EIF2B2

Summary

EIF2B2 (eukaryotic translation initiation factor 2B subunit beta, HGNC:3258) is a protein-coding gene on chromosome 14q24.3, encoding Translation initiation factor eIF2B subunit beta (P49770). 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 99.7% of cancer cell lines).

This gene encodes the beta subunit of eukaryotic initiation factor-2B (EIF2B). EIF2B is involved in protein synthesis and exchanges GDP and GTP for its activation and deactivation.

Source: NCBI Gene 8892 — RefSeq curated summary.

At a glance

• Gene–disease (curated): leukoencephalopathy with vanishing white matter 2 (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 6
• Clinical variants (ClinVar): 348 total — 20 pathogenic, 12 likely-pathogenic
• Phenotypes (HPO): 11
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 99.7% of screened cell lines (common-essential)
• MANE Select transcript: NM_014239

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3258
Approved symbol	EIF2B2
Name	eukaryotic translation initiation factor 2B subunit beta
Location	14q24.3
Locus type	gene with protein product
Status	Approved
Aliases	EIF2B, EIF-2Bbeta, EIF2Bbeta
Ensembl gene	ENSG00000119718
Ensembl biotype	protein_coding
OMIM	606454
Entrez	8892

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 7 protein_coding, 3 retained_intron, 2 nonsense_mediated_decay

ENST00000266126, ENST00000553401, ENST00000553539, ENST00000554748, ENST00000555522, ENST00000556028, ENST00000556668, ENST00000873642, ENST00000932124, ENST00000932125, ENST00000932126, ENST00000932127

RefSeq mRNA: 1 — MANE Select: NM_014239 NM_014239

CCDS: CCDS9836

Canonical transcript exons

ENST00000266126 — 8 exons

Exon	Start	End
ENSE00000808296	75002921	75003153
ENSE00000808299	75004737	75004900
ENSE00000808300	75005866	75005961
ENSE00001319743	75009031	75012366
ENSE00003467487	75003275	75003395
ENSE00003594845	75003551	75003699
ENSE00003607351	75006577	75006714
ENSE00003608647	75007722	75007788

Expression profiles

Bgee: expression breadth ubiquitous, 298 present calls, max score 95.96.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 27.3089 / max 206.9603, expressed in 1821 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
140595	26.9163	1821
140596	0.3926	95

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left lobe of thyroid gland	UBERON:0001120	95.96	gold quality
right lobe of thyroid gland	UBERON:0001119	95.82	gold quality
thyroid gland	UBERON:0002046	95.55	gold quality
right adrenal gland cortex	UBERON:0035827	95.45	gold quality
gastrocnemius	UBERON:0001388	95.30	gold quality
right adrenal gland	UBERON:0001233	95.15	gold quality
muscle of leg	UBERON:0001383	94.82	gold quality
left adrenal gland	UBERON:0001234	94.75	gold quality
hindlimb stylopod muscle	UBERON:0004252	94.58	gold quality
left adrenal gland cortex	UBERON:0035825	94.47	gold quality
popliteal artery	UBERON:0002250	94.36	gold quality
tibial artery	UBERON:0007610	94.35	gold quality
adrenal cortex	UBERON:0001235	94.00	gold quality
mucosa of transverse colon	UBERON:0004991	93.90	gold quality
adrenal gland	UBERON:0002369	93.74	gold quality
endometrium epithelium	UBERON:0004811	93.63	gold quality
muscle organ	UBERON:0001630	93.57	gold quality
skeletal muscle organ	UBERON:0014892	93.57	gold quality
aorta	UBERON:0000947	93.54	gold quality
metanephros cortex	UBERON:0010533	93.26	gold quality
descending thoracic aorta	UBERON:0002345	93.16	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	93.12	gold quality
right coronary artery	UBERON:0001625	92.98	gold quality
left coronary artery	UBERON:0001626	92.95	gold quality
cortical plate	UBERON:0005343	92.82	gold quality
ventricular zone	UBERON:0003053	92.72	gold quality
adenohypophysis	UBERON:0002196	92.64	gold quality
ascending aorta	UBERON:0001496	92.62	gold quality
thoracic aorta	UBERON:0001515	92.60	gold quality
right lung	UBERON:0002167	92.55	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.82
E-GEOD-124858	no	189.29

