EIF2B1

Summary

EIF2B1 (eukaryotic translation initiation factor 2B subunit alpha, HGNC:3257) is a protein-coding gene on chromosome 12q24.31, encoding Translation initiation factor eIF2B subunit alpha (Q14232). 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 95.9% of cancer cell lines).

This gene encodes one of five subunits of eukaryotic translation initiation factor 2B (EIF2B), a GTP exchange factor for eukaryotic initiation factor 2 and an essential regulator for protein synthesis. Mutations in this gene and the genes encoding other EIF2B subunits have been associated with leukoencephalopathy with vanishing white matter.

Source: NCBI Gene 1967 — RefSeq curated summary.

At a glance

• Gene–disease (curated): leukoencephalopathy with vanishing white matter 1 (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 6
• Clinical variants (ClinVar): 320 total — 29 pathogenic, 7 likely-pathogenic
• Phenotypes (HPO): 29
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 95.9% of screened cell lines (common-essential)
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_001414

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3257
Approved symbol	EIF2B1
Name	eukaryotic translation initiation factor 2B subunit alpha
Location	12q24.31
Locus type	gene with protein product
Status	Approved
Aliases	EIF-2Balpha, EIF-2B, EIF2BA, EIF2Balpha
Ensembl gene	ENSG00000111361
Ensembl biotype	protein_coding
OMIM	606686
Entrez	1967

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 9 protein_coding, 1 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000424014, ENST00000452159, ENST00000534960, ENST00000537073, ENST00000539951, ENST00000543940, ENST00000857210, ENST00000857211, ENST00000929734, ENST00000929735, ENST00000958403

RefSeq mRNA: 1 — MANE Select: NM_001414 NM_001414

CCDS: CCDS31924

Canonical transcript exons

ENST00000424014 — 9 exons

Exon	Start	End
ENSE00000757306	123630169	123630285
ENSE00001504354	123626425	123626493
ENSE00001504355	123627044	123627156
ENSE00002206351	123620406	123621920
ENSE00003479225	123630397	123630533
ENSE00003593306	123624787	123624862
ENSE00003600970	123632345	123632446
ENSE00003675282	123622636	123622761
ENSE00003894441	123633545	123633686

Expression profiles

Bgee: expression breadth ubiquitous, 279 present calls, max score 95.41.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 32.6134 / max 135.4164, expressed in 1823 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
133959	32.2865	1823
133960	0.3269	151

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
oocyte	CL:0000023	95.41	gold quality
secondary oocyte	CL:0000655	95.36	gold quality
monocyte	CL:0000576	93.38	gold quality
mononuclear cell	CL:0000842	93.35	gold quality
leukocyte	CL:0000738	93.27	gold quality
calcaneal tendon	UBERON:0003701	93.24	gold quality
body of uterus	UBERON:0009853	93.10	gold quality
skin of hip	UBERON:0001554	93.01	gold quality
upper leg skin	UBERON:0004262	92.94	gold quality
right coronary artery	UBERON:0001625	92.86	gold quality
granulocyte	CL:0000094	92.84	gold quality
popliteal artery	UBERON:0002250	92.69	gold quality
tibial artery	UBERON:0007610	92.69	gold quality
right ovary	UBERON:0002118	92.66	gold quality
body of pancreas	UBERON:0001150	92.59	gold quality
muscle layer of sigmoid colon	UBERON:0035805	92.50	gold quality
descending thoracic aorta	UBERON:0002345	92.49	gold quality
left ovary	UBERON:0002119	92.43	gold quality
left uterine tube	UBERON:0001303	92.32	gold quality
aorta	UBERON:0000947	92.28	gold quality
right adrenal gland	UBERON:0001233	92.27	gold quality
epithelium of nasopharynx	UBERON:0001951	92.26	gold quality
right hemisphere of cerebellum	UBERON:0014890	92.25	gold quality
subcutaneous adipose tissue	UBERON:0002190	92.24	gold quality
cerebellar hemisphere	UBERON:0002245	92.22	gold quality
left coronary artery	UBERON:0001626	92.21	gold quality
right adrenal gland cortex	UBERON:0035827	92.20	gold quality
lower esophagus muscularis layer	UBERON:0035833	92.16	gold quality
rectum	UBERON:0001052	92.15	gold quality
lower esophagus	UBERON:0013473	92.15	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.36

