EIF2B3

Summary

EIF2B3 (eukaryotic translation initiation factor 2B subunit gamma, HGNC:3259) is a protein-coding gene on chromosome 1p34.1, encoding Translation initiation factor eIF2B subunit gamma (Q9NR50). Acts as a component of the translation initiation factor 2B (eIF2B) complex, which catalyzes the exchange of GDP for GTP on the eukaryotic initiation factor 2 (eIF2) complex gamma subunit. It is a common-essential gene (DepMap: required in 99.8% of cancer cell lines).

The protein encoded by this gene is one of the subunits of initiation factor eIF2B, which catalyzes the exchange of eukaryotic initiation factor 2-bound GDP for GTP. It has also been found to function as a cofactor of hepatitis C virus internal ribosome entry site-mediated translation. Mutations in this gene have been associated with leukodystrophy with vanishing white matter. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 8891 — RefSeq curated summary.

At a glance

• Gene–disease (curated): leukoencephalopathy with vanishing white matter 3 (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 363 total — 3 pathogenic, 9 likely-pathogenic
• Phenotypes (HPO): 9
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 99.8% of screened cell lines (common-essential)
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_020365

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3259
Approved symbol	EIF2B3
Name	eukaryotic translation initiation factor 2B subunit gamma
Location	1p34.1
Locus type	gene with protein product
Status	Approved
Aliases	EIF2Bgamma, EIF-2B
Ensembl gene	ENSG00000070785
Ensembl biotype	protein_coding
OMIM	606273
Entrez	8891

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 13 protein_coding, 5 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000360403, ENST00000372182, ENST00000372183, ENST00000439363, ENST00000477953, ENST00000480675, ENST00000486491, ENST00000487532, ENST00000497010, ENST00000620860, ENST00000852379, ENST00000852380, ENST00000852381, ENST00000852382, ENST00000852383, ENST00000852384, ENST00000913758, ENST00000913759, ENST00000949285

RefSeq mRNA: 3 — MANE Select: NM_020365 NM_001166588, NM_001261418, NM_020365

CCDS: CCDS517, CCDS53313, CCDS72775

Canonical transcript exons

ENST00000360403 — 12 exons

Exon	Start	End
ENSE00000957325	44875618	44875695
ENSE00000957327	44857704	44857807
ENSE00001064941	44879818	44880008
ENSE00001064943	44897355	44897444
ENSE00001064945	44881612	44881739
ENSE00001935088	44986493	44986595
ENSE00003459389	44874678	44874826
ENSE00003470577	44981021	44981177
ENSE00003492966	44941506	44941665
ENSE00003581745	44926628	44926739
ENSE00003621555	44850522	44851003
ENSE00003666371	44978315	44978460

Expression profiles

Bgee: expression breadth ubiquitous, 271 present calls, max score 95.53.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 15.1422 / max 155.1186, expressed in 1786 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
12103	14.1507	1781
12102	0.9915	645

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
triceps brachii	UBERON:0001509	95.53	gold quality
gluteal muscle	UBERON:0002000	94.73	gold quality
gastrocnemius	UBERON:0001388	94.34	gold quality
muscle of leg	UBERON:0001383	94.22	gold quality
muscle organ	UBERON:0001630	94.01	gold quality
hindlimb stylopod muscle	UBERON:0004252	93.89	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	93.87	gold quality
biceps brachii	UBERON:0001507	93.67	gold quality
deltoid	UBERON:0001476	93.62	gold quality
vastus lateralis	UBERON:0001379	93.44	gold quality
quadriceps femoris	UBERON:0001377	93.39	gold quality
skeletal muscle tissue	UBERON:0001134	93.37	gold quality
islet of Langerhans	UBERON:0000006	92.78	gold quality
parotid gland	UBERON:0001831	92.65	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	92.56	gold quality
apex of heart	UBERON:0002098	92.13	gold quality
muscle tissue	UBERON:0002385	91.86	gold quality
heart left ventricle	UBERON:0002084	91.70	gold quality
cardiac ventricle	UBERON:0002082	91.52	gold quality
tibialis anterior	UBERON:0001385	90.67	gold quality
cortical plate	UBERON:0005343	90.16	gold quality
heart	UBERON:0000948	90.14	gold quality
left adrenal gland	UBERON:0001234	90.12	gold quality
diaphragm	UBERON:0001103	90.04	silver quality
right adrenal gland	UBERON:0001233	89.99	gold quality
right adrenal gland cortex	UBERON:0035827	89.82	gold quality
left adrenal gland cortex	UBERON:0035825	89.74	gold quality
ganglionic eminence	UBERON:0004023	89.50	gold quality
adrenal gland	UBERON:0002369	89.41	gold quality
heart right ventricle	UBERON:0002080	89.36	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

