Optic nerve glioma

Summary

Optic nerve glioma (MONDO:0003235) is a cancer with 2 cohort genes (136 GWAS associations across 2 studies; 1 CIViC-evidence somatic driver; 6 ClinVar predisposition records) and 6 clinical trials. Top therapeutic interventions include selumetinib, mebendazole, and temozolomide.

At a glance

• Classification: Cancer
• Cohort genes: 2
• GWAS associations: 136
• ClinVar variants: 6
• Clinical trials: 6

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	optic nerve glioma
Mondo ID	MONDO:0003235
EFO	EFO:0009254
MeSH	D020339
DOID	DOID:4992
NCIT	C4537
SNOMED CT	254976006
UMLS	C0346326
MedGen	138056
GARD	0023417
Anatomy (UBERON)	UBERON:0000941
Is cancer (heuristic)	yes

Also known as: cranial nerve II glioma · glioma of cranial nerve II · glioma of optic nerve · glioma of the optic nerve · optic nerve glioma

Data availability: 6 ClinVar variants · 136 GWAS associations (2 studies).

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › optic nerve disorder › optic nerve neoplasm › optic nerve glioma

Related subtypes (2): optic nerve sheath meningioma, bilateral meningioma of optic nerve

Subtypes (2): optic nerve astrocytoma, childhood optic nerve glioma

Genetics & variants

GWAS landscape

136 GWAS associations across 2 studies. Top hits map to 34 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs534382666	3e-09	MAPRE1P2 - RPL31P31	?	8.29
rs190927527	2e-08	LINC02473 - HNRNPA1P65	?	6.05
rs573687	5e-08	CDKN2B-AS1	?	1.3
rs73092544	9e-08	SRSF8CP - TNS3	?	1.95
rs553177297	2e-07	MAPRE1P2 - RPL31P31	?	8.7
rs2811713	2e-07	CDKN2B-AS1	?	1.33
rs112499531	3e-07	SESN1	?	2.36
rs145205847	3e-07	TMEM232	?	3.2
rs549570772	4e-07	OPCML	?	6.34
rs112339499	4e-07	SNAP23	?	1.57
rs140509912	4e-07	LMO7-AS1, LMO7	?	3.13
rs146815729	4e-07	WWOX	?	6.76
rs35324202	4e-07	RPS17P11 - MFSD4BP1	?	1.6
rs188964335	5e-07	KLF3-AS1	?	6.49
rs61070491	5e-07	Y_RNA - CARS1P2	?	2.87
rs3742828	6e-07	ZFYVE1	?	1.28
rs61903468	6e-07	NTM	?	2.73
rs116896998	7e-07	COPB2	?	1.55
rs75229881	8e-07	AGBL1	?	3.11
rs79082403	8e-07	Y_RNA - CARS1P2	?	2.66
rs140530603	8e-07	TRAF3IP1 - RNU6-234P	?	5.6
rs80216717	9e-07	MANEA	?	1.77
rs72746794	1e-06	RPS17P11 - MFSD4BP1	?	1.47
rs72856830	1e-06	CACNB4	?	1.63
rs10066758	1e-06	LINC02208	?	1.27
rs149510476	1e-06	TBC1D4 - COMMD6	?	3.08
rs187871189	1e-06	RBMX2P4 - ETV1	?	7.3
rs355217	1e-06	LRRC4C	?	0.8
rs6056275	1e-06	RSPO4	?	1.41
rs75823431	1e-06	LINC02879 - MIR302F	?	2.54

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90296470	Foss-Skiftesvik J	2023	936	7,183	Multi-ancestry genome-wide association study of 4,069 children with glioma identifies 9p21.3 risk locus.
GCST90296480	Foss-Skiftesvik J	2023	936	7,183	Multi-ancestry genome-wide association study of 4,069 children with glioma identifies 9p21.3 risk locus.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	0
Tier 2: splice/UTR	3
Tier 3: regulatory	0
Tier 4: intronic/intergenic	47

MAF distribution

Bucket	Variants
common (>=0.05)	31
low_freq (0.01-0.05)	0
rare (<0.01)	0
unknown	19