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

53 targeting EIF2B1, 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-4789-3P	99.99	70.75	2484
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-605-3P	99.88	69.22	1833
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-1299	99.77	71.24	2389
HSA-MIR-320A-3P	99.77	69.73	2107
HSA-MIR-320B	99.77	69.73	2107
HSA-MIR-320C	99.77	69.73	2107
HSA-MIR-320D	99.77	69.73	2107
HSA-MIR-4429	99.77	69.62	2111
HSA-MIR-466	99.67	70.85	2863
HSA-MIR-6762-3P	99.66	66.94	1188
HSA-MIR-7150	99.62	66.80	1322
HSA-MIR-1252-3P	99.55	67.71	2862
HSA-MIR-671-5P	99.52	67.11	1277
HSA-MIR-4437	99.52	65.29	1266
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-4519	99.48	66.10	859
HSA-MIR-6722-3P	99.45	67.62	1919
HSA-MIR-6513-5P	99.43	67.81	1071
HSA-MIR-5695	99.41	67.48	1047
HSA-MIR-504-3P	99.30	67.18	1745
HSA-MIR-642A-3P	99.23	67.67	1258
HSA-MIR-642B-3P	99.23	67.67	1258
HSA-MIR-3199	99.17	65.19	696
HSA-MIR-8052	99.17	65.01	719

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 95.9% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 11)

• mutational analysis of the eIF2B genes of patients with an antenatal- or early-infantile-onset encephalopathy and an early demise (PMID:14566705)
• Biochemical analyses indicate that mutations analyzed in eIF2Balpha and -epsilon reduce the steady-state level of the affected subunit, while the most severe mutant tested, eIF2Bbeta(V341D), forms complexes with reduced stability and lower eIF2B activity. (PMID:14993275)
• analysis of novel mutations in patients with eIF2B-related disorders (PMID:15776425)
• 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)
• Crystal structure of the alpha subunit of human translation initiation factor 2B. (PMID:19631657)
• These data emphasize the importance of eIF2Balpha in mediating the eIF2 kinase translation-inhibitory activity and may provide insight into the complex nature of vesiculovirus oncolysis. (PMID:21795329)
• Oligodendrocytes with truncated or deletion mutants eIF2B showed less tolerable to endoplasmic reticulum stress (PMID:26112719)
• Data show that eIF2Balpha and eIF2Bbeta bind to adjacent surfaces on eIF2alpha-N-terminal domains (NTDs). (PMID:29036434)
• Our results establish de novo EIF2B1 mutations as a novel cause of permanent diabetes and liver dysfunction. These findings confirm the importance of cell stress regulation for beta-cells and highlight EIF2B1’s fundamental role within this pathway. (PMID:31882561)
• Shielding the mRNA-translation factor eIF2B from inhibitory p-eIF2 as a viral strategy to evade protein kinase R-mediated innate immunity. (PMID:36242870)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	eif2b1	ENSDARG00000091402
mus_musculus	Eif2b1	ENSMUSG00000029388
rattus_norvegicus	Eif2b1	ENSRNOG00000001039
drosophila_melanogaster	eIF2Balpha	FBGN0039726
caenorhabditis_elegans		WBGENE00014221

Paralogs (3): MRI1 (ENSG00000037757), EIF2B4 (ENSG00000115211), EIF2B2 (ENSG00000119718)

Protein

Protein identifiers

Translation initiation factor eIF2B subunit alpha — Q14232 (reviewed: Q14232)

Alternative names: eIF2B GDP-GTP exchange factor subunit alpha

All UniProt accessions (3): Q14232, F5H0D0, H0YGG4

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 1 (VWM1) [MIM:603896] 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 (2)