miRNA regulators (miRDB)

21 targeting EIF2B3, 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-450A-1-3P	100.00	69.33	1837
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-6733-5P	99.74	67.94	2759
HSA-MIR-4797-5P	99.39	68.01	1354
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
HSA-MIR-4478	99.07	65.16	2320
HSA-MIR-4424	98.91	70.33	1145
HSA-MIR-4297	98.77	66.95	2013
HSA-MIR-3929	98.32	65.58	1026
HSA-MIR-5088-3P	98.29	66.63	1310
HSA-MIR-4443	98.02	66.25	1928
HSA-MIR-4294	97.86	65.72	1110
HSA-MIR-3614-3P	97.81	67.15	582
HSA-MIR-4475	97.36	66.95	761
HSA-MIR-6886-3P	96.96	66.36	844
HSA-MIR-601	95.98	67.59	421

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 99.8% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 4)

• 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)
• Results show significant higher incidence of Chinese patients with EIF2B3 mutations compared with Caucasian patients. The c.1037T>C in EIF2B3 was confirmed to be a founder mutation in Chinese explaining the genotypic differences between ethnicities. (PMID:25761052)
• To determine the tolerance differences to ERS, cell viability and apoptosis rates were detected in oligodendrocyte cell lines transfected with EIF2B3-c.1037T>C or the wild type. We confirmed that oligodendrocytes with mutant EIF2B3 was less tolerant to ERS than the wild type, with decreased cell viability and increased apoptosis rates. (PMID:26625702)
• Eif2b3 mutants recapitulate phenotypes of vanishing white matter disease and validate novel disease alleles in zebrafish. (PMID:33517449)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	eif2b3	ENSDARG00000018106
mus_musculus	Eif2b3	ENSMUSG00000028683
rattus_norvegicus	Eif2b3	ENSRNOG00000018375
drosophila_melanogaster	eIF2Bgamma	FBGN0034029
caenorhabditis_elegans		WBGENE00004090

Paralogs (3): GMPPA (ENSG00000144591), EIF2B5 (ENSG00000145191), GMPPB (ENSG00000173540)

Protein

Protein identifiers

Translation initiation factor eIF2B subunit gamma — Q9NR50 (reviewed: Q9NR50)

Alternative names: eIF2B GDP-GTP exchange factor subunit gamma

All UniProt accessions (3): Q9NR50, A0A0D9SEN0, H0Y580

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 the eukaryotic initiation factor 2 (eIF2) complex 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 3 (VWM3) [MIM:620313] 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 gamma/epsilon subunits family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9NR50-1	1	yes
Q9NR50-2	2
Q9NR50-3	3

RefSeq proteins (3): NP_001160060, NP_001248347, NP_065098* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005835	NTP_transferase_dom	Domain
IPR029044	Nucleotide-diphossugar_trans	Homologous_superfamily
IPR051960	eIF2B_gamma	Family
IPR056764	LbH_EIF2B3/5	Domain

Pfam: PF00483, PF25084

UniProt features (49 total): strand 23, helix 13, sequence variant 6, modified residue 2, splice variant 2, chain 1, sequence conflict 1, turn 1

Structure

Experimental structures (PDB)

26 structures.

