Leukoencephalopathy with vanishing white matter

Summary

Leukoencephalopathy with vanishing white matter (MONDO:0800448) is a disease (an umbrella term covering 9 Mondo subtypes) caused by EIF2B2 (GenCC Strong), with 8 cohort genes and 7 clinical trials. The dominant Reactome pathway is Recycling of eIF2:GDP (5 cohort genes). Top therapeutic interventions include fosigotifator.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: EIF2B2 (GenCC Strong)
• Umbrella term: 9 Mondo subtypes
• Cohort genes: 8
• ClinVar variants: 387
• Phenotypes (HPO): 55
• Clinical trials: 7

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		148	Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

55 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0006978	Dysmyelinating leukodystrophy	Very frequent (80-99%)
HP:0410263	Brain imaging abnormality	Very frequent (80-99%)
HP:0000648	Optic atrophy	Frequent (30-79%)
HP:0000737	Irritability	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001257	Spasticity	Frequent (30-79%)
HP:0001272	Cerebellar atrophy	Frequent (30-79%)
HP:0001347	Hyperreflexia	Frequent (30-79%)
HP:0002059	Cerebral atrophy	Frequent (30-79%)
HP:0002070	Limb ataxia	Frequent (30-79%)
HP:0002078	Truncal ataxia	Frequent (30-79%)
HP:0002344	Progressive neurologic deterioration	Frequent (30-79%)
HP:0006855	Cerebellar vermis atrophy	Frequent (30-79%)
HP:0007366	Atrophy/Degeneration affecting the brainstem	Frequent (30-79%)
HP:0008209	Premature ovarian insufficiency	Frequent (30-79%)
HP:0000089	Renal hypoplasia	Occasional (5-29%)
HP:0000133	Gonadal dysgenesis	Occasional (5-29%)
HP:0000252	Microcephaly	Occasional (5-29%)
HP:0000518	Cataract	Occasional (5-29%)
HP:0000618	Blindness	Occasional (5-29%)
HP:0000708	Atypical behavior	Occasional (5-29%)
HP:0000741	Apathy	Occasional (5-29%)
HP:0000786	Primary amenorrhea	Occasional (5-29%)
HP:0000869	Secondary amenorrhea	Occasional (5-29%)
HP:0001260	Dysarthria	Occasional (5-29%)
HP:0001264	Spastic diplegia	Occasional (5-29%)
HP:0001269	Hemiparesis	Occasional (5-29%)
HP:0001270	Motor delay	Occasional (5-29%)
HP:0001298	Encephalopathy	Occasional (5-29%)
HP:0001310	Dysmetria	Occasional (5-29%)
HP:0001371	Flexion contracture	Occasional (5-29%)
HP:0001433	Hepatosplenomegaly	Occasional (5-29%)
HP:0001510	Growth delay	Occasional (5-29%)
HP:0001511	Intrauterine growth retardation	Occasional (5-29%)
HP:0001558	Decreased fetal movement	Occasional (5-29%)
HP:0001562	Oligohydramnios	Occasional (5-29%)
HP:0001733	Pancreatitis	Occasional (5-29%)
HP:0002013	Vomiting	Occasional (5-29%)
HP:0002015	Dysphagia	Occasional (5-29%)
HP:0002076	Migraine	Occasional (5-29%)
HP:0002315	Headache	Occasional (5-29%)
HP:0002804	Arthrogryposis multiplex congenita	Occasional (5-29%)
HP:0006956	Dilation of lateral ventricles	Occasional (5-29%)
HP:0007361	Abnormality of the pons	Occasional (5-29%)
HP:0008288	Nonketotic hyperglycinemia	Occasional (5-29%)
HP:0008947	Floppy infant	Occasional (5-29%)
HP:0011342	Mild global developmental delay	Occasional (5-29%)
HP:0011968	Feeding difficulties	Occasional (5-29%)
HP:0012690	T2 hypointense thalamus	Occasional (5-29%)
HP:0012704	Widened subarachnoid space	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	leukoencephalopathy with vanishing white matter
Mondo ID	MONDO:0800448
OMIM	603896
Orphanet	135
DOID	DOID:0060868
NCIT	C122664
SNOMED CT	447351004
UMLS	C1858991
MedGen	347037
GARD	0000231
Is cancer (heuristic)	no

