EIF2B4

Summary

EIF2B4 (eukaryotic translation initiation factor 2B subunit delta, HGNC:3260) is a protein-coding gene on chromosome 2p23.3, encoding Translation initiation factor eIF2B subunit delta (Q9UI10). Acts as a component of the translation initiation factor 2B (eIF2B) complex, which catalyzes the exchange of GDP for GTP on eukaryotic initiation factor 2 (eIF2) gamma subunit. It is a common-essential gene (DepMap: required in 99.5% of cancer cell lines).

Eukaryotic initiation factor 2B (EIF2B), which is necessary for protein synthesis, is a GTP exchange factor composed of five different subunits. The protein encoded by this gene is the fourth, or delta, subunit. Defects in this gene are a cause of leukoencephalopathy with vanishing white matter (VWM) and ovarioleukodystrophy. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 8890 — RefSeq curated summary.

At a glance

• Gene–disease (curated): leukoencephalopathy with vanishing white matter 4 (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 489 total — 20 pathogenic, 14 likely-pathogenic
• Phenotypes (HPO): 15
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 99.5% of screened cell lines (common-essential)
• MANE Select transcript: NM_001034116

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3260
Approved symbol	EIF2B4
Name	eukaryotic translation initiation factor 2B subunit delta
Location	2p23.3
Locus type	gene with protein product
Status	Approved
Aliases	EIF2Bdelta, EIF-2B, DKFZP586J0119, EIF2B
Ensembl gene	ENSG00000115211
Ensembl biotype	protein_coding
OMIM	606687
Entrez	8890

Gene structure

Transcript identifiers

Ensembl transcripts: 35 — 29 protein_coding, 3 retained_intron, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000347454, ENST00000405940, ENST00000417567, ENST00000418146, ENST00000445933, ENST00000451130, ENST00000462749, ENST00000475582, ENST00000478311, ENST00000493344, ENST00000878175, ENST00000878176, ENST00000878177, ENST00000878178, ENST00000920928, ENST00000920929, ENST00000920930, ENST00000920931, ENST00000920932, ENST00000920933, ENST00000920934, ENST00000920935, ENST00000920936, ENST00000920937, ENST00000920938, ENST00000920939, ENST00000920940, ENST00000945151, ENST00000945152, ENST00000945153, ENST00000945154, ENST00000945155, ENST00000945156, ENST00000945157, ENST00000945158

RefSeq mRNA: 8 — MANE Select: NM_001034116 NM_001034116, NM_001318965, NM_001318966, NM_001318967, NM_001318968, NM_001318969, NM_015636, NM_172195

CCDS: CCDS33164, CCDS46244, CCDS46245, CCDS82432

Canonical transcript exons

ENST00000347454 — 13 exons

Exon	Start	End
ENSE00000733177	27368025	27368139
ENSE00000733180	27368372	27368463
ENSE00001136000	27370284	27370338
ENSE00003504473	27369006	27369212
ENSE00003558303	27364718	27364898
ENSE00003558450	27367074	27367201
ENSE00003571678	27367457	27367559
ENSE00003597745	27369876	27369919
ENSE00003613089	27369414	27369549
ENSE00003618964	27367746	27367822
ENSE00003678537	27368654	27368733
ENSE00003693152	27366759	27366936
ENSE00003901410	27364352	27364599