UniProt ID	Names	Canonical?
Q14232-1	1	yes
Q14232-2	2

RefSeq proteins (1): NP_001405* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000649	IF-2B-related	Family
IPR037171	NagB/RpiA_transferase-like	Homologous_superfamily
IPR042528	elF-2B_alpha_N	Homologous_superfamily
IPR042529	IF_2B-like_C	Homologous_superfamily
IPR051501	eIF2B_alpha/beta/delta	Family

Pfam: PF01008

UniProt features (36 total): helix 15, strand 13, turn 2, splice variant 2, sequence variant 2, chain 1, modified residue 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
3ECS	X-RAY DIFFRACTION	2.65
7KMA	X-RAY DIFFRACTION	2.7
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
6O81	ELECTRON MICROSCOPY	3.21
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-Q14232-F1	91.67	0.71

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 (1): 35

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

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

MSigDB gene sets: 242 (showing top): GOBP_CYTOPLASMIC_TRANSLATION, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GOBP_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, GOBP_GLIAL_CELL_DEVELOPMENT, 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, GOBP_REGULATION_OF_IMMUNE_RESPONSE, BIOCARTA_VEGF_PATHWAY, GOBP_CYTOPLASMIC_TRANSLATIONAL_INITIATION, DER_IFN_BETA_RESPONSE_UP

GO Biological Process (8): cytoplasmic translational initiation (GO:0002183), translational initiation (GO:0006413), response to heat (GO:0009408), response to glucose (GO:0009749), oligodendrocyte development (GO:0014003), response to peptide hormone (GO:0043434), T cell receptor signaling pathway (GO:0050852), translation (GO:0006412)

GO Molecular Function (4): translation initiation factor activity (GO:0003743), guanyl-nucleotide exchange factor activity (GO:0005085), identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (5): cytoplasm (GO:0005737), cytosol (GO:0005829), eukaryotic translation initiation factor 2B complex (GO:0005851), plasma membrane (GO:0005886), membrane (GO:0016020)

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
cellular anatomical structure	3
cytoplasm	2
cytoplasmic translation	1
formation of translation initiation ternary complex	1
translation	1
metabolic process	1
response to stress	1
response to temperature stimulus	1
response to hexose	1
glial cell development	1
oligodendrocyte differentiation	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
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
membrane	1
cell periphery	1

Protein interactions and networks

STRING

2122 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EIF2B1	EIF2B5	Q13144	998
EIF2B1	EIF2B3	Q9NR50	996
EIF2B1	EIF2B4	Q9UI10	947
EIF2B1	EIF2B2	P49770	924
EIF2B1	RABIF	P47224	743
EIF2B1	EIF2S3	P41091	717
EIF2B1	EIF2S1	P05198	667
EIF2B1	EIF2S2	P20042	659
EIF2B1	EIF2AK4	Q9P2K8	619
EIF2B1	MRPL19	P49406	598
EIF2B1	EIF4A1	P04765	586
EIF2B1	EIF5	P55010	577
EIF2B1	EIF1	P41567	494
EIF2B1	EIF2AK1	Q9BQI3	478
EIF2B1	EIF3I	Q13347	476

IntAct

227 interactions, top by confidence:

A	B	Type	Score
EIF2B1	EIF2B1	psi-mi:“MI:0915”(physical association)	0.870
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
GORASP2	EIF2B1	psi-mi:“MI:0915”(physical association)	0.830
EIF2B1	GORASP2	psi-mi:“MI:0915”(physical association)	0.830
RD3	EIF2B1	psi-mi:“MI:0915”(physical association)	0.780
EIF2B1	NTAQ1	psi-mi:“MI:0915”(physical association)	0.780
EIF2B1	RD3	psi-mi:“MI:0915”(physical association)	0.780
NTAQ1	EIF2B1	psi-mi:“MI:0915”(physical association)	0.780
rep	GTF2F2	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710