PDB	Method	Resolution (Å)
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
7F67	ELECTRON MICROSCOPY	3.59
7D45	ELECTRON MICROSCOPY	3.8
9HVF	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-Q9NR50-F1	72.51	0.06

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 (2): 1, 260

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

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

MSigDB gene sets: 207 (showing top): GOBP_CYTOPLASMIC_TRANSLATION, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GCANCTGNY_MYOD_Q6, 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, WEI_MYCN_TARGETS_WITH_E_BOX, GOBP_POST_TRANSCRIPTIONAL_REGULATION_OF_GENE_EXPRESSION, GOBP_REGULATION_OF_IMMUNE_RESPONSE, RUTELLA_RESPONSE_TO_CSF2RB_AND_IL4_UP, AML_Q6

GO Biological Process (10): 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), central nervous system development (GO:0007417), biosynthetic process (GO:0009058)

GO Molecular Function (4): translation initiation factor activity (GO:0003743), guanyl-nucleotide exchange factor activity (GO:0005085), protein binding (GO:0005515), translation factor activity, RNA binding (GO:0008135)

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
translation	2
metabolic process	2
translation factor activity	2
cellular anatomical structure	2
cytoplasm	2
cytoplasmic translation	1
formation of translation initiation ternary complex	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
nervous system development	1
system development	1
GTP binding	1
GDP binding	1
GTPase regulator activity	1
binding	1
RNA binding	1
intracellular anatomical structure	1
guanyl-nucleotide exchange factor complex	1

Protein interactions and networks

STRING

2860 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EIF2B3	EIF2B4	Q9UI10	998
EIF2B3	EIF2B2	P49770	996
EIF2B3	EIF2B1	Q14232	996
EIF2B3	EIF2B5	Q13144	985
EIF2B3	EIF2S3	P41091	847
EIF2B3	RABIF	P47224	844
EIF2B3	CDCP2	Q5VXM1	776
EIF2B3	USP24	Q9UPU5	773
EIF2B3	EIF2S1	P05198	749
EIF2B3	EIF2S2	P20042	691
EIF2B3	HIVEP3	Q5T1R4	655
EIF2B3	EIF5	P55010	616
EIF2B3	EIF2AK4	Q9P2K8	573
EIF2B3	EIF3B	P55884	545
EIF2B3	ELAVL4	P26378	509

IntAct

164 interactions, top by confidence:

A	B	Type	Score
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
EIF2B2	SLC27A2	psi-mi:“MI:0914”(association)	0.640
P2RX4	FAM20B	psi-mi:“MI:0914”(association)	0.640
GYPA	TCAF2	psi-mi:“MI:0914”(association)	0.640
STX12	SNAP23	psi-mi:“MI:0914”(association)	0.640
ECH1	ECI2	psi-mi:“MI:0914”(association)	0.620
PIP4P2	NEDD4	psi-mi:“MI:0914”(association)	0.590
HTR2C	KLRG2	psi-mi:“MI:0914”(association)	0.530
GYPB	TCAF2	psi-mi:“MI:0914”(association)	0.530
CD4	CCDC85C	psi-mi:“MI:0914”(association)	0.530
EPHA1	EXOC5	psi-mi:“MI:0914”(association)	0.530
PTGER3	PIK3R2	psi-mi:“MI:0914”(association)	0.530
GPR183	NRP1	psi-mi:“MI:0914”(association)	0.530
FZD10	NRP1	psi-mi:“MI:0914”(association)	0.530
ECH1	ECI2	psi-mi:“MI:0914”(association)	0.530
SYT1	PGK2	psi-mi:“MI:0914”(association)	0.530
OPN3	EIF2B2	psi-mi:“MI:0914”(association)	0.530