Expression profiles

Bgee: expression breadth ubiquitous, 290 present calls, max score 96.51.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 28.2642 / max 290.7500, expressed in 1817 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
27489	26.1903	1817
27490	0.7484	413
27491	0.7150	384
202124	0.3230	133
202125	0.1099	33
27492	0.1042	28
27488	0.0479	14
27487	0.0255	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	96.51	gold quality
body of pancreas	UBERON:0001150	95.46	gold quality
left testis	UBERON:0004533	95.37	gold quality
right testis	UBERON:0004534	95.14	gold quality
lower esophagus muscularis layer	UBERON:0035833	94.82	gold quality
lower esophagus	UBERON:0013473	94.81	gold quality
muscle layer of sigmoid colon	UBERON:0035805	94.73	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	94.57	gold quality
sural nerve	UBERON:0015488	94.53	gold quality
gingival epithelium	UBERON:0001949	94.51	gold quality
adenohypophysis	UBERON:0002196	94.50	gold quality
skin of abdomen	UBERON:0001416	94.29	gold quality
mucosa of transverse colon	UBERON:0004991	94.23	gold quality
skin of leg	UBERON:0001511	94.16	gold quality
mucosa of stomach	UBERON:0001199	94.05	gold quality
tibial nerve	UBERON:0001323	93.93	gold quality
gastrocnemius	UBERON:0001388	93.93	gold quality
esophagus	UBERON:0001043	93.90	gold quality
testis	UBERON:0000473	93.81	gold quality
sperm	CL:0000019	93.75	gold quality
endocervix	UBERON:0000458	93.68	gold quality
body of stomach	UBERON:0001161	93.67	gold quality
left adrenal gland cortex	UBERON:0035825	93.64	gold quality
right lobe of thyroid gland	UBERON:0001119	93.52	gold quality
esophagus mucosa	UBERON:0002469	93.51	gold quality
ectocervix	UBERON:0012249	93.51	gold quality
prostate gland	UBERON:0002367	93.48	gold quality
minor salivary gland	UBERON:0001830	93.46	gold quality
right ovary	UBERON:0002118	93.44	gold quality
hindlimb stylopod muscle	UBERON:0004252	93.43	gold quality

Single-cell (SCXA)

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

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

Regulation

Is transcription factor: no

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 99.5% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 16)

• Mutation in EIF2B4 causes childhood ataxia with central nervous system hypomyelination/ vanishing white matter leukodystrophy. (PMID:12707859)
• We report for the first time that in vitro fertilization and embryo transfer can lead to a successful procreation in patients with OLD related to EIF2B mutations. (PMID:18005052)
• This study describe here a case suggestive of ovarioleukodistrophy carrying no eIF2B mutations. (PMID:18061208)
• A novel mechanism for the control of translation initiation by amino acids, mediated by phosphorylation of EIF-2B, is reported. (PMID:18160716)
• Study reports 9 novel mutations in EIF2B genes in 8 patients, increasing number of known mutations to more than 120. Using homology modeling, analyzed the impact of novel mutations on the 5 subunits of eIF2B protein (alpha, beta, gamma, delta, epsilon) (PMID:18263758)
• The authors suspected VWM and sequenced the genes EIF2B1-5, which revealed one heterozygous mutation in EIF2B4. (PMID:18330844)
• We describe the first Chinese patient with typical clinical and radiological features genetically confirmed to have vanishing white matter disease for a mutation in EIF2B4. (PMID:18539998)
• A unique EIF2B mutation spectrum in Chinese Vanishing white matter patients was shown. (PMID:19158808)
• These results validate the measurement of eIF2B GEF activity in patients’ transformed-lymphocytes as an important tool for the diagnosis of eIF2B-related disorders. (PMID:20016818)
• Data demonstrate that cellular response resulting from eIF2alpha phosphorylation is attenuated in several cancer cell lines, and correlates with the expression of a specific isoform of a regulatory eIF2B subunit, eIF2Bdelta variant 1 (V1). (PMID:20709751)
• A mutation .626G>A [p.Arg209Gln] in exon 7 and c.1399C>T [p.Arg467Trp] in exon 13 of the EIF2B4-Gens. (PMID:21503715)
• The functional effects of selected vanishing white matter disease mutations in EIF2B2-5 by coexpressing mutated and wild-type subunits in human cells. (PMID:21560189)
• analysis of developmental splicing deregulation in leukodystrophies related to EIF2B mutations (PMID:22737209)
• A novel missense mutation within EIF2B4 is associated with vanishing white matter disease. (PMID:25600065)
• demonstrate that DAP5 associates with eIF2beta and eIF4AI to stimulate IRES-dependent translation of cellular mRNAs (PMID:25779044)
• Leukodystrophy Due to eIF2B Mutations in Adults. (PMID:34663487)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	eif2b4	ENSDARG00000014004
mus_musculus	Eif2b4	ENSMUSG00000029145
rattus_norvegicus	Eif2b4	ENSRNOG00000005301
drosophila_melanogaster	eIF2Bdelta	FBGN0034858
caenorhabditis_elegans		WBGENE00008670

