subunits
R-HSA-72695	Formation of the ternary complex, and subsequently, the 43S complex
R-HSA-72702	Ribosomal scanning and start codon recognition
R-HSA-72706	GTP hydrolysis and joining of the 60S ribosomal subunit

MSigDB gene sets: 204 (showing top): GOBP_CYTOPLASMIC_TRANSLATION, MORF_SNRP70, MORF_UBE2I, MORF_HDAC1, GOBP_TRANSLATIONAL_INITIATION, GOCC_EUKARYOTIC_TRANSLATION_INITIATION_FACTOR_3_COMPLEX, GOMF_TRANSLATION_INITIATION_FACTOR_ACTIVITY, MODULE_149, GOBP_TRANSLATION, WANG_LMO4_TARGETS_DN, MORF_CCNI, GOBP_CYTOPLASMIC_TRANSLATIONAL_INITIATION, GNF2_FBL, GOBP_PROTEIN_RNA_COMPLEX_ORGANIZATION, GNF2_ST13

GO Biological Process (7): formation of cytoplasmic translation initiation complex (GO:0001732), cap-dependent translational initiation (GO:0002191), translational initiation (GO:0006413), IRES-dependent viral translational initiation (GO:0075522), viral translational termination-reinitiation (GO:0075525), cytoplasmic translational initiation (GO:0002183), translation (GO:0006412)

GO Molecular Function (4): RNA binding (GO:0003723), translation initiation factor activity (GO:0003743), mRNA cap binding (GO:0098808), protein binding (GO:0005515)

GO Cellular Component (8): cytosol (GO:0005829), eukaryotic translation initiation factor 3 complex (GO:0005852), membrane (GO:0016020), eukaryotic 43S preinitiation complex (GO:0016282), eukaryotic 48S preinitiation complex (GO:0033290), synapse (GO:0045202), eukaryotic translation initiation factor 3 complex, eIF3m (GO:0071541), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Cap-dependent Translation Initiation	4
Eukaryotic Translation Initiation	1
Activation of the mRNA upon binding of the cap-binding complex and eIFs, and subsequent binding to 43S	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
translational initiation	3
cellular anatomical structure	3
cytoplasmic translational initiation	2
viral process	2
viral translation	2
cytoplasm	2
cytosolic small ribosomal subunit	2
cytosolic translation preinitiation complex	2
protein-RNA complex assembly	1
cap-dependent translation initiation factor activity	1
formation of translation initiation ternary complex	1
translation	1
metabolic process	1
cytoplasmic translation	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
translation factor activity	1
RNA cap binding	1
mRNA binding	1
binding	1
protein-containing complex	1
cell junction	1
eukaryotic translation initiation factor 3 complex	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

2318 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EIF3D	EIF3E	P60228	995
EIF3D	EIF3B	P55884	992
EIF3D	EIF3C	Q99613	984
EIF3D	EIF3F	O00303	982
EIF3D	EIF3G	O75821	974
EIF3D	EIF3J	O75822	957
EIF3D	EIF3I	Q13347	953
EIF3D	EIF3H	O15372	949
EIF3D	EIF5	P55010	930
EIF3D	PSMD7	P51665	915
EIF3D	EIF3M	Q7L2H7	901
EIF3D	EIF3A	Q14152	893
EIF3D	EIF3K	Q9UBQ5	835
EIF3D	EIF4G1	Q04637	826
EIF3D	EIF3L	Q9Y262	797

IntAct

318 interactions, top by confidence:

A	B	Type	Score
EIF3B	EIF3F	psi-mi:“MI:0915”(physical association)	0.920
EIF3A	EIF3F	psi-mi:“MI:0915”(physical association)	0.910
EIF3D	EIF3E	psi-mi:“MI:0915”(physical association)	0.850
EIF3D	EIF3E	psi-mi:“MI:0407”(direct interaction)	0.850
EIF3C	EIF3F	psi-mi:“MI:0915”(physical association)	0.800
EIF3D	EIF3F	psi-mi:“MI:0914”(association)	0.730
EIF3G	EIF3F	psi-mi:“MI:0914”(association)	0.730
HOMER3	EIF3D	psi-mi:“MI:0915”(physical association)	0.720
EIF3D	TRIM27	psi-mi:“MI:0915”(physical association)	0.720
EIF3D	HOMER3	psi-mi:“MI:0915”(physical association)	0.720
TRIM27	EIF3D	psi-mi:“MI:0915”(physical association)	0.720
EIF3C	EIF3D	psi-mi:“MI:0915”(physical association)	0.670
EIF3H	EIF3CL	psi-mi:“MI:0914”(association)	0.670
EIF3F	EIF3CL	psi-mi:“MI:0914”(association)	0.640