BioGRID (199): EIF2B1 (Two-hybrid), GORASP2 (Two-hybrid), WDYHV1 (Two-hybrid), RD3 (Two-hybrid), EIF2B1 (Affinity Capture-MS), EIF2B1 (Reconstituted Complex), EIF2B1 (Affinity Capture-MS), EIF2B1 (Affinity Capture-MS), EIF2B1 (Affinity Capture-MS), EIF2B1 (Affinity Capture-MS), EIF2B1 (Affinity Capture-MS), EIF2B1 (Affinity Capture-MS), EIF2B1 (Affinity Capture-MS), EIF2B1 (Affinity Capture-MS), EIF2B1 (Affinity Capture-MS)

ESM2 similar proteins: A1CY38, A6ZP88, A8XDI8, B2AML6, B3RLE6, B4JRX2, B4K8A4, B4LWZ8, B4NG41, B4QSM8, B6K4Q2, B8C6V3, C4JWQ7, C5FY68, C5PBM5, C7Z638, C9SB02, D0A8W2, D2VAA9, O60185, O74427, O94200, O94634, P00927, P0CI29, P14741, P27515, P32502, P34604, P78875, Q03216, Q08685, Q0IIF2, Q0ZB81, Q14232, Q16I17, Q383H9, Q4R4V8, Q54I81, Q5RAR0

Diamond homologs: A0LIZ1, A0R946, A1ALC1, A1VHH2, A3DD27, A4J678, A4XKS3, A5D1G8, A5FRU8, A5G9J7, A5IIM2, A5UQK6, A6LJM7, A7GS56, A7HN79, A7NFR2, A7Z3X0, A8F7V1, A9BHC5, A9FD66, A9JRE2, A9WGQ8, B0K2V6, B0K8S2, B0SFD6, B0SNY3, B0TH58, B1I2P1, B1LC23, B1YIY4, B2A5S2, B2V8N9, B3E3M5, B3RLE6, B4UIU8, B5ED21, B5YGA0, B8DQQ9, B8FRM1, B8J4S7

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
GSK3B	down-regulates	EIF2B1	binding
EIF2B1	“up-regulates activity”	EIF2S1	“guanine nucleotide exchange factor”
EIF2B1	“up-regulates activity”	EIF2S2	“guanine nucleotide exchange factor”
EIF2B1	“up-regulates activity”	EIF2S3	“guanine nucleotide exchange factor”
EIF2B1	“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 176 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	6	15.2×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	29
Likely pathogenic	7
Uncertain significance	98
Likely benign	149
Benign	15

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1416368	NM_001414.4(EIF2B1):c.585dup (p.Gly196fs)	Pathogenic
1461865	NM_001414.4(EIF2B1):c.719del (p.Pro240fs)	Pathogenic
2126425	NM_001414.4(EIF2B1):c.453C>A (p.Tyr151Ter)	Pathogenic
217277	NM_001414.4(EIF2B1):c.547G>T (p.Val183Phe)	Pathogenic
217279	NM_001414.4(EIF2B1):c.328A>G (p.Lys110Glu)	Pathogenic
217280	NM_001414.4(EIF2B1):c.610GGA[1] (p.Gly205del)	Pathogenic
217282	NM_001414.4(EIF2B1):c.715T>G (p.Phe239Val)	Pathogenic
2424164	NC_000012.11:g.(?124116872)(124118104_?)del	Pathogenic
2719446	NM_001414.4(EIF2B1):c.320C>G (p.Ser107Ter)	Pathogenic
2762330	NM_001414.4(EIF2B1):c.693_694del (p.Ser232fs)	Pathogenic
2765961	NM_001414.4(EIF2B1):c.458_459del (p.Thr153fs)	Pathogenic
2767181	NM_001414.4(EIF2B1):c.65C>G (p.Ser22Ter)	Pathogenic
2769348	NM_001414.4(EIF2B1):c.812_813insT (p.Trp272fs)	Pathogenic
2802843	NM_001414.4(EIF2B1):c.383dup (p.His128fs)	Pathogenic
2828613	NM_001414.4(EIF2B1):c.256_257del (p.Tyr86fs)	Pathogenic
2839826	NM_001414.4(EIF2B1):c.576del (p.Val193fs)	Pathogenic
2846761	NM_001414.4(EIF2B1):c.292G>T (p.Glu98Ter)	Pathogenic
2858770	NM_001414.4(EIF2B1):c.41dup (p.Met14fs)	Pathogenic
2874636	NM_001414.4(EIF2B1):c.25_26del (p.Tyr9fs)	Pathogenic
2962147	NM_001414.4(EIF2B1):c.30dup (p.Lys11Ter)	Pathogenic
3244367	NC_000012.11:g.(?124106303)(124118104_?)del	Pathogenic
3244368	NC_000012.11:g.(?124118072)(124118104_?)del	Pathogenic
3244370	NC_000012.11:g.(?124109314)(124109429_?)del	Pathogenic
3244371	NC_000012.11:g.(?124114696)(124118104_?)del	Pathogenic
3244372	NC_000012.11:g.(?124106303)(124111060_?)del	Pathogenic
3639835	NM_001414.4(EIF2B1):c.171T>A (p.Cys57Ter)	Pathogenic
4526364	NM_001414.4(EIF2B1):c.552-2A>T	Pathogenic
4700314	NM_001414.4(EIF2B1):c.816G>A (p.Trp272Ter)	Pathogenic
4848543	NM_001414.4(EIF2B1):c.353dup (p.Ile119fs)	Pathogenic
2025721	NM_001414.4(EIF2B1):c.13+1G>T	Likely pathogenic