Paralogs (3): MRI1 (ENSG00000037757), EIF2B1 (ENSG00000111361), EIF2B2 (ENSG00000119718)

Protein

Protein identifiers

Translation initiation factor eIF2B subunit delta — Q9UI10 (reviewed: Q9UI10)

Alternative names: eIF2B GDP-GTP exchange factor subunit delta

All UniProt accessions (4): Q9UI10, E7ERK9, F8W8L6, F8WEV6

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a component of the translation initiation factor 2B (eIF2B) complex, which catalyzes the exchange of GDP for GTP on eukaryotic initiation factor 2 (eIF2) gamma subunit. Its guanine nucleotide exchange factor activity is repressed when bound to eIF2 complex phosphorylated on the alpha subunit, thereby limiting the amount of methionyl-initiator methionine tRNA available to the ribosome and consequently global translation is repressed.

Subunit / interactions. Component of the translation initiation factor 2B (eIF2B) complex which is a heterodecamer of two sets of five different subunits: alpha, beta, gamma, delta and epsilon. Subunits alpha, beta and delta comprise a regulatory subcomplex and subunits epsilon and gamma comprise a catalytic subcomplex. Within the complex, the hexameric regulatory complex resides at the center, with the two heterodimeric catalytic subcomplexes bound on opposite sides.

Subcellular location. Cytoplasm. Cytosol.

Disease relevance. Leukoencephalopathy with vanishing white matter 4 (VWM4) [MIM:620314] An autosomal recessive brain disease characterized by neurological features including progressive cerebellar ataxia, spasticity, and cognitive deficits. Brain imaging shows abnormal white matter that vanishes over time and is replaced by cerebrospinal fluid. Disease severity ranges from fatal infantile forms to adult forms without neurological deterioration. The disease is progressive with, in most individuals, additional episodes of rapid deterioration following febrile infections or minor head trauma. Death may occurs after a variable period after disease onset, usually following an episode of fever and coma. A subset of affected females with milder forms of the disease who survive to adolescence exhibit ovarian dysfunction. This variant of the disorder is called ovarioleukodystrophy. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Activated by the chemical integrated stress response (ISR) inhibitor ISRIB which stimulates guanine nucleotide exchange factor activity for both phosphorylated and unphosphorylated eIF2.

Similarity. Belongs to the eIF-2B alpha/beta/delta subunits family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9UI10-1	1	yes
Q9UI10-2	2
Q9UI10-3	3

RefSeq proteins (8): NP_001029288, NP_001305894, NP_001305895, NP_001305896, NP_001305897, NP_001305898, NP_056451, NP_751945 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000649	IF-2B-related	Family
IPR037171	NagB/RpiA_transferase-like	Homologous_superfamily
IPR042529	IF_2B-like_C	Homologous_superfamily

Pfam: PF01008

UniProt features (65 total): helix 19, strand 19, sequence variant 9, modified residue 4, sequence conflict 3, compositionally biased region 3, splice variant 2, region of interest 2, turn 2, initiator methionine 1, chain 1

Structure

Experimental structures (PDB)

27 structures.