Also known as: CACH/VWM · CACH/VWM syndrome · childhood ataxia with central nervous system hypomyelination/vanishing white matter · childhood ataxia with diffuse central nervous system hypomyelination · Cree leukoencephalopathy · leukoencephalopathy with vanishing white matter · myelinosis centralis diffusa · vanishing white matter disease · VWM

Data availability: 387 ClinVar variants · 1 GenCC gene-disease record · 12 cell lines.

Disease family

An umbrella term covering 9 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › neurodegenerative disease › inherited neurodegenerative disorder › leukodystrophy › leukoencephalopathy with vanishing white matter

Related subtypes (64): Alexander disease, cerebrotendinous xanthomatosis, polycystic lipomembranous osteodysplasia with sclerosing leukoencephaly, dermatoleukodystrophy, Krabbe disease, Sjogren-Larsson syndrome, Canavan disease, Pelizaeus-Merzbacher spectrum disorder, hereditary spastic paraplegia 2, megalencephalic leukoencephalopathy with subcortical cysts, ribose-5-P isomerase deficiency, hypomyelinating leukodystrophy 5, leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome, hypomyelinating leukodystrophy 6, cystic leukoencephalopathy without megalencephaly, sterol carrier protein 2 deficiency, leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome, hypomyelination with brain stem and spinal cord involvement and leg spasticity, leukoencephalopathy with mild cerebellar ataxia and white matter edema, progressive encephalopathy with leukodystrophy due to DECR deficiency, hypomyelinating leukodystrophy 9, multiple mitochondrial dysfunctions syndrome 4, hypomyelinating leukodystrophy 10, hypomyelinating leukodystrophy 12, hypomyelinating leukodystrophy 13, leukoencephalopathy with bilateral anterior temporal lobe cysts, progressive cavitating leukoencephalopathy, Pelizaeus-Merzbacher-like disease, CADDS, adrenoleukodystrophy, non-progressive predominantly posterior cavitating leukoencephalopathy with peripheral neuropathy, Aicardi-Goutieres syndrome, metachromatic leukodystrophy, peroxisome biogenesis disorder, unknown leukodystrophy, ravine syndrome, leukodystrophy, hypomyelinating, 22, leukodystrophy, hypomyelinating, 23, with ataxia, deafness, liver dysfunction, and dilated cardiomyopathy, neurodevelopmental disorder with microcephaly, epilepsy, and hypomyelination, leukodystrophy, hypomyelinating, 18, leukodystrophy, hypomyelinating, 19, transient infantile, spastic ataxia 8, autosomal recessive, with hypomyelinating leukodystrophy, leukodystrophy, hypomyelinating, 14, leukodystrophy, hypomyelinating, 20, early-onset calcifying leukoencephalopathy-skeletal dysplasia, c11orf73-related autosomal recessive hypomyelinating leukodystrophy, alkaline ceramidase 3 deficiency, leukodystrophy, hypomyelinating, 15, leukodystrophy, hypomyelinating, 16, leukodystrophy, hypomyelinating, 17, POLR-related leukodystrophy, leukoencephalopathy, diffuse hereditary, with spheroids 1, leukodystrophy, hypomyelinating, 24, leukodystrophy, childhood-onset, remitting, leukodystrophy, hypomyelinating, 25, leukodystrophy, hypomyelinating, 26, with chondrodysplasia, adult-onset progressive leukoencephalopathy-early-onset deafness, leukoencephalopathy, porphyria-related, episodic memory defect leukoencephalopathy, leukodystrophy, hypomyelinating, 28, leukodystrophy, demyelinating, adult-onset, leukodystrophy, adult-onset, autosomal dominant, without amyloid angiopathy, leukoencephalopathy without lacunae, adult-onset, AARS1-related leukoencephalopathy