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F4

miRNA regulators (miRDB)

28 targeting EIF2B2, 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-3119	99.92	71.34	2390
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-4302	99.89	67.94	1187
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-12119	99.87	68.35	1653
HSA-MIR-4766-5P	99.75	69.23	2662
HSA-MIR-1197	99.70	67.75	1027
HSA-MIR-378A-5P	99.65	66.33	1311
HSA-MIR-6733-3P	99.54	67.80	1281
HSA-MIR-4762-3P	99.43	69.72	2363
HSA-MIR-532-3P	99.34	65.76	1195
HSA-MIR-4291	99.20	68.88	2969
HSA-MIR-877-3P	99.09	68.10	1637
HSA-MIR-5001-3P	98.91	67.28	1394
HSA-MIR-4764-5P	98.88	65.53	894
HSA-MIR-4451	98.82	68.17	1455
HSA-MIR-4686	98.77	66.87	964
HSA-MIR-1199-5P	98.44	66.51	829
HSA-MIR-6751-3P	98.44	66.35	835
HSA-MIR-6838-3P	98.40	65.88	559
HSA-MIR-4303	98.01	68.13	2304
HSA-MIR-4733-5P	97.75	67.44	866
HSA-MIR-4678	97.59	68.31	902
HSA-MIR-3156-5P	96.93	67.36	800
HSA-MIR-103B	95.51	66.85	441

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 10)

• Mutation in EIF2B2 causes childhood ataxia with central nervous system hypomyelination/ vanishing white matter leukodystrophy. (PMID:12707859)
• 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)
• The role of the residues Ser2 and Ser67 contribute to the important role of the N-terminal region of eIF2beta for its function in mammals. (PMID:16225457)
• CACH syndrome is linked to mutations in the five EIF2B–REVIEW (PMID:17878805)
• Study reports 9 novel mutations in EIF2B genes in 8 patients, increasing number of known mutations to >120. Using homology modeling, analyzed the impact of novel mutations on the 5 subunits of eIF2B protein (alpha, beta, gamma, delta, epsilon). (PMID:18263758)
• analysis of vanishing white matter disease caused by EIF2B2 mutation with the presentation of an adrenoleukodystrophy phenotype [case report] (PMID:22285377)
• An Italian patient is described with a c.638A>G mutation in exon 5 of EIF2B2 gene with very slow progressive vanishing white matter disease. (PMID:22729508)
• It would be better to consider Vanishing White Matter Disease as an eIF2B-related multisystem disorder, not just as a neurological disorder. (PMID:28041799)
• Data show that eIF2Balpha and eIF2Bbeta bind to adjacent surfaces on eIF2alpha-N-terminal domains (NTDs). (PMID:29036434)
• Mutational analysis of the alpha subunit of eIF2B provides insights into the role of eIF2B bodies in translational control and VWM disease. (PMID:33334879)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	eif2b2	ENSDARG00000041397
mus_musculus	Eif2b2	ENSMUSG00000004788
rattus_norvegicus	Eif2b2	ENSRNOG00000006467
drosophila_melanogaster	eIF2Bbeta	FBGN0024996
caenorhabditis_elegans	eif-2Bbeta	WBGENE00012950

Paralogs (3): MRI1 (ENSG00000037757), EIF2B1 (ENSG00000111361), EIF2B4 (ENSG00000115211)

Protein

Protein identifiers

Translation initiation factor eIF2B subunit beta — P49770 (reviewed: P49770)

Alternative names: S20I15, S20III15, eIF2B GDP-GTP exchange factor subunit beta

All UniProt accessions (5): P49770, G3V5E5, H0YJJ8, H0YK01, Q53XC2

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 2 (VWM2) [MIM:620312] 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.