BioGRID (188): EIF2B3 (Affinity Capture-MS), EIF2B3 (Affinity Capture-MS), EIF2B3 (Affinity Capture-MS), EIF2B3 (Affinity Capture-MS), EIF2B3 (Affinity Capture-MS), EIF2B3 (Affinity Capture-MS), EIF2B3 (Affinity Capture-MS), EIF2B3 (Affinity Capture-MS), EIF2B3 (Affinity Capture-MS), EIF2B3 (Affinity Capture-MS), EIF2B3 (Affinity Capture-MS), EIF2B3 (Affinity Capture-MS), EIF2B3 (Affinity Capture-MS), EIF2B3 (Affinity Capture-MS), EIF2B1 (Co-fractionation)

ESM2 similar proteins: A5PJI7, A7SBF0, F4I8U2, O60064, P12299, P15280, P23509, P30524, P52416, P52417, P55228, P55229, P55230, P55231, P55232, P55234, P55238, P55241, P55242, P56287, P56288, P70541, P80361, P87163, Q0D7I3, Q0VFM6, Q29LW1, Q3SYG4, Q42882, Q4R6T3, Q66KG5, Q69T99, Q6AVT2, Q6AX60, Q6DKE9, Q6GMK8, Q6NRS1, Q6NTR1, Q6ZPR6, Q7TS68

Diamond homologs: A0QPF9, A5GLA9, A5PJI7, B0RVK9, B7K5U7, B7LSE1, D4GU70, D4GYH1, P08075, P0C7J4, P26393, P37744, P37762, P37779, P39629, P55253, P55254, P55255, P55257, P55464, P57040, P61887, P61888, P70541, P80361, P95778, P9WH12, P9WH13, Q0AA25, Q1H1K1, Q4R6T3, Q8DPI6, Q9L9E6, Q9NR50, Q9RR29, Q9ZAE7, B9CM12, O06486, P0A2K7, P0A2K8

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
GSK3B	down-regulates	EIF2B3	binding
EIF2B3	“up-regulates activity”	EIF2S1	“guanine nucleotide exchange factor”
EIF2B3	“up-regulates activity”	EIF2S2	“guanine nucleotide exchange factor”
EIF2B3	“up-regulates activity”	EIF2S3	“guanine nucleotide exchange factor”
EIF2B3	“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 167 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
RHOJ GTPase cycle	6	9.8×	9e-03

GO biological processes:

GO term	Partners	Fold	FDR
T cell costimulation	7	18.2×	5e-05
translational initiation	7	17.4×	5e-05
response to peptide hormone	5	13.6×	7e-03
T cell proliferation	5	13.3×	7e-03
positive regulation of T cell proliferation	6	10.8×	6e-03
T cell receptor signaling pathway	7	7.4×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	9
Uncertain significance	125
Likely benign	171
Benign	24

Top pathogenic / likely-pathogenic (12)

Variant ID	HGVS	Classification
1285271	NM_020365.5(EIF2B3):c.674G>C (p.Arg225Pro)	Pathogenic
40179	NM_020365.5(EIF2B3):c.80T>A (p.Leu27Gln)	Pathogenic
4438	NM_020365.5(EIF2B3):c.1193_1194del (p.Val398fs)	Pathogenic
1517841	NM_020365.5(EIF2B3):c.673C>T (p.Arg225Trp)	Likely pathogenic
3584635	NM_020365.5(EIF2B3):c.938_939del (p.Val313fs)	Likely pathogenic
3584646	NM_020365.5(EIF2B3):c.455-2A>G	Likely pathogenic
3767195	NM_020365.5(EIF2B3):c.614A>G (p.Tyr205Cys)	Likely pathogenic
3767196	NM_020365.5(EIF2B3):c.935G>T (p.Arg312Leu)	Likely pathogenic
431961	NM_020365.5(EIF2B3):c.272G>A (p.Arg91His)	Likely pathogenic
4813330	NM_020365.5(EIF2B3):c.266C>A (p.Ser89Tyr)	Likely pathogenic
806132	NM_020365.5(EIF2B3):c.450del (p.Ala151fs)	Likely pathogenic
972716	NM_020365.5(EIF2B3):c.503T>C (p.Leu168Pro)	Likely pathogenic