PDB	Method	Resolution (Å)
9ZUZ	X-RAY DIFFRACTION	2.25
7VLK	ELECTRON MICROSCOPY	2.27
7F64	ELECTRON MICROSCOPY	2.42
7RLO	ELECTRON MICROSCOPY	2.6
9HVE	ELECTRON MICROSCOPY	2.7
7F66	ELECTRON MICROSCOPY	2.76
6CAJ	ELECTRON MICROSCOPY	2.8
7L70	ELECTRON MICROSCOPY	2.8
7TRJ	ELECTRON MICROSCOPY	2.8
9QC6	ELECTRON MICROSCOPY	2.83
8TQZ	ELECTRON MICROSCOPY	2.9
7KMF	ELECTRON MICROSCOPY	2.91
7L7G	ELECTRON MICROSCOPY	3
6O85	ELECTRON MICROSCOPY	3.03
6O9Z	ELECTRON MICROSCOPY	3.03
9HVD	ELECTRON MICROSCOPY	3.04
8TQO	ELECTRON MICROSCOPY	3.1
6O81	ELECTRON MICROSCOPY	3.21
12FH	X-RAY DIFFRACTION	3.5
7F67	ELECTRON MICROSCOPY	3.59
7D45	ELECTRON MICROSCOPY	3.8
7D44	ELECTRON MICROSCOPY	4
7D46	ELECTRON MICROSCOPY	4
6EZO	ELECTRON MICROSCOPY	4.1
6K71	ELECTRON MICROSCOPY	4.3
7D43	ELECTRON MICROSCOPY	4.3
6K72	ELECTRON MICROSCOPY	4.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UI10-F1	77.37	0.50

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): 130, 2, 12, 86

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-72731	Recycling of eIF2:GDP

MSigDB gene sets: 243 (showing top): GSE45365_NK_CELL_VS_CD8_TCELL_UP, GOBP_CYTOPLASMIC_TRANSLATION, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, MODULE_255, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, GOBP_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, GOBP_GLIAL_CELL_DEVELOPMENT, MODULE_317, GOBP_TRANSLATIONAL_INITIATION, GOBP_NEUROGENESIS, GOMF_TRANSLATION_INITIATION_FACTOR_ACTIVITY, GOBP_TRANSLATION, GOBP_POSITIVE_REGULATION_OF_TRANSLATIONAL_INITIATION, GOBP_POST_TRANSCRIPTIONAL_REGULATION_OF_GENE_EXPRESSION, TCF4_Q5

GO Biological Process (13): ovarian follicle development (GO:0001541), cytoplasmic translational initiation (GO:0002183), translational initiation (GO:0006413), regulation of translation (GO:0006417), response to heat (GO:0009408), response to glucose (GO:0009749), oligodendrocyte development (GO:0014003), myelination (GO:0042552), response to peptide hormone (GO:0043434), T cell receptor signaling pathway (GO:0050852), translation (GO:0006412), central nervous system development (GO:0007417), animal organ development (GO:0048513)

GO Molecular Function (4): translation initiation factor activity (GO:0003743), guanyl-nucleotide exchange factor activity (GO:0005085), translation initiation factor binding (GO:0031369), protein binding (GO:0005515)

GO Cellular Component (3): cytoplasm (GO:0005737), cytosol (GO:0005829), eukaryotic translation initiation factor 2B complex (GO:0005851)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Cap-dependent Translation Initiation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
translational initiation	3
anatomical structure development	2
translation	2
cellular anatomical structure	2
cytoplasm	2
female gonad development	1
cytoplasmic translation	1
formation of translation initiation ternary complex	1
metabolic process	1
post-transcriptional regulation of gene expression	1
regulation of protein metabolic process	1
response to stress	1
response to temperature stimulus	1
response to hexose	1
glial cell development	1
oligodendrocyte differentiation	1
axon ensheathment	1
response to hormone	1
response to nitrogen compound	1
response to oxygen-containing compound	1
antigen receptor-mediated signaling pathway	1
peptidyltransferase activity	1
translational elongation	1
translational termination	1
macromolecule biosynthetic process	1
protein metabolic process	1
protein biosynthetic process	1
nervous system development	1
system development	1
translation factor activity	1
GTP binding	1
GDP binding	1
GTPase regulator activity	1
protein binding	1
binding	1
intracellular anatomical structure	1
guanyl-nucleotide exchange factor complex	1