RefSeq proteins (1): NP_055054* (*=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
IPR051855	eIF2B_beta_subunit	Family

Pfam: PF01008

UniProt features (57 total): helix 21, strand 15, sequence variant 10, sequence conflict 7, turn 3, 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-P49770-F1	86.82	0.55

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

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

MSigDB gene sets: 238 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_UP, GOBP_CYTOPLASMIC_TRANSLATION, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GU_PDEF_TARGETS_DN, MORF_RAB5A, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, 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_OVARIAN_FOLLICLE_DEVELOPMENT

GO Biological Process (13): ovarian follicle development (GO:0001541), cytoplasmic translational initiation (GO:0002183), translational initiation (GO:0006413), regulation of translational initiation (GO:0006446), central nervous system development (GO:0007417), 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), animal organ development (GO:0048513)

GO Molecular Function (5): translation initiation factor activity (GO:0003743), guanyl-nucleotide exchange factor activity (GO:0005085), ATP binding (GO:0005524), GTP binding (GO:0005525), 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	4
anatomical structure development	2
purine ribonucleoside triphosphate binding	2
cellular anatomical structure	2
cytoplasm	2
female gonad development	1
cytoplasmic translation	1
formation of translation initiation ternary complex	1
translation	1
metabolic process	1
regulation of translation	1
nervous system development	1
system development	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
translation factor activity	1
GTP binding	1
GDP binding	1
GTPase regulator activity	1
adenyl ribonucleotide binding	1
guanyl ribonucleotide binding	1
binding	1
intracellular anatomical structure	1
guanyl-nucleotide exchange factor complex	1

Protein interactions and networks

STRING

2437 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EIF2B2	EIF2B3	Q9NR50	996
EIF2B2	EIF2B5	Q13144	995
EIF2B2	EIF2B4	Q9UI10	977
EIF2B2	EIF2B1	Q14232	924
EIF2B2	RABIF	P47224	839
EIF2B2	EIF2S3	P41091	710
EIF2B2	EIF2S2	P20042	656
EIF2B2	EIF2S1	P05198	648
EIF2B2	TMED10	P49755	621
EIF2B2	EIF5	P55010	574
EIF2B2	EIF2AK4	Q9P2K8	567
EIF2B2	EIF2AK3	Q9NZJ5	520
EIF2B2	ICAM5	Q9UMF0	494
EIF2B2	EIF4G2	P78344	485
EIF2B2	HMBS	P08396	470

IntAct

156 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	EIF2B2	psi-mi:“MI:0914”(association)	0.860
EIF2B2	EIF2B5	psi-mi:“MI:0915”(physical association)	0.830
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
DCC	NTN1	psi-mi:“MI:0914”(association)	0.700
EIF2B2	C9orf72	psi-mi:“MI:0915”(physical association)	0.670
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
SDC2	PDPK1	psi-mi:“MI:0914”(association)	0.640
STX12	SNAP23	psi-mi:“MI:0914”(association)	0.640
PIP4P2	NEDD4	psi-mi:“MI:0914”(association)	0.590
GYPB	TCAF2	psi-mi:“MI:0914”(association)	0.530
EFNB2	FAM171A2	psi-mi:“MI:0914”(association)	0.530

BioGRID (207): EIF2B2 (Two-hybrid), MRFAP1L1 (Two-hybrid), C9orf72 (Two-hybrid), EIF2B2 (Affinity Capture-MS), EIF2B2 (Affinity Capture-MS), EIF2B2 (Affinity Capture-MS), EIF2B2 (Affinity Capture-MS), EIF2B2 (Affinity Capture-MS), EIF2B2 (Affinity Capture-MS), EIF2B2 (Affinity Capture-MS), EIF2B2 (Affinity Capture-MS), EIF2B2 (Affinity Capture-MS), EIF2B2 (Affinity Capture-MS), EIF2B2 (Affinity Capture-MS), EIF2B2 (Affinity Capture-MS)