Subtypes (9): leukoencephalopathy, progressive, with ovarian failure, congenital or early infantile CACH syndrome, late infantile CACH syndrome, juvenile or adult CACH syndrome, leukoencephalopathy with vanishing white matter 1, leukoencephalopathy with vanishing white matter 2, leukoencephalopathy with vanishing white matter 3, leukoencephalopathy with vanishing white matter 4, leukoencephalopathy with vanishing white matter 5

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

387 retrieved; paginated sample, class counts are floors:

164 uncertain significance, 55 conflicting classifications of pathogenicity, 36 pathogenic/likely pathogenic, 31 pathogenic, 31 likely pathogenic, 30 benign, 26 likely benign, 14 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
930179	NM_015114.3(ANKLE2):c.1870C>T (p.Arg624Ter)	ANKLE2	Pathogenic	criteria provided, multiple submitters, no conflicts
217277	NM_001414.4(EIF2B1):c.547G>T (p.Val183Phe)	EIF2B1	Pathogenic	no assertion criteria provided
217279	NM_001414.4(EIF2B1):c.328A>G (p.Lys110Glu)	EIF2B1	Pathogenic	no assertion criteria provided
217280	NM_001414.4(EIF2B1):c.610GGA[1] (p.Gly205del)	EIF2B1	Pathogenic	no assertion criteria provided
217281	NM_001414.4(EIF2B1):c.824A>G (p.Tyr275Cys)	EIF2B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
217282	NM_001414.4(EIF2B1):c.715T>G (p.Phe239Val)	EIF2B1	Pathogenic	no assertion criteria provided
4848543	NM_001414.4(EIF2B1):c.353dup (p.Ile119fs)	EIF2B1	Pathogenic	criteria provided, single submitter
995942	NM_001414.4(EIF2B1):c.439C>T (p.Arg147Ter)	EIF2B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1030309	NM_014239.4(EIF2B2):c.94G>T (p.Glu32Ter)	EIF2B2	Pathogenic	criteria provided, single submitter
208575	NM_014239.4(EIF2B2):c.599G>T (p.Gly200Val)	EIF2B2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2691460	NM_014239.4(EIF2B2):c.871C>T (p.Pro291Ser)	EIF2B2	Pathogenic	criteria provided, multiple submitters, no conflicts
3768546	NM_014239.4(EIF2B2):c.877dup (p.Glu293fs)	EIF2B2	Pathogenic	criteria provided, single submitter
40180	NM_014239.4(EIF2B2):c.254T>A (p.Val85Glu)	EIF2B2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4336	NM_014239.4(EIF2B2):c.638A>G (p.Glu213Gly)	EIF2B2	Pathogenic	criteria provided, multiple submitters, no conflicts
4337	NM_014239.4(EIF2B2):c.947T>A (p.Val316Asp)	EIF2B2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4339	NM_014239.4(EIF2B2):c.512C>T (p.Ser171Phe)	EIF2B2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4340	NM_014239.4(EIF2B2):c.607_612delinsTG (p.Met203fs)	EIF2B2	Pathogenic	criteria provided, multiple submitters, no conflicts
495050	NM_014239.4(EIF2B2):c.818A>G (p.Lys273Arg)	EIF2B2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
522641	NM_014239.4(EIF2B2):c.922G>A (p.Val308Met)	EIF2B2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