Functional consequences

Consequence	Count
intron_variant	36
intergenic_variant	11
3_prime_UTR_variant	2
5_prime_UTR_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs534382666	4	33735687	G>A,T		intergenic_variant	MAPRE1P2 - RPL31P31	3e-09	Tier 4: intronic/intergenic
rs190927527	4	24765988	T>C		intergenic_variant	LINC02473 - HNRNPA1P65	2e-08	Tier 4: intronic/intergenic
rs573687	9	22011643	G>A	0.05	intron_variant	CDKN2B-AS1	5e-08	Tier 4: intronic/intergenic
rs73092544	7	47058600	A>G	0.05	intron_variant	SRSF8CP - TNS3	9e-08	Tier 4: intronic/intergenic
rs553177297	4	33584822	T>G		intron_variant	MAPRE1P2 - RPL31P31	2e-07	Tier 4: intronic/intergenic
rs2811713	9	21999329	G>A,T	0.05	intron_variant	CDKN2B-AS1	2e-07	Tier 4: intronic/intergenic
rs112499531	6	108984907	A>G	0.05	3_prime_UTR_variant	SESN1	3e-07	Tier 2: splice/UTR
rs145205847	5	110712395	A>G		intron_variant	TMEM232	3e-07	Tier 4: intronic/intergenic
rs549570772	11	132713485	C>T		intron_variant	OPCML	4e-07	Tier 4: intronic/intergenic
rs112339499	15	42493350	C>A	0.05	intergenic_variant	SNAP23	4e-07	Tier 4: intronic/intergenic
rs140509912	13	75632535	A>G		intron_variant	LMO7-AS1, LMO7	4e-07	Tier 4: intronic/intergenic
rs146815729	16	78537671	G>A		intron_variant	WWOX	4e-07	Tier 4: intronic/intergenic
rs35324202	5	52471140	C>T	0.05	intergenic_variant	RPS17P11 - MFSD4BP1	4e-07	Tier 4: intronic/intergenic
rs188964335	4	38632512	C>T		intron_variant	KLF3-AS1	5e-07	Tier 4: intronic/intergenic
rs61070491	8	114490512	G>A	0.05	intron_variant	Y_RNA - CARS1P2	5e-07	Tier 4: intronic/intergenic
rs3742828	14	73024599	C>A,G,T	0.05	5_prime_UTR_variant	ZFYVE1	6e-07	Tier 2: splice/UTR
rs61903468	11	131990671	A>G	0.05	intron_variant	NTM	6e-07	Tier 4: intronic/intergenic
rs116896998	3	139376755	T>A,C	0.05	intron_variant	COPB2	7e-07	Tier 4: intronic/intergenic
rs75229881	15	86759406	G>A,T		intron_variant	AGBL1	8e-07	Tier 4: intronic/intergenic
rs79082403	8	114365676	C>G	0.05	intron_variant	Y_RNA - CARS1P2	8e-07	Tier 4: intronic/intergenic
rs140530603	2	238406045	G>A		intergenic_variant	TRAF3IP1 - RNU6-234P	8e-07	Tier 4: intronic/intergenic
rs80216717	6	95606825	G>A	0.05	3_prime_UTR_variant	MANEA	9e-07	Tier 2: splice/UTR
rs72746794	5	52519662	C>A,T	0.05	intergenic_variant	RPS17P11 - MFSD4BP1	1e-06	Tier 4: intronic/intergenic
rs72856830	2	152037455	G>A	0.05	intron_variant	CACNB4	1e-06	Tier 4: intronic/intergenic
rs10066758	5	118467354	C>G,T	0.05	intron_variant	LINC02208	1e-06	Tier 4: intronic/intergenic
rs149510476	13	75511797	G>A,C		intron_variant	TBC1D4 - COMMD6	1e-06	Tier 4: intronic/intergenic
rs187871189	7	13031109	G>A,C		intron_variant	RBMX2P4 - ETV1	1e-06	Tier 4: intronic/intergenic
rs355217	11	41048130	A>G,T	0.05	intron_variant	LRRC4C	1e-06	Tier 4: intronic/intergenic
rs6056275	20	965666	C>G	0.05	intron_variant	RSPO4	1e-06	Tier 4: intronic/intergenic
rs75823431	18	29924018	T>A,C	0.05	intergenic_variant	LINC02879 - MIR302F	1e-06	Tier 4: intronic/intergenic