ESM2 similar proteins: A1DCB2, A2R1F6, A5PJM5, B0YCF6, B3DNN5, C3RZA1, D3ZG52, E1BMP7, E7F590, F4IDS7, F4JEP5, F4JP48, O23617, O24617, O65607, P36195, P49770, P51530, P54319, P97443, Q0DGP6, Q0P585, Q0WUI9, Q24498, Q28690, Q2UT70, Q3UR70, Q4WGB7, Q5B6T1, Q5BJI7, Q5E9B4, Q5IH13, Q5IH14, Q62818, Q6GN68, Q6L4V0, Q6ZQJ5, Q7M6Z3, Q7ZXV5, Q8CCT7

Diamond homologs: P32502, P49770, Q28690, Q54EY2, Q5E9B4, Q62818, Q90511, Q99LD9, Q9UT76, A1WUJ7, A4VLZ8, A4XTE5, A9WGQ8, B1I2P1, B1J5G5, B3RLE6, B4LWZ8, B9HCR2, B9LBK4, B9RR88, C1A6J9, P12754, P14741, P41111, Q09924, Q0IIF2, Q14232, Q2NL31, Q31LP7, Q3AMB7, Q3AWF5, Q3M785, Q3T058, Q4R4V8, Q54FM3, Q54I81, Q5HZE4, Q5JFM9, Q5N076, Q5RAR0

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
GSK3B	down-regulates	EIF2B2	binding
EIF2B2	“up-regulates activity”	EIF2S1	“guanine nucleotide exchange factor”
EIF2B2	“up-regulates activity”	EIF2S2	“guanine nucleotide exchange factor”
EIF2B2	“up-regulates activity”	EIF2S3	“guanine nucleotide exchange factor”
EIF2B2	“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 159 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
Ribosomal scanning and start codon recognition	6	10.2×	6e-03

GO biological processes:

GO term	Partners	Fold	FDR
translational initiation	10	27.2×	3e-09
T cell costimulation	7	19.9×	2e-05
T cell receptor signaling pathway	7	8.1×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	20
Likely pathogenic	12
Uncertain significance	105
Likely benign	149
Benign	23

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1030309	NM_014239.4(EIF2B2):c.94G>T (p.Glu32Ter)	Pathogenic
2634104	NM_014239.4(EIF2B2):c.607del (p.Met203fs)	Pathogenic
2691460	NM_014239.4(EIF2B2):c.871C>T (p.Pro291Ser)	Pathogenic
2736128	NM_014239.4(EIF2B2):c.551dup (p.Arg185fs)	Pathogenic
2760253	NM_014239.4(EIF2B2):c.939dup (p.Asp314Ter)	Pathogenic
2804360	NM_014239.4(EIF2B2):c.936_937del (p.Val312_Phe313insTer)	Pathogenic
2826660	NM_014239.4(EIF2B2):c.710del (p.Lys237fs)	Pathogenic
2826857	NM_014239.4(EIF2B2):c.488_507del (p.Glu163fs)	Pathogenic
2841267	NM_014239.4(EIF2B2):c.365del (p.Phe122fs)	Pathogenic
2875995	NM_014239.4(EIF2B2):c.932_933del (p.Pro311fs)	Pathogenic
3244088	NC_000014.8:g.(?75469694)(75489741_?)del	Pathogenic
3244089	NC_000014.8:g.(?75470100)(75494246_?)del	Pathogenic
3244090	NC_000014.8:g.(?75473260)(75475891_?)del	Pathogenic
3768546	NM_014239.4(EIF2B2):c.877dup (p.Glu293fs)	Pathogenic
4075750	NM_014239.4(EIF2B2):c.794_798del (p.Leu265fs)	Pathogenic
4336	NM_014239.4(EIF2B2):c.638A>G (p.Glu213Gly)	Pathogenic
4340	NM_014239.4(EIF2B2):c.607_612delinsTG (p.Met203fs)	Pathogenic
4806161	NM_014239.4(EIF2B2):c.677del (p.Met226fs)	Pathogenic
495049	NM_014239.4(EIF2B2):c.514C>T (p.Arg172Ter)	Pathogenic
984939	NM_014239.4(EIF2B2):c.42del (p.Ile15fs)	Pathogenic
1205361	NM_014239.4(EIF2B2):c.285-1G>A	Likely pathogenic
1804795	NM_014239.4(EIF2B2):c.829C>T (p.Gln277Ter)	Likely pathogenic
1936590	NM_014239.4(EIF2B2):c.832-2A>T	Likely pathogenic
2758537	NM_014239.4(EIF2B2):c.421_433+19del	Likely pathogenic
2800462	NM_014239.4(EIF2B2):c.832-2A>G	Likely pathogenic
2882070	NM_014239.4(EIF2B2):c.163+1G>A	Likely pathogenic
3252687	NM_014239.4(EIF2B2):c.586C>T (p.Pro196Ser)	Likely pathogenic
3576753	NM_014239.4(EIF2B2):c.544_545insA (p.Ala182fs)	Likely pathogenic
430268	NM_014239.4(EIF2B2):c.581G>A (p.Cys194Tyr)	Likely pathogenic
800970	NM_014239.4(EIF2B2):c.591C>G (p.Phe197Leu)	Likely pathogenic