BioGRID (474): EIF3D (Two-hybrid), EIF3D (Two-hybrid), EIF3D (Two-hybrid), HOMER3 (Two-hybrid), BEND5 (Two-hybrid), LZTS2 (Two-hybrid), EIF3D (Affinity Capture-MS), EIF3D (Affinity Capture-MS), EIF3D (Affinity Capture-MS), EIF3D (Affinity Capture-MS), EIF3D (Affinity Capture-MS), EIF3D (Affinity Capture-MS), EIF3D (Affinity Capture-MS), EIF3D (Affinity Capture-MS), EIF3D (Affinity Capture-MS)

ESM2 similar proteins: A1C777, A1DI25, A4RFH6, A5ABX6, A6SJW6, A7F8K7, A7SMR1, A8X371, B0X6P7, B0XU47, B3LY71, B3LZN3, B3P8G6, B4HFV9, B4JTN0, B4K892, B4LYI3, B4NLG2, B4PNN4, B4PNV2, B4R222, B5DY99, K7IM66, O15371, O70194, O94236, P0CN48, P0CN49, P30642, P56820, Q0UVG7, Q0ZB77, Q16UF8, Q1E4Z3, Q2H5T8, Q2UE04, Q3T122, Q4PEZ2, Q4R8R4, Q4X054

Diamond homologs: A1C777, A1DI25, A4RFH6, A5ABX6, A6SJW6, A7F8K7, A7SMR1, A8X371, B0X6P7, B0XU47, B3LY71, B3LZN3, B3P1F9, B3P8G6, B4GFS1, B4GP93, B4HFV9, B4HHG8, B4JTN0, B4JUM0, B4K892, B4KDI2, B4LYI3, B4M5A7, B4N8Z4, B4NLG2, B4PNN4, B4PNV2, B4QT07, B4R222, B5DY99, K7IM66, O15371, O70194, O94236, P0CN48, P0CN49, P30642, P56820, Q0UVG7

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
EIF3D	“form complex”	EIF3_complex	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 121 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	15	37.1×	9e-18
Ribosomal scanning and start codon recognition	15	37.1×	9e-18
Formation of the ternary complex, and subsequently, the 43S complex	12	33.6×	1e-13
L13a-mediated translational silencing of Ceruloplasmin expression	15	19.7×	1e-13
GTP hydrolysis and joining of the 60S ribosomal subunit	15	19.5×	1e-13
Activation of the mRNA upon binding of the cap-binding complex and eIFs, and subsequent binding to 43S	5	17.7×	8e-04
Formation of a pool of free 40S subunits	12	17.4×	3e-10
Signaling by ALK fusions and activated point mutants	5	9.8×	6e-03

GO biological processes:

GO term	Partners	Fold	FDR
formation of cytoplasmic translation initiation complex	11	127.4×	2e-19
translational initiation	14	51.8×	2e-18
regulation of translational initiation	5	24.1×	3e-04
insulin receptor signaling pathway	5	11.4×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	24
Likely benign	1
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

1918 predictions. Top by Δscore:

Variant	Effect	Δscore
22:36511499:ACAC:A	donor_loss	1.0000
22:36511500:CACCT:C	donor_loss	1.0000
22:36511501:A:C	donor_loss	1.0000
22:36511502:CCTT:C	donor_gain	1.0000
22:36511511:T:TA	donor_gain	1.0000
22:36511520:T:TA	donor_gain	1.0000
22:36511782:CATAA:C	acceptor_gain	1.0000
22:36511784:TAA:T	acceptor_gain	1.0000
22:36511785:AA:A	acceptor_gain	1.0000
22:36511787:C:CC	acceptor_gain	1.0000
22:36516405:AG:A	donor_gain	1.0000
22:36516472:GCTCA:G	donor_loss	1.0000
22:36516473:CTCAC:C	donor_loss	1.0000
22:36516474:TCAC:T	donor_loss	1.0000
22:36516475:CACCC:C	donor_loss	1.0000
22:36516476:A:AC	donor_gain	1.0000
22:36516476:AC:A	donor_gain	1.0000
22:36516477:C:CC	donor_gain	1.0000
22:36516477:C:G	donor_loss	1.0000
22:36516477:CC:C	donor_gain	1.0000
22:36516493:A:AC	donor_gain	1.0000
22:36516524:T:TA	donor_gain	1.0000
22:36516525:C:A	donor_gain	1.0000
22:36516604:GTAA:G	acceptor_gain	1.0000
22:36516605:TAA:T	acceptor_gain	1.0000
22:36516606:AA:A	acceptor_gain	1.0000
22:36516608:C:CC	acceptor_gain	1.0000
22:36516612:A:T	acceptor_gain	1.0000
22:36516614:C:CT	acceptor_gain	1.0000
22:36516700:CCT:C	donor_loss	1.0000