SpliceAI

2272 predictions. Top by Δscore:

Variant	Effect	Δscore
1:44874681:T:TA	donor_gain	1.0000
1:44874732:T:C	donor_gain	1.0000
1:44880029:C:CT	acceptor_gain	1.0000
1:44880030:A:T	acceptor_gain	1.0000
1:44881607:CTGA:C	donor_loss	1.0000
1:44881608:TGA:T	donor_loss	1.0000
1:44881609:GAC:G	donor_loss	1.0000
1:44881610:A:C	donor_loss	1.0000
1:44897353:AC:A	donor_gain	1.0000
1:44897354:CC:C	donor_gain	1.0000
1:44926621:GGCTT:G	donor_loss	1.0000
1:44926622:GCTTA:G	donor_loss	1.0000
1:44926623:CTTA:C	donor_loss	1.0000
1:44926624:TTAC:T	donor_loss	1.0000
1:44926625:TACTT:T	donor_loss	1.0000
1:44926626:A:AC	donor_gain	1.0000
1:44926626:A:C	donor_loss	1.0000
1:44926627:C:CT	donor_gain	1.0000
1:44926627:CTT:C	donor_gain	1.0000
1:44926629:T:TA	donor_gain	1.0000
1:44926740:C:CC	acceptor_gain	1.0000
1:44926746:CA:C	acceptor_gain	1.0000
1:44926747:A:AC	acceptor_gain	1.0000
1:44926747:A:C	acceptor_gain	1.0000
1:44926750:C:CT	acceptor_gain	1.0000
1:44941500:CCTTA:C	donor_loss	1.0000
1:44941501:CTTAC:C	donor_loss	1.0000
1:44941502:TTACC:T	donor_loss	1.0000
1:44941503:TACC:T	donor_loss	1.0000
1:44941504:A:AC	donor_gain	1.0000

AlphaMissense

2962 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:44941637:A:G	L108P	0.999
1:44981080:A:T	V30D	0.999
1:44981086:A:G	L28P	0.999
1:44941645:G:C	S105R	0.998
1:44941645:G:T	S105R	0.998
1:44941647:T:G	S105R	0.998
1:44857789:A:C	S407R	0.997
1:44857789:A:T	S407R	0.997
1:44857791:T:G	S407R	0.997
1:44879838:A:C	Y319D	0.997
1:44881713:A:G	L228P	0.997
1:44941640:T:A	D107V	0.997
1:44897400:A:G	L204P	0.996
1:44978340:A:G	L90S	0.996
1:44981041:A:T	L43H	0.996
1:44981057:A:C	Y38D	0.996
1:44981094:T:A	K25N	0.996
1:44981094:T:G	K25N	0.996
1:44981143:G:T	A9E	0.996
1:44857787:A:T	V408D	0.995
1:44881729:A:G	S223P	0.995
1:44941655:A:G	L102P	0.995
1:44978337:C:G	R91P	0.995
1:44978349:G:T	A87E	0.995
1:44981086:A:C	L28R	0.995
1:44981086:A:T	L28H	0.995
1:44897410:C:G	D201H	0.994
1:44941640:T:G	D107A	0.994
1:44941652:A:T	V103E	0.994
1:44978451:A:T	V53E	0.994

dbSNP variants (sampled 300 via entrez): RS1000024489 (1:44902412 TG>T), RS1000044971 (1:44902760 C>A,T), RS1000061529 (1:44894234 G>A), RS1000065384 (1:44949726 C>T), RS1000077297 (1:44853996 TTTTTTTTTTTG>T), RS1000078379 (1:44913188 A>G), RS1000212686 (1:44929124 T>C), RS1000223426 (1:44880976 A>T), RS1000267581 (1:44922482 G>A), RS1000275219 (1:44969297 A>G), RS1000289879 (1:44873306 T>C), RS1000312092 (1:44901990 G>A), RS1000321848 (1:44860444 C>G), RS1000351872 (1:44888224 T>C), RS1000363863 (1:44868652 G>A)