SpliceAI

892 predictions. Top by Δscore:

Variant	Effect	Δscore
14:75003150:GCGG:G	donor_gain	1.0000
14:75003152:GG:G	donor_gain	1.0000
14:75003153:GG:G	donor_gain	1.0000
14:75003154:G:GG	donor_gain	1.0000
14:75003155:T:G	donor_loss	1.0000
14:75003361:A:T	donor_gain	1.0000
14:75003393:C:T	donor_gain	1.0000
14:75003531:G:A	acceptor_gain	1.0000
14:75003548:T:G	acceptor_gain	1.0000
14:75003549:A:AG	acceptor_gain	1.0000
14:75003550:G:GA	acceptor_gain	1.0000
14:75003672:GCGAT:G	donor_gain	1.0000
14:75003695:GCTGG:G	donor_gain	1.0000
14:75003696:CTGGG:C	donor_loss	1.0000
14:75003697:TGGG:T	donor_loss	1.0000
14:75003698:GG:G	donor_gain	1.0000
14:75003699:GG:G	donor_gain	1.0000
14:75003699:GGT:G	donor_loss	1.0000
14:75003700:G:GC	donor_loss	1.0000
14:75003701:T:A	donor_loss	1.0000
14:75004718:T:TA	acceptor_gain	1.0000
14:75004721:A:AG	acceptor_gain	1.0000
14:75004722:A:G	acceptor_gain	1.0000
14:75004724:ACC:A	acceptor_gain	1.0000
14:75004726:C:CA	acceptor_gain	1.0000
14:75004735:A:AG	acceptor_gain	1.0000
14:75004735:AGAAG:A	acceptor_gain	1.0000
14:75004736:G:GG	acceptor_gain	1.0000
14:75004736:GA:G	acceptor_gain	1.0000
14:75004736:GAA:G	acceptor_gain	1.0000