632219	NM_014239.4(EIF2B2):c.570del (p.Ile190fs)	EIF2B2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
977721	NM_014239.4(EIF2B2):c.910G>T (p.Glu304Ter)	EIF2B2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
984939	NM_014239.4(EIF2B2):c.42del (p.Ile15fs)	EIF2B2	Pathogenic	criteria provided, single submitter
1285271	NM_020365.5(EIF2B3):c.674G>C (p.Arg225Pro)	EIF2B3	Pathogenic	criteria provided, single submitter
4439	NM_020365.5(EIF2B3):c.260C>T (p.Ala87Val)	EIF2B3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4440	NM_020365.5(EIF2B3):c.1037T>C (p.Ile346Thr)	EIF2B3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
617677	NM_020365.5(EIF2B3):c.89T>C (p.Val30Ala)	EIF2B3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3385144	NM_001034116.2(EIF2B4):c.731C>T (p.Pro244Leu)	EIF2B4	Pathogenic	criteria provided, single submitter
4122	NM_001034116.2(EIF2B4):c.1465T>C (p.Tyr489His)	EIF2B4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
420062	NM_001034116.2(EIF2B4):c.728C>T (p.Pro243Leu)	EIF2B4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1028674	NM_003907.3(EIF2B5):c.1485C>G (p.Tyr495Ter)	EIF2B5	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 27 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
EIF2B2	Definitive	Autosomal recessive	leukoencephalopathy with vanishing white matter	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
EIF2B2	Orphanet:157713	Congenital or early infantile CACH syndrome
EIF2B2	Orphanet:157716	Late infantile CACH syndrome
EIF2B2	Orphanet:157719	Juvenile or adult CACH syndrome
EIF2B2	Orphanet:99853	Ovarioleukodystrophy
EIF2B2	Orphanet:99854	Cree leukoencephalopathy
ANKLE2	Orphanet:2512	Autosomal recessive primary microcephaly
EIF2B1	Orphanet:157713	Congenital or early infantile CACH syndrome
EIF2B1	Orphanet:157716	Late infantile CACH syndrome
EIF2B1	Orphanet:157719	Juvenile or adult CACH syndrome
EIF2B1	Orphanet:99853	Ovarioleukodystrophy
EIF2B1	Orphanet:99854	Cree leukoencephalopathy
EIF2B3	Orphanet:157713	Congenital or early infantile CACH syndrome
EIF2B3	Orphanet:157716	Late infantile CACH syndrome
EIF2B3	Orphanet:157719	Juvenile or adult CACH syndrome
EIF2B3	Orphanet:99853	Ovarioleukodystrophy
EIF2B3	Orphanet:99854	Cree leukoencephalopathy
EIF2B4	Orphanet:157713	Congenital or early infantile CACH syndrome
EIF2B4	Orphanet:157716	Late infantile CACH syndrome
EIF2B4	Orphanet:157719	Juvenile or adult CACH syndrome
EIF2B4	Orphanet:99853	Ovarioleukodystrophy
EIF2B4	Orphanet:99854	Cree leukoencephalopathy
EIF2B5	Orphanet:157713	Congenital or early infantile CACH syndrome
EIF2B5	Orphanet:157716	Late infantile CACH syndrome
EIF2B5	Orphanet:157719	Juvenile or adult CACH syndrome
EIF2B5	Orphanet:99853	Ovarioleukodystrophy
EIF2B5	Orphanet:99854	Cree leukoencephalopathy
ARHGEF6	Orphanet:777	X-linked non-syndromic intellectual disability