AlphaMissense

3667 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:36511606:C:A	K510N	1.000
22:36511606:C:G	K510N	1.000
22:36511610:A:G	L509P	1.000
22:36511616:A:G	L507P	1.000
22:36511674:A:G	W488R	1.000
22:36511674:A:T	W488R	1.000
22:36511739:A:G	L466P	1.000
22:36511776:G:C	R454G	1.000
22:36512460:C:T	G450D	1.000
22:36512461:C:G	G450R	1.000
22:36512478:G:A	S444F	1.000
22:36512506:A:G	W435R	1.000
22:36512506:A:T	W435R	1.000
22:36512525:G:C	N428K	1.000
22:36512525:G:T	N428K	1.000
22:36512535:A:G	L425P	1.000
22:36512544:G:T	A422D	1.000
22:36512550:A:T	V420D	1.000
22:36512553:G:T	A419D	1.000
22:36512556:C:T	G418E	1.000
22:36512557:C:A	G418W	1.000
22:36512557:C:G	G418R	1.000
22:36512557:C:T	G418R	1.000
22:36512571:A:G	L413P	1.000
22:36512580:C:G	R410P	1.000
22:36512581:G:T	R410S	1.000
22:36512582:C:A	W409C	1.000
22:36512582:C:G	W409C	1.000
22:36512583:C:G	W409S	1.000
22:36512584:A:G	W409R	1.000

dbSNP variants (sampled 300 via entrez): RS1000097604 (22:36529490 C>T), RS1000113034 (22:36524836 G>A), RS1000282450 (22:36529017 TG>T), RS1000404012 (22:36529298 T>A,C), RS1000416121 (22:36524120 G>C), RS1000515938 (22:36513226 T>C), RS1000525212 (22:36517994 C>T), RS1000696539 (22:36528887 G>A), RS1000795821 (22:36518648 T>C), RS1001000662 (22:36518199 A>G), RS1001009118 (22:36528439 G>A,C), RS1001456051 (22:36529122 G>A,T), RS1001522189 (22:36528605 T>A,C,G), RS1001572380 (22:36529226 C>G,T), RS1001730197 (22:36524163 T>C)

Disease associations

OMIM: gene MIM:603915 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066324 (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
7.30	Kd	50.36	nM	CHEMBL5653589
7.30	ED50	50.36	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 4 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	2148149: Binding affinity to human EIF3D incubated for 45 mins by Kinobead based pull down assay	kd	0.0504	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Particulate Matter	decreases expression, increases abundance, affects cotreatment, increases expression, affects expression	4
Air Pollutants	decreases expression, increases abundance, increases expression	3
Valproic Acid	decreases expression, affects expression	3
bisphenol A	affects expression, decreases expression	2
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	2
Smoke	decreases expression, increases abundance, increases expression	2
Cyclosporine	increases expression	2
TAK-243	increases sumoylation	1
2,4,6-tribromophenol	decreases expression	1
triphenyl phosphate	affects expression	1
deoxynivalenol	increases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, decreases expression, affects localization	1
perfluorooctanoic acid	decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
CD 437	decreases expression	1
chloropicrin	increases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
perfluorohexanesulfonic acid	decreases expression	1
3-(4’-hydroxy-3’-adamantylbiphenyl-4-yl)acrylic acid	decreases expression	1
ICG 001	increases expression	1
abrine	increases expression	1
LDN 193189	affects cotreatment, decreases expression	1
picoxystrobin	increases expression	1
Sunitinib	increases expression	1
Arsenic	affects cotreatment, increases abundance, increases expression	1
Atrazine	increases expression	1
Vehicle Emissions	affects expression, increases abundance	1
Doxorubicin	increases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651191	Binding	Binding affinity to human EIF3D 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

Clinical trials (associated diseases)

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