AlphaMissense

2309 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:75004836:T:C	L178P	0.999
14:75004869:T:A	V189D	0.999
14:75006610:G:T	G243W	0.999
14:75006611:G:A	G243E	0.999
14:75009079:T:A	V316D	0.999
14:75003380:G:C	R90P	0.998
14:75004779:T:A	I159N	0.998
14:75006611:G:T	G243V	0.998
14:75006655:G:C	A258P	0.998
14:75006656:C:A	A258E	0.998
14:75006683:T:A	V267D	0.998
14:75006685:T:C	C268R	0.998
14:75006687:T:G	C268W	0.998
14:75009100:T:C	L323P	0.998
14:75004766:G:C	A155P	0.997
14:75004767:C:A	A155D	0.997
14:75004832:T:C	F177L	0.997
14:75004834:C:A	F177L	0.997
14:75004834:C:G	F177L	0.997
14:75004858:G:C	R185S	0.997
14:75004858:G:T	R185S	0.997
14:75005866:G:C	G200R	0.997
14:75005879:C:A	A204D	0.997
14:75005954:T:A	V229D	0.997
14:75005961:G:C	K231N	0.997
14:75005961:G:T	K231N	0.997
14:75006578:T:A	V232E	0.997
14:75006647:C:A	A255E	0.997
14:75006653:C:A	A257E	0.997
14:75006686:G:A	C268Y	0.997

dbSNP variants (sampled 300 via entrez): RS1000766150 (14:75001945 T>C), RS1000854378 (14:75007317 C>T), RS1000885496 (14:75011281 C>T), RS1001154614 (14:75006929 T>C), RS1001322194 (14:75002885 C>A,G,T), RS1001515850 (14:75010858 G>A), RS1001821993 (14:75010454 T>C,G), RS1003237944 (14:75012027 T>C), RS1003830020 (14:75005606 A>G), RS1004201495 (14:75001037 G>A), RS1004322147 (14:75008774 G>A), RS1004661037 (14:75006808 G>A), RS1004989825 (14:75006523 C>G,T), RS1005845642 (14:75002747 G>T), RS1006058686 (14:75008525 G>T)

Disease associations

OMIM: gene MIM:606454 | disease phenotypes: MIM:603896, MIM:620312, MIM:166200

GenCC curated gene-disease

Disease	Classification	Inheritance
leukoencephalopathy with vanishing white matter	Definitive	Autosomal recessive
leukoencephalopathy with vanishing white matter 1	Strong	Autosomal recessive
leukoencephalopathy with vanishing white matter 2	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 2	Definitive	AR

Mondo (8): leukoencephalopathy with vanishing white matter (MONDO:0800448), leukoencephalopathy with vanishing white matter 2 (MONDO:0957870), leukoencephalopathy with vanishing white matter 1 (MONDO:0020507), congenital nervous system disorder (MONDO:0002320), premature menopause (MONDO:0001119), osteogenesis imperfecta (MONDO:0019019), (MONDO:0011380), (MONDO:0020506)

Orphanet (4): CACH syndrome (Orphanet:135), Ovarioleukodystrophy (Orphanet:99853), Cree leukoencephalopathy (Orphanet:99854), Osteogenesis imperfecta (Orphanet:666)

HPO phenotypes

11 total (11 of 11 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000518	Cataract
HP:0000648	Optic atrophy
HP:0000869	Secondary amenorrhea
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0002317	Unsteady gait
HP:0002352	Leukoencephalopathy
HP:0002354	Memory impairment
HP:0007340	Lower limb muscle weakness
HP:0008209	Premature ovarian insufficiency

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST005237_3	Mood instability	1.000000e-06
GCST005238_3	Mood instability	3.000000e-09
GCST010866_57	Coronary artery disease	1.000000e-12
GCST011011_45	Youthful appearance (self-reported)	1.000000e-10
GCST90000514_22	Gastroesophageal reflux disease	2.000000e-09
GCST90011900_113	Serum alkaline phosphatase levels	4.000000e-15

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0008475	mood instability measurement
EFO:0004533	alkaline phosphatase measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008594	Menopause, Premature	C12.050.351.500.056.630.250; C12.100.250.056.630.250; G08.686.157.500.500; G08.686.841.249.500.500
D010013	Osteogenesis Imperfecta	C05.116.099.708.685; C16.320.737; C17.300.200.540

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067331 (SINGLE PROTEIN)

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

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
7.96	Kd	10.87	nM	CHEMBL5653589
7.96	ED50	10.87	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 2 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	2148298: Binding affinity to human EIF2B2 incubated for 45 mins by Kinobead based pull down assay	kd	0.0109	uM