Cohort genes → proteins

8 cohort genes, 7 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	8

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
EIF2B2	HGNC:3258	ENSG00000119718	P49770	Translation initiation factor eIF2B subunit beta	gencc,clinvar
ANKLE2	HGNC:29101	ENSG00000176915	Q86XL3	Ankyrin repeat and LEM domain-containing protein 2	clinvar
EIF2B1	HGNC:3257	ENSG00000111361	Q14232	Translation initiation factor eIF2B subunit alpha	clinvar
EIF2B3	HGNC:3259	ENSG00000070785	Q9NR50	Translation initiation factor eIF2B subunit gamma	clinvar
EIF2B4	HGNC:3260	ENSG00000115211	Q9UI10	Translation initiation factor eIF2B subunit delta	clinvar
EIF2B5	HGNC:3261	ENSG00000145191	Q13144	Translation initiation factor eIF2B subunit epsilon	clinvar
GTF3C2-AS2	HGNC:55699	ENSG00000234072		GTF3C2 antisense RNA 2	clinvar
ARHGEF6	HGNC:685	ENSG00000129675	Q15052	Rho guanine nucleotide exchange factor 6	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
EIF2B2	Translation initiation factor eIF2B subunit beta	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.
ANKLE2	Ankyrin repeat and LEM domain-containing protein 2	Involved in mitotic nuclear envelope reassembly by promoting dephosphorylation of BAF/BANF1 during mitotic exit.
EIF2B1	Translation initiation factor eIF2B subunit alpha	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.
EIF2B3	Translation initiation factor eIF2B subunit gamma	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.
EIF2B4	Translation initiation factor eIF2B subunit delta	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.
EIF2B5	Translation initiation factor eIF2B subunit epsilon	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.
ARHGEF6	Rho guanine nucleotide exchange factor 6	Acts as a RAC1 guanine nucleotide exchange factor (GEF).

Protein-family classification

Druggable: 0 · Difficult: 2 · Unknown: 6 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Scaffold/PPI	2	4.3×	0.148
Other/Unknown	6	1.3×	0.234

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
EIF2B2	Other/Unknown	no		IF-2B-related, NagB/RpiA_transferase-like, IF_2B-like_C
ANKLE2	Scaffold/PPI	no		Ankyrin_rpt, LEM_dom, LEM/LEM-like_dom_sf
EIF2B1	Other/Unknown	no		IF-2B-related, NagB/RpiA_transferase-like, elF-2B_alpha_N
EIF2B3	Other/Unknown	no		NTP_transferase_dom, Nucleotide-diphossugar_trans, eIF2B_gamma
EIF2B4	Other/Unknown	no		IF-2B-related, NagB/RpiA_transferase-like, IF_2B-like_C
EIF2B5	Other/Unknown	no		W2_domain, Trimer_LpxA-like_sf, ARM-type_fold
GTF3C2-AS2	Other/Unknown	no
ARHGEF6	Scaffold/PPI	no		DH_dom, SH3_domain, CH_dom

Expression context

Cohort genes with no expression data: 0.

7 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	8
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left testis	2
gastrocnemius	2
sural nerve	2
left lobe of thyroid gland	1
right lobe of thyroid gland	1
thyroid gland	1
right testis	1
stromal cell of endometrium	1
monocyte	1
oocyte	1
secondary oocyte	1
gluteal muscle	1
triceps brachii	1
body of pancreas	1
lower esophagus mucosa	1
tendon of biceps brachii	1
bone marrow cell	1
right uterine tube	1
biceps brachii	1
medial globus pallidus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
EIF2B2	298	ubiquitous	marker	left lobe of thyroid gland, right lobe of thyroid gland, thyroid gland
ANKLE2	289	ubiquitous	marker	stromal cell of endometrium, left testis, right testis
EIF2B1	279	ubiquitous	marker	oocyte, secondary oocyte, monocyte
EIF2B3	271	ubiquitous	marker	triceps brachii, gluteal muscle, gastrocnemius
EIF2B4	290	ubiquitous	marker	lower esophagus mucosa, body of pancreas, left testis
EIF2B5	286	ubiquitous	marker	sural nerve, tendon of biceps brachii, gastrocnemius
GTF3C2-AS2	134		yes	sural nerve, right uterine tube, bone marrow cell
ARHGEF6	289	ubiquitous	marker	biceps brachii, skeletal muscle tissue of biceps brachii, medial globus pallidus

Protein interactions among cohort

Intra-cohort edges: 10.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
EIF2B3	3,212
EIF2B5	2,989
EIF2B2	2,800
EIF2B4	2,747
EIF2B1	2,548
ANKLE2	1,917
ARHGEF6	1,668
GTF3C2-AS2	0