ClinVar germline variants

6 retrieved; paginated sample, class counts are floors:

4 pathogenic, 1 uncertain significance, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
188280	NM_001042492.3(NF1):c.2041C>T (p.Arg681Ter)	NF1	Pathogenic	criteria provided, multiple submitters, no conflicts
336	NM_001042492.3(NF1):c.4330A>G (p.Lys1444Glu)	NF1	Pathogenic	criteria provided, multiple submitters, no conflicts
374108	NM_001042492.3(NF1):c.1721+3A>G	NF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
439997	NM_001042492.3(NF1):c.4577+1G>A	NF1	Pathogenic	criteria provided, multiple submitters, no conflicts
590843	NM_001042492.3(NF1):c.2351_2352delinsC (p.Trp784fs)	NF1	Pathogenic	criteria provided, single submitter
1077147	NM_021926.4(ALX4):c.2T>C (p.Met1Thr)	ALX4	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 13 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Somatic driver evidence (intOGen + CIViC, cohort fanout)

Gene	intOGen role	Cancer types	CIViC
NF1	LoF	ACC,ALL,AML,ANGS,BLCA,BRCA,CCRCC,CHOL,CLLSLL,COADREAD,GB,GBM,GIST,HCC,HNSC,LGGNOS,LMS,LUAD,LUNG,LUSC,MEL,NBL,NSCLC,OVT,PAST,PGNG,PLMESO,RMS,SKCM,SOFT_TISSUE,STAD,THYM,UCS	CIViC #3867

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ALX4	Orphanet:228390	Frontonasal dysplasia-alopecia-genital anomalies syndrome
ALX4	Orphanet:35093	Non-syndromic sagittal craniosynostosis
ALX4	Orphanet:52022	Potocki-Shaffer syndrome
ALX4	Orphanet:60015	Enlarged parietal foramina
NF1	Orphanet:139474	17q11.2 microduplication syndrome
NF1	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
NF1	Orphanet:293199	Pleomorphic rhabdomyosarcoma
NF1	Orphanet:363700	Neurofibromatosis type 1 due to NF1 mutation or intragenic deletion
NF1	Orphanet:638	Neurofibromatosis-Noonan syndrome
NF1	Orphanet:86834	Juvenile myelomonocytic leukemia
NF1	Orphanet:97685	17q11 microdeletion syndrome
NF1	Orphanet:99756	Alveolar rhabdomyosarcoma
NF1	Orphanet:99757	Embryonal rhabdomyosarcoma

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ALX4	HGNC:450	ENSG00000052850	Q9H161	Homeobox protein aristaless-like 4	clinvar
NF1	HGNC:7765	ENSG00000196712	P21359	Neurofibromin	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ALX4	Homeobox protein aristaless-like 4	Transcription factor involved in skull and limb development.
NF1	Neurofibromin	Stimulates the GTPase activity of Ras.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 1 · 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
Transcription factor	1	4.1×	0.455
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ALX4	Transcription factor	no		HD, OAR_dom, Homeodomain-like_sf
NF1	Other/Unknown	no		CRAL-TRIO_dom, RasGAP_dom, Rho_GTPase_activation_prot

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
buccal mucosa cell	1
cranial nerve II	1
primordial germ cell in gonad	1
adrenal tissue	1
calcaneal tendon	1
colonic epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ALX4	82	broad	yes	primordial germ cell in gonad, buccal mucosa cell, cranial nerve II
NF1	283	ubiquitous	marker	colonic epithelium, calcaneal tendon, adrenal tissue