CTD chemical–gene interactions

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Fluorouracil	decreases expression	2
Particulate Matter	affects cotreatment, decreases expression, increases abundance, affects expression	2
bisphenol F	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	increases expression	1
sodium arsenite	decreases expression, increases abundance, affects cotreatment	1
manganese chloride	decreases expression, increases abundance, affects cotreatment	1
di-n-butylphosphoric acid	affects expression	1
ICG 001	decreases expression	1
abrine	increases expression	1
bisphenol AF	increases expression	1
Ethanol	affects cotreatment, decreases expression, increases abundance	1
Arsenic	increases abundance, affects cotreatment, decreases expression	1
Doxorubicin	decreases expression	1
Gasoline	affects cotreatment, decreases expression, increases abundance	1
Ivermectin	decreases expression	1
Manganese	decreases expression, increases abundance, affects cotreatment	1
Methyl Methanesulfonate	increases expression	1
Polycyclic Aromatic Hydrocarbons	increases abundance, affects cotreatment, decreases expression	1
Quercetin	increases expression	1
Selenium	decreases expression	1
Smoke	decreases expression	1
Vitamin E	increases expression	1
Aflatoxin B1	increases methylation	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
CHEMBL5651340	Binding	Binding affinity to human EIF2B2 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

4 cell lines: 3 transformed cell line, 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_1M98	GM20073	Transformed cell line	Female
CVCL_1M99	GM20074	Transformed cell line	Male
CVCL_E4QF	KOLF2.1J EIF2B2 1.1kbdel DEL/WT	Induced pluripotent stem cell	Male
CVCL_F104	GM19988	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00417066	PHASE4	COMPLETED	Flexible GnRH Antagonist vs Flare up GnRH Agonist Protocol in Poor Responders
NCT00732693	PHASE4	COMPLETED	Evaluation of Physiologic and Standard Sex Steroid Replacement Regimens in Women With Premature Ovarian Failure
NCT00837616	PHASE4	COMPLETED	Estrogen Dosing in Turner Syndrome: Pharmacology and Metabolism
NCT01853501	PHASE4	UNKNOWN	Effects of ADSC Therapy in Women With POF
NCT02783937	PHASE4	COMPLETED	Filgrastim for Premature Ovarian Insufficiency
NCT03535480	PHASE4	UNKNOWN	Autologous Bone Marrow Stem Cell Ovarian Transplantation to Restore Ovarian Function in Premature Ovarian Failure
NCT00131469	PHASE4	COMPLETED	Study of Teriparatide (FORTEO) to Treat Adults With Osteogenesis Imperfecta
NCT00159419	PHASE4	COMPLETED	Bisphosphonate Therapy for Osteogenesis Imperfecta
NCT01713231	PHASE4	COMPLETED	Effect of High-Dose Vitamin D on Bone Density in Osteogenesis Imperfecta
NCT02303873	PHASE4	COMPLETED	Efficacy and Safety of Alendronate in Chinese Children or Adolescents With Osteogenesis Imperfecta
NCT03735537	PHASE4	COMPLETED	Treatment of Osteogenesis Imperfecta With Parathyroid Hormone and Zoledronic Acid
NCT04152551	PHASE4	RECRUITING	Effects of Bisphosphonates on OI-Related Hearing Loss
NCT00140998	PHASE3	COMPLETED	Estrogen Treatment (Oral vs. Patches) in Turner Syndrome
NCT00001305	PHASE3	COMPLETED	Growth Hormone Therapy in Osteogenesis Imperfecta
NCT00005901	PHASE3	COMPLETED	Pamidronate to Treat Osteogenesis Imperfecta in Children