SpliceAI

1355 predictions. Top by Δscore:

Variant	Effect	Δscore
12:123621916:TTATA:T	acceptor_gain	1.0000
12:123621917:TATA:T	acceptor_gain	1.0000
12:123621919:TA:T	acceptor_gain	1.0000
12:123621921:C:CC	acceptor_gain	1.0000
12:123622645:A:AC	donor_gain	1.0000
12:123622646:T:C	donor_gain	1.0000
12:123624781:TCTTA:T	donor_loss	1.0000
12:123624782:CTTAC:C	donor_loss	1.0000
12:123624783:TTAC:T	donor_loss	1.0000
12:123624784:TAC:T	donor_loss	1.0000
12:123624785:A:C	donor_loss	1.0000
12:123624858:TGTAG:T	acceptor_gain	1.0000
12:123624863:C:CC	acceptor_gain	1.0000
12:123630390:CACTT:C	donor_loss	1.0000
12:123630391:ACTT:A	donor_loss	1.0000
12:123630392:CTTAC:C	donor_loss	1.0000
12:123630393:TTACG:T	donor_loss	1.0000
12:123630394:TACGG:T	donor_loss	1.0000
12:123630395:A:AC	donor_gain	1.0000
12:123630396:C:CC	donor_gain	1.0000
12:123630396:CG:C	donor_gain	1.0000
12:123630396:CGG:C	donor_gain	1.0000
12:123630396:CGGA:C	donor_gain	1.0000
12:123630529:CTCCC:C	acceptor_gain	1.0000
12:123630531:CCC:C	acceptor_gain	1.0000
12:123630531:CCCCT:C	acceptor_loss	1.0000
12:123630532:CC:C	acceptor_gain	1.0000
12:123630532:CCC:C	acceptor_gain	1.0000
12:123630533:CC:C	acceptor_gain	1.0000
12:123630534:C:CA	acceptor_loss	1.0000

AlphaMissense

1979 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:123621775:A:G	L300P	0.998
12:123621787:A:T	V296D	0.998
12:123621854:C:G	D274H	0.998
12:123622757:C:T	G211E	0.998
12:123624803:C:T	G204E	0.998
12:123621775:A:T	L300H	0.997
12:123622684:A:C	F235L	0.997
12:123622684:A:T	F235L	0.997
12:123622686:A:G	F235L	0.997
12:123622733:G:T	A219D	0.997
12:123622742:G:T	A216D	0.997
12:123624803:C:A	G204V	0.997
12:123627077:A:T	V150E	0.997
12:123630503:A:G	L49P	0.997
12:123621817:G:A	T286I	0.996
12:123622685:A:G	F235S	0.996
12:123622706:A:T	V228E	0.996
12:123624790:G:C	N208K	0.996
12:123624790:G:T	N208K	0.996
12:123624800:C:T	G205E	0.996
12:123624815:A:T	V200D	0.996
12:123624819:C:G	G199R	0.996
12:123624819:C:T	G199R	0.996
12:123624824:G:T	A197D	0.996
12:123626432:C:G	A182P	0.996
12:123627152:A:T	I125K	0.996
12:123630251:C:G	R96P	0.996
12:123621783:G:C	S297R	0.995
12:123621783:G:T	S297R	0.995
12:123621785:T:G	S297R	0.995