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NF1	5,540
ALX4	1,162

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NF1	P21359	26
ALX4	Q9H161	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. Enrichment computed across 2 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
RAS signaling downstream of NF1 loss-of-function variants	1	1631.4×	0.006	NF1
Oncogenic MAPK signaling	1	248.3×	0.015	NF1
Regulation of RAS by GAPs	1	193.6×	0.015	NF1
MAPK1/MAPK3 signaling	1	131.3×	0.017	NF1
MAPK family signaling cascades	1	102.9×	0.017	NF1
RAF/MAP kinase cascade	1	61.1×	0.023	NF1
Diseases of signal transduction by growth factor receptors and second messengers	1	56.8×	0.023	NF1
Disease	1	13.1×	0.086	NF1
Signal Transduction	1	10.2×	0.098	NF1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of mast cell apoptotic process	1	8426.0×	0.004	NF1
regulation of glial cell differentiation	1	8426.0×	0.004	NF1
observational learning	1	8426.0×	0.004	NF1
gamma-aminobutyric acid secretion, neurotransmission	1	4213.0×	0.004	NF1
Schwann cell proliferation	1	2808.7×	0.004	NF1
forebrain astrocyte development	1	2808.7×	0.004	NF1
Schwann cell migration	1	2808.7×	0.004	NF1
glutamate secretion, neurotransmission	1	2808.7×	0.004	NF1
negative regulation of mast cell proliferation	1	2808.7×	0.004	NF1
negative regulation of Schwann cell migration	1	2808.7×	0.004	NF1
vascular associated smooth muscle cell migration	1	2808.7×	0.004	NF1
mast cell apoptotic process	1	2106.5×	0.004	NF1
negative regulation of Rac protein signal transduction	1	2106.5×	0.004	NF1
myeloid leukocyte migration	1	2106.5×	0.004	NF1
mast cell proliferation	1	1685.2×	0.004	NF1
amygdala development	1	1404.3×	0.004	NF1
regulation of blood vessel endothelial cell migration	1	1404.3×	0.004	NF1
vascular associated smooth muscle cell proliferation	1	1404.3×	0.004	NF1
negative regulation of Schwann cell proliferation	1	1203.7×	0.005	NF1
negative regulation of neurotransmitter secretion	1	1203.7×	0.005	NF1
hair follicle maturation	1	1053.2×	0.005	NF1
negative regulation of leukocyte migration	1	842.6×	0.005	NF1
negative regulation of vascular associated smooth muscle cell migration	1	842.6×	0.005	NF1
regulation of bone resorption	1	766.0×	0.005	NF1
negative regulation of astrocyte differentiation	1	766.0×	0.005	NF1
regulation of long-term synaptic potentiation	1	766.0×	0.005	NF1
positive regulation of extrinsic apoptotic signaling pathway in absence of ligand	1	766.0×	0.005	NF1
forebrain morphogenesis	1	702.2×	0.006	NF1
regulation of cell-matrix adhesion	1	648.1×	0.006	NF1
negative regulation of neuroblast proliferation	1	601.9×	0.006	NF1

Therapeutics

Drugs indicated or in trials for this disease

1 approved drug — disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Status
Temozolomide	Approved (phase 3)

2 drugs in clinical trials for this disease (phase 2–3, investigational): efficacy not established — a trial record, not an indication.

Drug	Highest phase
Doxorubicin	Phase 2
Etoposide	Phase 2

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ALX4	0	0
NF1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Drug repurposing candidates

0 approved/phased drugs hit cohort targets but don’t yet appear in disease-level clinical trials. Target-inhibition rationale is strongest for cancer driver genes; a bioactivity hit is a screening signal, not a treatment claim.

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	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	ALX4, NF1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ALX4	0	—
NF1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 6.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE1/PHASE2	2
PHASE3	1
PHASE2	1
EARLY_PHASE1	1
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01260103	PHASE3	WITHDRAWN	Phase 3 Study of ANP Therapy vs. TMZ for Optic Pathway Glioma
NCT01837862	PHASE1/PHASE2	COMPLETED	A Phase I Study of Mebendazole for the Treatment of Pediatric Gliomas
NCT02839720	PHASE2	COMPLETED	Selumetinib in Treating Patients With Neurofibromatosis Type 1 and Cutaneous Neurofibroma
NCT03326388	PHASE1/PHASE2	COMPLETED	Intermittent Dosing Of Selumetinib In Childhood NF1 Associated Tumours
NCT02976441	EARLY_PHASE1	WITHDRAWN	Autologous Stem Cell Collection and Reinfusion in Newly Diagnosed High Grade Gliomas
NCT04648462	Not specified	RECRUITING	Proton Therapy Research Infrastructure- ProTRAIT- Neuro-oncology

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
SELUMETINIB	4	3
MEBENDAZOLE	4	1
TEMOZOLOMIDE	4	1
CHEMBL4228794	0	3
CHEMBL4248195	0	1
CHEMBL4463209	0	1