NCT00106028	PHASE3	COMPLETED	Safety and Efficacy of Risedronate in the Treatment of Osteogenesis Imperfecta in Children
NCT00982124	PHASE3	COMPLETED	An Efficacy and Safety Trial of Intravenous Zoledronic Acid in Infants Less Than One Year of Age, With Severe Osteogenesis Imperfecta
NCT02352753	PHASE3	TERMINATED	Multicenter,Single-arm Study to Evaluate Efficacy, Safety, & Pharmacokinetics of Denosumab in Children w/ OI
NCT03638128	PHASE3	TERMINATED	Open-label Extension of Study 20130173 of Denosumab in Children and Young Adults With Osteogenesis Imperfecta
NCT05768854	PHASE3	ACTIVE_NOT_RECRUITING	Setrusumab vs Bisphosphonates in Pediatric Subjects With Osteogenesis Imperfecta
NCT05972551	PHASE3	ACTIVE_NOT_RECRUITING	Study to Evaluate Efficacy and Safety of Romosozumab Compared With Bisphosphonates in Children and Adolescents With Osteogenesis Imperfecta
NCT06636071	PHASE3	ACTIVE_NOT_RECRUITING	Setrusumab in Pediatric Japanese Subjects With Osteogenesis Imperfecta
NCT07366086	PHASE3	RECRUITING	Pediatric Safety Follow-up Study of Prior Treatment With Romosozumab for Osteogenesis Imperfecta
NCT00001951	PHASE2	COMPLETED	Hormone Replacement in Young Women With Premature Ovarian Failure
NCT00370019	PHASE2	WITHDRAWN	Effects of an Estrogen Replacement Therapy Skin Patch on Ovulation in Women With Premature Ovarian Failure
NCT00429494	PHASE2	COMPLETED	GnRH Analogue for Ovarian Function Preservation in Hematopoietic Stem Cell Transplantation Patients
NCT03816852	PHASE2	SUSPENDED	The Safety and Efficiency Study of Mesenchymal Stem Cell (19#iSCLife®-POI) in Premature Ovarian Insufficiency
NCT04536467	PHASE2	UNKNOWN	Prevention of Chemotherapy-Induced Ovarian Failure With Goserelin in Premenopausal Lymphoma Patients
NCT06117982	PHASE2	COMPLETED	The Impact of Granulocyte Colony Stimulating Factor on Premature Ovarian Insufficiency
NCT00063479	PHASE2	COMPLETED	Bisphosphonate Treatment of Osteogenesis Imperfecta
NCT00131118	PHASE2	COMPLETED	Zoledronic Acid in Children (1 -17 Years) With Severe Osteogenesis Imperfecta
NCT01417091	PHASE2	COMPLETED	Safety, Pharmacokinetics and Pharmacodynamics of BPS804 in Osteogenesis Imperfecta
NCT01679080	PHASE2	TERMINATED	The Effect of Treatment With Teriparatide and Zoledronic Acid in Patients With Osteogenesis Imperfecta
NCT01799798	PHASE2	COMPLETED	Translational Therapy in Patients With Osteogenesis Imperfecta - A Pilot Trial on Treatment With the Rankl-Antibody Denosumab
NCT03208582	PHASE2	COMPLETED	Do Bisphosphonates Alter the Skeletal Response to Mechanical Stimulation in Children With Osteogenesis Imperfecta?
NCT03216486	PHASE2	WITHDRAWN	An Exploratory Study of BPS804 Treatment in Adult Patients With Type I, III or IV Osteogenesis Imperfecta
NCT05312697	PHASE2	TERMINATED	Long-term Extension Study of Setrusumab in Adults With Type I, III, or IV Osteogenesis Imperfecta
NCT07062588	PHASE2	RECRUITING	Osteogenesis Imperfecta Trial of AGA2115 for ADUlts With COL1A1 and/or COL1A2 GeNetic Variations (IDUN)
NCT07557446	PHASE2	NOT_YET_RECRUITING	A Dose REgimen-Finding Study of AGA2115 in Chinese Patients With Osteogenesis ImpeRfecta (EIR)
NCT02912104	PHASE1	COMPLETED	A Therapeutic Trial of Human Amniotic Epithelial Cells Transplantation for Primary Ovarian Failure