Intra-cohort edges

A	B	Sources
EIF2B1	EIF2B2	biogrid_interaction, intact, string_interaction
EIF2B1	EIF2B3	biogrid_interaction, intact, string_interaction
EIF2B1	EIF2B4	biogrid_interaction, intact, string_interaction
EIF2B1	EIF2B5	biogrid_interaction, intact, string_interaction
EIF2B2	EIF2B3	biogrid_interaction, intact, string_interaction
EIF2B2	EIF2B4	biogrid_interaction, intact, string_interaction
EIF2B2	EIF2B5	biogrid_interaction, intact, string_interaction
EIF2B3	EIF2B4	biogrid_interaction, string_interaction
EIF2B3	EIF2B5	biogrid_interaction, string_interaction
EIF2B4	EIF2B5	biogrid_interaction, string_interaction

Structural data

PDB: 6 · AlphaFold-only: 1 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
EIF2B2	P49770	27
EIF2B1	Q14232	27
EIF2B4	Q9UI10	27
EIF2B3	Q9NR50	26
EIF2B5	Q13144	26
ARHGEF6	Q15052	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ANKLE2	Q86XL3	65.14

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 30. Enrichment computed across 8 evidence-associated genes (7 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 7 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Recycling of eIF2:GDP	5	906.4×	5e-14	EIF2B2, EIF2B1, EIF2B3, EIF2B4, EIF2B5
G-protein beta:gamma signalling	1	271.9×	0.041	ARHGEF6
Regulation of cytoskeletal remodeling and cell spreading by IPP complex components	1	203.9×	0.041	ARHGEF6
RHO GTPase cycle	2	17.2×	0.041	ANKLE2, ARHGEF6
Cell-extracellular matrix interactions	1	96.0×	0.052	ARHGEF6
Initiation of Nuclear Envelope (NE) Reformation	1	85.9×	0.052	ANKLE2
G beta:gamma signalling through CDC42	1	81.6×	0.052	ARHGEF6
Signaling by Rho GTPases	2	9.8×	0.056	ANKLE2, ARHGEF6
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	2	9.6×	0.056	ANKLE2, ARHGEF6
Nuclear Envelope (NE) Reassembly	1	41.8×	0.068	ANKLE2
RHOU GTPase cycle	1	39.8×	0.068	ARHGEF6
Cell death signalling via NRAGE, NRIF and NADE	1	31.4×	0.075	ARHGEF6
p75 NTR receptor-mediated signalling	1	26.7×	0.075	ARHGEF6
Cell junction organization	1	26.7×	0.075	ARHGEF6
NRAGE signals death through JNK	1	26.3×	0.075	ARHGEF6
RHOG GTPase cycle	1	21.2×	0.079	ANKLE2
Death Receptor Signaling	1	19.9×	0.079	ARHGEF6
Cell-Cell communication	1	19.7×	0.079	ARHGEF6
G alpha (12/13) signalling events	1	19.7×	0.079	ARHGEF6
RAC2 GTPase cycle	1	18.1×	0.081	ANKLE2
Mitotic Metaphase and Anaphase	1	13.8×	0.096	ANKLE2
Mitotic Anaphase	1	13.8×	0.096	ANKLE2
CDC42 GTPase cycle	1	10.3×	0.121	ARHGEF6
M Phase	1	9.4×	0.127	ANKLE2
RAC1 GTPase cycle	1	8.7×	0.131	ARHGEF6
Cell Cycle, Mitotic	1	6.9×	0.158	ANKLE2
GPCR downstream signalling	1	6.2×	0.161	ARHGEF6
Signal Transduction	2	2.9×	0.161	ANKLE2, ARHGEF6
Signaling by GPCR	1	5.7×	0.168	ARHGEF6
Cell Cycle	1	5.2×	0.179	ANKLE2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 7 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cytoplasmic translational initiation	5	1003.1×	4e-14	EIF2B2, EIF2B1, EIF2B3, EIF2B4, EIF2B5
oligodendrocyte development	5	429.9×	2e-12	EIF2B2, EIF2B1, EIF2B3, EIF2B4, EIF2B5
response to heat	5	300.9×	1e-11	EIF2B2, EIF2B1, EIF2B3, EIF2B4, EIF2B5
response to peptide hormone	5	279.9×	1e-11	EIF2B2, EIF2B1, EIF2B3, EIF2B4, EIF2B5
translational initiation	5	256.1×	1e-11	EIF2B2, EIF2B1, EIF2B3, EIF2B4, EIF2B5
response to glucose	5	182.4×	7e-11	EIF2B2, EIF2B1, EIF2B3, EIF2B4, EIF2B5
T cell receptor signaling pathway	5	108.4×	9e-10	EIF2B2, EIF2B1, EIF2B3, EIF2B4, EIF2B5
ovarian follicle development	3	168.0×	2e-06	EIF2B2, EIF2B4, EIF2B5
myelination	3	107.8×	6e-06	EIF2B2, EIF2B4, EIF2B5
central nervous system development	2	33.0×	0.004	EIF2B2, ANKLE2
regulation of catalytic activity	1	481.5×	0.005	ANKLE2
negative regulation of phosphorylation	1	401.2×	0.005	ANKLE2
mitotic nuclear membrane reassembly	1	240.7×	0.008	ANKLE2
astrocyte development	1	160.5×	0.012	EIF2B5
positive regulation of translational initiation	1	120.4×	0.014	EIF2B5
astrocyte differentiation	1	109.4×	0.015	EIF2B5
regulation of translational initiation	1	66.9×	0.023	EIF2B2
lamellipodium assembly	1	63.4×	0.023	ARHGEF6
JNK cascade	1	38.8×	0.035	ARHGEF6
hippocampus development	1	33.0×	0.039	EIF2B5
regulation of translation	1	31.3×	0.039	EIF2B4
response to endoplasmic reticulum stress	1	23.8×	0.049	EIF2B5
positive regulation of apoptotic process	1	8.1×	0.132	EIF2B5
cell division	1	6.6×	0.154	ANKLE2
negative regulation of apoptotic process	1	5.0×	0.192	ANKLE2
apoptotic process	1	4.1×	0.220	ARHGEF6