Protein interactions and networks

STRING

2344 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EIF2B4	EIF2B3	Q9NR50	998
EIF2B4	EIF2B5	Q13144	995
EIF2B4	EIF2B2	P49770	977
EIF2B4	EIF2B1	Q14232	947
EIF2B4	RABIF	P47224	857
EIF2B4	EIF2S3	P41091	708
EIF2B4	EIF2S2	P20042	666
EIF2B4	EIF2S1	P05198	643
EIF2B4	EIF5	P55010	621
EIF2B4	FNDC4	Q9H6D8	584
EIF2B4	EIF2AK4	Q9P2K8	573
EIF2B4	EIF1	P41567	571
EIF2B4	EIF3I	Q13347	556
EIF2B4	AMMECR1L	Q6DCA0	545
EIF2B4	EIF3D	O15371	540

IntAct

191 interactions, top by confidence:

A	B	Type	Score
EIF2B4	EIF2B2	psi-mi:“MI:0915”(physical association)	0.910
EIF2B2	EIF2B4	psi-mi:“MI:0915”(physical association)	0.910
EIF2B1	EIF2B2	psi-mi:“MI:0915”(physical association)	0.860
EIF2B1	EIF2B5	psi-mi:“MI:0914”(association)	0.860
EIF2B1	EIF2B2	psi-mi:“MI:0914”(association)	0.860
EIF2B2	EIF2B5	psi-mi:“MI:0915”(physical association)	0.830
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
DCC	NTN1	psi-mi:“MI:0914”(association)	0.700
EIF2B2	SLC27A2	psi-mi:“MI:0914”(association)	0.640
P2RX4	FAM20B	psi-mi:“MI:0914”(association)	0.640
PIP4P2	NEDD4	psi-mi:“MI:0914”(association)	0.590
EIF2B4	EIF2B2	psi-mi:“MI:0915”(physical association)	0.560
EIF2B2	EIF2B4	psi-mi:“MI:0915”(physical association)	0.560
AGT	EIF2B4	psi-mi:“MI:0915”(physical association)	0.560
EIF2B4	FOS	psi-mi:“MI:0915”(physical association)	0.560
EIF2B4	GATM	psi-mi:“MI:0915”(physical association)	0.560
EIF2B4	GRB2	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (212): EIF2B2 (Two-hybrid), EIF2B4 (Affinity Capture-MS), EIF2B4 (Affinity Capture-MS), EIF2B4 (Affinity Capture-MS), EIF2B4 (Affinity Capture-MS), EIF2B4 (Affinity Capture-MS), EIF2B4 (Affinity Capture-MS), EIF2B4 (Affinity Capture-MS), EIF2B4 (Affinity Capture-MS), EIF2B4 (Affinity Capture-MS), EIF2B4 (Affinity Capture-MS), EIF2B4 (Affinity Capture-MS), EIF2B4 (Affinity Capture-MS), EIF2B4 (Affinity Capture-MS), EIF2B4 (Affinity Capture-MS)

ESM2 similar proteins: B9VTT2, D3ZBP4, D4A1F2, E7F9T0, F1MF74, F1N4M2, F1QWK4, F1RA39, F6QZ15, O00763, O88509, O94851, P0DOY1, P41111, P51432, P70218, Q01970, Q09M05, Q2YDM7, Q3T058, Q3UN70, Q4R537, Q5BJT6, Q5EBA1, Q5ZL23, Q61749, Q63186, Q63744, Q6TH47, Q7ZU92, Q80YD1, Q8BMA3, Q8BMI3, Q8BML1, Q8NHH9, Q8R424, Q8TDZ2, Q8VDP3, Q923Q2, Q96LU7

Diamond homologs: P12754, P41111, Q09924, Q3T058, Q54EY2, Q54FM3, Q54I81, Q61749, Q63186, Q9UI10, A1WUJ7, A4VLZ8, A4XTE5, A9WGQ8, B1I2P1, B1J5G5, B3RLE6, B4LWZ8, B9HCR2, B9LBK4, B9RR88, C1A6J9, P14741, P49770, Q0IIF2, Q14232, Q28690, Q2NL31, Q31LP7, Q3AMB7, Q3AWF5, Q3M785, Q4R4V8, Q5E9B4, Q5HZE4, Q5JFM9, Q5N076, Q5RAR0, Q62818, Q64270

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
GSK3B	down-regulates	EIF2B4	binding
EIF2B4	“up-regulates activity”	EIF2S1	“guanine nucleotide exchange factor”
EIF2B4	“up-regulates activity”	EIF2S2	“guanine nucleotide exchange factor”
EIF2B4	“up-regulates activity”	EIF2S3	“guanine nucleotide exchange factor”
EIF2B4	“up-regulates activity”	Ternary_GTP_eIF2_tRNA_complex	“guanine nucleotide exchange factor”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 192 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.