Disease associations

OMIM: gene MIM:606273 | disease phenotypes: MIM:603896, MIM:620313, MIM:608456

GenCC curated gene-disease

Disease	Classification	Inheritance
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 3	Definitive	AR

Mondo (6): leukoencephalopathy with vanishing white matter (MONDO:0800448), leukoencephalopathy with vanishing white matter 3 (MONDO:0957871), leukoencephalopathy with vanishing white matter 1 (MONDO:0020507), familial adenomatous polyposis 2 (MONDO:0012041), (MONDO:0011380), (MONDO:0020506)

Orphanet (5): CACH syndrome (Orphanet:135), Ovarioleukodystrophy (Orphanet:99853), Cree leukoencephalopathy (Orphanet:99854), Attenuated familial adenomatous polyposis (Orphanet:220460), MUTYH-related polyposis (Orphanet:247798)

HPO phenotypes

9 total (9 of 9 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000869	Secondary amenorrhea
HP:0001250	Seizure
HP:0001260	Dysarthria
HP:0002352	Leukoencephalopathy
HP:0002505	Loss of ambulation
HP:0007340	Lower limb muscle weakness
HP:0011462	Young adult onset
HP:0012377	Hemianopia

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST90002401_17	Platelet distribution width	1.000000e-12

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007984	platelet component distribution width

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C563924	Colorectal Adenomatous Polyposis, Autosomal Recessive (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295961 (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
6.48	Kd	330.2	nM	CHEMBL5653589
6.48	ED50	332.4	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 12 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	2148299: Binding affinity to human EIF2B3 incubated for 45 mins by Kinobead based pull down assay	kd	0.3302	uM

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, decreases methylation	2
sodium arsenite	decreases expression	2
Benzo(a)pyrene	affects methylation, decreases expression	2
Cyclosporine	increases expression	2
afuresertib	decreases expression	1
TAK-243	increases sumoylation	1
dicrotophos	decreases expression	1
butyraldehyde	increases expression	1
benzo(e)pyrene	increases methylation	1
microcystin RR	increases expression	1
bisphenol S	decreases methylation	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	affects methylation	1
Diethylstilbestrol	increases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Estradiol	affects expression	1
Formaldehyde	decreases expression	1
Ivermectin	decreases expression	1
Methapyrilene	increases methylation	1
Oxygen	decreases expression	1
Plant Extracts	affects cotreatment, increases expression	1
Tretinoin	decreases expression	1
Isotretinoin	decreases expression	1
Aflatoxin B1	increases methylation	1
Cadmium Chloride	decreases expression	1
beta-Naphthoflavone	increases expression	1
Particulate Matter	decreases expression, increases abundance	1

ChEMBL screening assays

9 unique, capped per target: 9 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4118644	Binding	Binding affinity to EIF2B3 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: 3 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_E7KP	KOLF2.1J EIF2B3 I229M SNV/SNV	Induced pluripotent stem cell	Male
CVCL_E7KQ	KOLF2.1J EIF2B3 I229M SNV/WT	Induced pluripotent stem cell	Male
CVCL_E7NG	KOLF2.1J EIF2B3 PTC PTC/WT	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

11 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
NCT02198092	Not specified	COMPLETED	Preliminary Evaluation of Septin9 in Patients With Hereditary Colon Cancer Syndromes
NCT03847532	Not specified	UNKNOWN	MUTYH-associated Polyposis
NCT06163365	Not specified	UNKNOWN	Inherited Cancer Early Diagnosis (ICED) Study
NCT07461246	Not specified	ACTIVE_NOT_RECRUITING	Familial Adenomatous Poliposys Italian Network (Rete Italiana Poliposi Adenomatosa Familiare)