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 1 · Undrugged: 7

Druggability breadth: 6 of 8 evidence-associated genes (75%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
EIF2B5	1	2
EIF2B2	0	0
ANKLE2	0	0
EIF2B1	0	0
EIF2B3	0	0
EIF2B4	0	0
GTF3C2-AS2	0	0
ARHGEF6	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	EIF2B5

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
EIF2B3	9	Binding:9
EIF2B5	7	Binding:7
ARHGEF6	6	Binding:6
EIF2B2	1	Binding:1
EIF2B1	1	Binding:1
EIF2B4	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 7; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

1 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
MOLIBRESIB	2	EIF2B5

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	1	EIF2B5
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	7	EIF2B2, ANKLE2, EIF2B1, EIF2B3, EIF2B4, GTF3C2-AS2, ARHGEF6

Undrugged target profiles

7 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
EIF2B2	1	EIF2B5
EIF2B1	1	EIF2B5
EIF2B3	9	EIF2B5
EIF2B4	1	EIF2B5
ANKLE2	0	—
GTF3C2-AS2	0	—
ARHGEF6	6	—

Clinical trials & evidence

Clinical trials

Clinical trials: 7.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	5
PHASE1/PHASE2	1
EARLY_PHASE1	1

Top trials by phase / activity

NCT	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
NCT03047369	Not specified	RECRUITING	The Myelin Disorders Biorepository Project
NCT03333200	Not specified	RECRUITING	Longitudinal Study of Neurodegenerative Disorders
NCT07300397	Not specified	ACTIVE_NOT_RECRUITING	Single Patient Investigational Treatment for Cree Leukoencephalopathy
NCT02699190	Not specified	COMPLETED	LeukoSEQ: Whole Genome Sequencing as a First-Line Diagnostic Tool for Leukodystrophies
NCT06594016	Not specified	NO_LONGER_AVAILABLE	Expanded Access to Fosigotifator

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
FOSIGOTIFATOR	2	4