GO biological processes:

GO term	Partners	Fold	FDR
translational initiation	9	19.7×	5e-07
T cell costimulation	6	13.7×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	20
Likely pathogenic	14
Uncertain significance	137
Likely benign	263
Benign	21

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1387736	NM_001034116.2(EIF2B4):c.481A>T (p.Lys161Ter)	Pathogenic
2119151	NM_001034116.2(EIF2B4):c.806del (p.Leu269fs)	Pathogenic
2189501	NM_001034116.2(EIF2B4):c.805_806del (p.Leu269fs)	Pathogenic
2671575	NM_001034116.2(EIF2B4):c.1447C>T (p.Arg483Trp)	Pathogenic
2671577	NM_001034116.2(EIF2B4):c.620T>C (p.Met207Thr)	Pathogenic
2692765	NM_001034116.2(EIF2B4):c.1331_1344del (p.Cys444fs)	Pathogenic
2704520	NM_001034116.2(EIF2B4):c.325del (p.Glu109fs)	Pathogenic
2754906	NM_001034116.2(EIF2B4):c.1013+67_1169del	Pathogenic
2759961	NM_001034116.2(EIF2B4):c.104_108del (p.Glu35fs)	Pathogenic
2782086	NM_001034116.2(EIF2B4):c.84dup (p.Arg29fs)	Pathogenic
2785772	NM_001034116.2(EIF2B4):c.508C>T (p.Arg170Ter)	Pathogenic
2825673	NM_001034116.2(EIF2B4):c.637C>T (p.Gln213Ter)	Pathogenic
2840472	NM_001034116.2(EIF2B4):c.1030C>T (p.Arg344Ter)	Pathogenic
2963806	NM_001034116.2(EIF2B4):c.752dup (p.Asp251fs)	Pathogenic
2984742	NM_001034116.2(EIF2B4):c.868del (p.Ser290fs)	Pathogenic
3385144	NM_001034116.2(EIF2B4):c.731C>T (p.Pro244Leu)	Pathogenic
4119	NM_001034116.2(EIF2B4):c.1191+1G>A	Pathogenic
4120	NM_001034116.2(EIF2B4):c.683C>T (p.Ala228Val)	Pathogenic
4121	NM_001034116.2(EIF2B4):c.1393T>C (p.Cys465Arg)	Pathogenic
4746948	NM_001034116.2(EIF2B4):c.625C>T (p.Arg209Ter)	Pathogenic
1696337	NM_001034116.2(EIF2B4):c.32-1G>T	Likely pathogenic
1699333	NM_001034116.2(EIF2B4):c.631G>T (p.Gly211Cys)	Likely pathogenic
2581282	NM_001034116.2(EIF2B4):c.498+2_498+5del	Likely pathogenic
2751898	NM_001034116.2(EIF2B4):c.31+1G>A	Likely pathogenic
2817204	NM_001034116.2(EIF2B4):c.66_75+18del	Likely pathogenic
2827149	NM_001034116.2(EIF2B4):c.1013+1G>T	Likely pathogenic
3339607	NM_001034116.2(EIF2B4):c.1183C>T (p.Leu395Phe)	Likely pathogenic
3692880	NM_001034116.2(EIF2B4):c.782+2T>C	Likely pathogenic
3767198	NM_001034116.2(EIF2B4):c.613C>G (p.Pro205Ala)	Likely pathogenic
4849314	NM_001034116.2(EIF2B4):c.32-1G>A	Likely pathogenic

SpliceAI

2070 predictions. Top by Δscore:

Variant	Effect	Δscore
2:27364597:CAT:C	acceptor_gain	1.0000
2:27364717:CCTAG:C	donor_gain	1.0000
2:27366755:TTA:T	donor_loss	1.0000
2:27366756:TAC:T	donor_loss	1.0000
2:27366757:A:AC	donor_gain	1.0000
2:27366758:C:CC	donor_gain	1.0000
2:27366758:C:CT	donor_loss	1.0000
2:27366758:CCT:C	donor_gain	1.0000
2:27366933:TGAG:T	acceptor_gain	1.0000
2:27366937:C:CC	acceptor_gain	1.0000
2:27367017:C:A	donor_gain	1.0000
2:27367040:C:CA	donor_gain	1.0000
2:27367434:T:A	donor_gain	1.0000
2:27367448:A:AC	donor_gain	1.0000
2:27367449:C:CC	donor_gain	1.0000
2:27367452:ATCAC:A	donor_gain	1.0000
2:27367453:T:C	donor_gain	1.0000
2:27367458:T:TA	donor_gain	1.0000
2:27368648:TCCTA:T	donor_loss	1.0000
2:27368649:CCTA:C	donor_loss	1.0000
2:27368650:CTA:C	donor_loss	1.0000
2:27368651:TA:T	donor_loss	1.0000
2:27368652:ACC:A	donor_loss	1.0000
2:27368729:CACTC:C	acceptor_gain	1.0000
2:27368731:CTC:C	acceptor_gain	1.0000
2:27368732:TC:T	acceptor_gain	1.0000
2:27368733:CC:C	acceptor_gain	1.0000
2:27368733:CCTG:C	acceptor_loss	1.0000
2:27368734:C:CC	acceptor_gain	1.0000
2:27368735:T:A	acceptor_loss	1.0000

AlphaMissense

3326 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:27364725:A:C	N455K	0.998
2:27364725:A:T	N455K	0.998
2:27367526:G:C	S272R	0.998
2:27367526:G:T	S272R	0.998
2:27367528:T:G	S272R	0.998
2:27367773:A:G	L252P	0.998
2:27364428:A:T	V515D	0.997
2:27364871:C:G	A407P	0.997
2:27364855:C:T	G412E	0.996
2:27367542:C:G	R267P	0.996
2:27368098:C:T	G211D	0.996
2:27364422:C:G	R517P	0.995
2:27364425:A:G	L516P	0.995
2:27364431:A:T	V514D	0.995
2:27364761:G:C	F443L	0.995
2:27364761:G:T	F443L	0.995
2:27364763:A:G	F443L	0.995
2:27364783:A:T	V436D	0.995
2:27364810:G:T	A427D	0.995
2:27364844:A:G	S416P	0.995
2:27364856:C:A	G412W	0.995
2:27367543:G:T	R267S	0.995
2:27367556:G:C	F262L	0.995
2:27367556:G:T	F262L	0.995
2:27367558:A:G	F262L	0.995
2:27368414:A:G	L183P	0.995
2:27364437:A:T	V512E	0.994
2:27364504:C:G	D490H	0.994
2:27364742:C:G	D450H	0.994
2:27364776:A:C	C438W	0.994

dbSNP variants (sampled 300 via entrez): RS1000261636 (2:27371663 C>T), RS1001291963 (2:27371154 C>A,T), RS1001299104 (2:27370820 G>T), RS1001421740 (2:27365461 C>G), RS1001449608 (2:27365806 A>C), RS1001764216 (2:27371415 A>T), RS1002297713 (2:27370329 G>A,C), RS1002364984 (2:27370517 G>A,C), RS1002473404 (2:27364076 G>A,C,T), RS1002593768 (2:27372209 T>C), RS1002749615 (2:27366651 C>T), RS1003299688 (2:27369094 G>A), RS1003373283 (2:27369442 G>A), RS1003695472 (2:27370969 G>A), RS1003799225 (2:27365286 G>A)

Disease associations

OMIM: gene MIM:606687 | disease phenotypes: MIM:603896, MIM:620314

GenCC curated gene-disease

Disease	Classification	Inheritance
leukoencephalopathy with vanishing white matter 4	Definitive	Autosomal recessive
leukoencephalopathy with vanishing white matter	Strong	Autosomal recessive
leukoencephalopathy with vanishing white matter 1	Strong	Autosomal recessive
ovarioleukodystrophy	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
leukoencephalopathy with vanishing white matter 4	Definitive	AR