dbSNP variants (sampled 300 via entrez): RS1000409499 (12:123633489 G>A,C), RS1000843417 (12:123621687 G>A,C), RS1000960735 (12:123628809 G>A), RS1001076873 (12:123628991 G>A), RS1001293045 (12:123627150 A>G), RS1001303169 (12:123621508 G>A,C,T), RS1001376485 (12:123623114 C>G), RS1001399707 (12:123633709 G>A), RS1001410543 (12:123627400 G>C,T), RS1001466471 (12:123634882 A>G), RS1001516558 (12:123623977 C>A,T), RS1001567587 (12:123624126 T>C), RS1001927018 (12:123628740 T>C), RS1001951553 (12:123632165 G>C), RS1002078746 (12:123634395 T>C)

Disease associations

OMIM: gene MIM:606686 | disease phenotypes: MIM:213300, MIM:249000, MIM:603896

GenCC curated gene-disease

Disease	Classification	Inheritance
leukoencephalopathy with vanishing white matter	Strong	Autosomal recessive
leukoencephalopathy with vanishing white matter 1	Strong	Autosomal recessive
neonatal diabetes mellitus	Strong	Autosomal dominant
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 1	Definitive	AR

Mondo (8): Joubert syndrome (MONDO:0018772), Meckel syndrome (MONDO:0018921), leukoencephalopathy with vanishing white matter (MONDO:0800448), leukoencephalopathy with vanishing white matter 1 (MONDO:0020507), microcephaly (MONDO:0001149), (MONDO:0011380), (MONDO:0020506), neonatal diabetes mellitus (MONDO:0016391)

Orphanet (5): Isolated Joubert syndrome (Orphanet:475), Meckel syndrome (Orphanet:564), CACH syndrome (Orphanet:135), Ovarioleukodystrophy (Orphanet:99853), Cree leukoencephalopathy (Orphanet:99854)

HPO phenotypes

29 total (30 of 29 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000256	Macrocephaly
HP:0000618	Blindness
HP:0000648	Optic atrophy
HP:0000712	Emotional lability
HP:0000746	Delusion
HP:0000751	Personality changes
HP:0000786	Primary amenorrhea
HP:0000869	Secondary amenorrhea
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001254	Lethargy
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001288	Gait disturbance
HP:0001290	Generalized hypotonia
HP:0001945	Fever
HP:0002171	Gliosis
HP:0002317	Unsteady gait
HP:0002352	Leukoencephalopathy
HP:0002354	Memory impairment
HP:0002376	Developmental regression
HP:0003621	Juvenile onset
HP:0004485	Cessation of head growth
HP:0006808	Cerebral hypomyelination
HP:0007305	CNS demyelination
HP:0008193	Primary gonadal insufficiency
HP:0008209	Premature ovarian insufficiency
HP:0008233	Decreased circulating progesterone
HP:0000252	Microcephaly

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST005956_10	Waist-to-hip ratio adjusted for BMI	6.000000e-08
GCST005958_11	Waist-to-hip ratio adjusted for BMI (age >50)	4.000000e-07
GCST005962_22	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	1.000000e-08
GCST90020025_55	Waist-to-hip ratio adjusted for BMI	5.000000e-09
GCST90020027_1230	Waist-hip index	7.000000e-10
GCST90020029_252	Waist circumference adjusted for body mass index	2.000000e-08