Mondo (5): leukoencephalopathy with vanishing white matter (MONDO:0800448), leukoencephalopathy with vanishing white matter 4 (MONDO:0957872), leukoencephalopathy with vanishing white matter 1 (MONDO:0020507), (MONDO:0011380), (MONDO:0020506)

Orphanet (3): CACH syndrome (Orphanet:135), Ovarioleukodystrophy (Orphanet:99853), Cree leukoencephalopathy (Orphanet:99854)

HPO phenotypes

15 total (15 of 15 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000648	Optic atrophy
HP:0000786	Primary amenorrhea
HP:0000869	Secondary amenorrhea
HP:0001256	Mild intellectual disability
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0002119	Ventriculomegaly
HP:0002120	Cerebral cortical atrophy
HP:0002317	Unsteady gait
HP:0002352	Leukoencephalopathy
HP:0003621	Juvenile onset
HP:0007371	Corpus callosum atrophy
HP:0011463	Childhood onset
HP:0031936	Delayed ability to walk

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST010134_1	Non-oily fish consumption	9.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0008111	diet measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067328 (SINGLE PROTEIN)

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

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
6.51	Kd	308.3	nM	CHEMBL5653589
6.51	ED50	308.3	nM	CHEMBL5653589
5.02	Kd	9564	nM	CHEMBL3752910
5.02	ED50	9564	nM	CHEMBL3752910

PubChem BioAssay actives

2 with measured affinity, of 4 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148300: Binding affinity to human EIF2B4 incubated for 45 mins by Kinobead based pull down assay	kd	0.3083	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148300: Binding affinity to human EIF2B4 incubated for 45 mins by Kinobead based pull down assay	kd	9.5645	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases abundance, increases expression	3
Lead	affects expression, decreases expression	2
Particulate Matter	affects expression, decreases expression, increases abundance	2
FR900359	affects phosphorylation	1
bisphenol F	increases expression	1
2,4,6-tribromophenol	decreases expression	1
bisphenol A	affects cotreatment, increases expression	1
deoxynivalenol	increases expression	1
decabromobiphenyl ether	decreases expression	1
o,p’-DDT	increases expression	1
tetrabromobisphenol A	decreases expression	1
manganese chloride	increases expression, increases abundance	1
CGP 52608	affects binding, increases reaction	1
bisphenol B	increases expression	1
abrine	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
bisphenol AF	increases expression	1
Resveratrol	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	increases abundance, increases expression	1
Caffeine	affects phosphorylation	1
Doxorubicin	decreases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Manganese	increases abundance, increases expression	1
Phenolsulfonphthalein	affects cotreatment, increases expression	1
Smoke	decreases expression	1
Thiram	decreases expression	1
Valproic Acid	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651342	Binding	Binding affinity to human EIF2B4 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

1 cell lines: 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_E4QG	KOLF2.1J EIF2B4 1.8kbdel DEL/WT	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05757141	PHASE1/PHASE2	RECRUITING	An Open-Label Exploratory Study of Fosigotifator in Participants With Vanishing White Matter Disease
NCT07272525	EARLY_PHASE1	ACTIVE_NOT_RECRUITING	Research Study for Single-Patient Treatment of Cree Leukoencephalopathy/Vanishing White Matter Disease
NCT02699190	Not specified	COMPLETED	LeukoSEQ: Whole Genome Sequencing as a First-Line Diagnostic Tool for Leukodystrophies
NCT03047369	Not specified	RECRUITING	The Myelin Disorders Biorepository Project
NCT03333200	Not specified	RECRUITING	Longitudinal Study of Neurodegenerative Disorders
NCT06594016	Not specified	NO_LONGER_AVAILABLE	Expanded Access to Fosigotifator
NCT07300397	Not specified	ACTIVE_NOT_RECRUITING	Single Patient Investigational Treatment for Cree Leukoencephalopathy