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0007789	BMI-adjusted waist circumference

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066508 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, increases expression	2
sodium arsenite	affects expression, decreases expression	2
Cisplatin	increases expression	2
Smoke	decreases expression, increases abundance, increases expression	2
Valproic Acid	increases expression, increases methylation	2
2,4,6-tribromophenol	decreases expression	1
triphenyl phosphate	affects expression	1
decabromobiphenyl ether	decreases expression	1
beta-lapachone	decreases expression	1
cobaltous chloride	decreases expression	1
tetrabromobisphenol A	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
K 7174	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
nutlin 3	affects cotreatment, increases secretion	1
bisphenol B	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 S	increases expression	1
LDN 193189	affects cotreatment, increases expression	1
picoxystrobin	increases expression	1
bisphenol AF	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Air Pollutants	increases abundance, increases expression	1
Carbamazepine	affects expression	1
Carmustine	increases expression	1
Dactinomycin	affects cotreatment, increases secretion	1
Dichlorodiphenyl Dichloroethylene	increases 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
CHEMBL5651339	Binding	Binding affinity to human EIF2B1 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

3 cell lines: 3 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_E4U2	KOLF2.1J EIF2B1 12.3kbdel DEL/WT	Induced pluripotent stem cell	Male
CVCL_E7KL	KOLF2.1J EIF2B1 V183F SNV/SNV	Induced pluripotent stem cell	Male
CVCL_E7KM	KOLF2.1J EIF2B1 V183F SNV/WT	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00873678	Not specified	COMPLETED	Assessment of the Prevalence of Genes AHI1, NPHP1 and CEP290 in Joubert Syndrome
NCT01401998	Not specified	RECRUITING	ARPKD Database Study
NCT04874909	Not specified	COMPLETED	Classification, Functional Stratification and Biomarkers in Ciliopathy (CILLICORIRCM)
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
NCT05518188	PHASE1/PHASE2	RECRUITING	Melpida: Recombinant Adeno-associated Virus (serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)
NCT00001639	Not specified	COMPLETED	Evaluation of Patients With Unresolved Chromosome Abnormalities
NCT01151462	Not specified	WITHDRAWN	Postnatal HCMV Infection in Very Preterm Infants. Implications, Morbidity, Growth and Neurodevelopmental Outcomes.
NCT01565005	Not specified	COMPLETED	Microcephaly Genetic Deficiency in Neural Progenitors
NCT02510170	Not specified	COMPLETED	Fetal and Maternal Head Circumference During Pregnancy in Israeli Population
NCT02741882	Not specified	COMPLETED	Zika and Microcephaly: Case-control Study
NCT02943304	Not specified	COMPLETED	Neurodevelopment Outcome of Newborns Exposed to Zika Virus (ZIKV) in Utero
NCT03255369	Not specified	UNKNOWN	Vertical Exposure to Zika Virus and Its Consequences for Child Neurodevelopment (ZIKVIRUSIFF)
NCT03325946	Not specified	RECRUITING	The FBRI VTC Neuromotor Research Clinic
NCT03330600	Not specified	COMPLETED	Efficacy of Aquatic Physiotherapy in Children With Microcephaly by Zika Virus Congenital Syndrome
NCT03548779	Not specified	COMPLETED	North Carolina Genomic Evaluation by Next-generation Exome Sequencing, 2
NCT03651687	Not specified	COMPLETED	Guangzhou Surveillance and Clinical Study in Microcephaly (GSCSM)
NCT03922594	Not specified	TERMINATED	Surveillance of Zika-related Microcephaly in Sub-Saharan Africa and Asia
NCT04816175	Not specified	COMPLETED	Intensive Therapy for Children With Microcephaly, Hyperkinetic Movements, or Global Developmental Delay
NCT05322980	Not specified	COMPLETED	Summary of Infants Weighing 500 Grams or Less
NCT06019182	Not specified	RECRUITING	MEHMO Natural History and Biomarkers
NCT06566066	Not specified	RECRUITING	Register for Patients With Thyroid Hormone Resistance.