Plexiform neurofibroma

Summary

Plexiform neurofibroma (MONDO:0003304) is a disease with 1 cohort gene and 31 clinical trials. Molecularly, NF1 Mutation confers sensitivity to Selumetinib in Plexiform Neurofibroma (CIViC Level A). Top therapeutic interventions include selumetinib, binimetinib, and cabozantinib.

At a glance

• Cohort genes: 1
• ClinVar variants: 1
• Clinical trials: 31
• Precision-medicine evidence (CIViC): 1 subtype–drug association

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	plexiform neurofibroma
Mondo ID	MONDO:0003304
MeSH	D018318
DOID	DOID:5151
NCIT	C3797
SNOMED CT	403818001
UMLS	C0206728
MedGen	64640
GARD	0023439
Is cancer (heuristic)	no

Also known as: plexiform neurofibroma · plexiform neurofibroma (disease)

Data availability: 1 ClinVar variant · 1 HPO phenotype.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › peripheral nervous system disorder › peripheral nervous system neoplasm › nerve sheath neoplasm › neurofibroma › plexiform neurofibroma

Related subtypes (10): mediastinum neurofibroma, neurofibroma of spinal cord, Pacinian tumor, neurofibrosarcoma, epithelioid neurofibroma, neurofibroma of gallbladder, cellular neurofibroma, atypical neurofibroma, neurofibroma of the heart, neurofibroma of the esophagus

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

1 retrieved; paginated sample, class counts are floors:

1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
374204	NM_001042492.3(NF1):c.5813-1G>A	NF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 9 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NF1	HGNC:7765	ENSG00000196712	P21359	Neurofibromin	clinvar,civic_evidence

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NF1	Neurofibromin	Stimulates the GTPase activity of Ras.

Protein-family classification

Druggable: 0 · Difficult: 0 · 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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adrenal tissue	1
calcaneal tendon	1
colonic epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
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

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NF1	P21359	26

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. Enrichment computed across 1 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 1 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	16852.0×	0.002	NF1
regulation of glial cell differentiation	1	16852.0×	0.002	NF1
observational learning	1	16852.0×	0.002	NF1
gamma-aminobutyric acid secretion, neurotransmission	1	8426.0×	0.002	NF1
Schwann cell proliferation	1	5617.3×	0.002	NF1
forebrain astrocyte development	1	5617.3×	0.002	NF1
Schwann cell migration	1	5617.3×	0.002	NF1
glutamate secretion, neurotransmission	1	5617.3×	0.002	NF1
negative regulation of mast cell proliferation	1	5617.3×	0.002	NF1
negative regulation of Schwann cell migration	1	5617.3×	0.002	NF1
vascular associated smooth muscle cell migration	1	5617.3×	0.002	NF1
mast cell apoptotic process	1	4213.0×	0.002	NF1
negative regulation of Rac protein signal transduction	1	4213.0×	0.002	NF1
myeloid leukocyte migration	1	4213.0×	0.002	NF1
mast cell proliferation	1	3370.4×	0.002	NF1
amygdala development	1	2808.7×	0.002	NF1
regulation of blood vessel endothelial cell migration	1	2808.7×	0.002	NF1
vascular associated smooth muscle cell proliferation	1	2808.7×	0.002	NF1
negative regulation of Schwann cell proliferation	1	2407.4×	0.002	NF1
negative regulation of neurotransmitter secretion	1	2407.4×	0.002	NF1
hair follicle maturation	1	2106.5×	0.002	NF1
negative regulation of leukocyte migration	1	1685.2×	0.002	NF1
negative regulation of vascular associated smooth muscle cell migration	1	1685.2×	0.002	NF1
regulation of bone resorption	1	1532.0×	0.002	NF1
negative regulation of astrocyte differentiation	1	1532.0×	0.002	NF1
regulation of long-term synaptic potentiation	1	1532.0×	0.002	NF1
positive regulation of extrinsic apoptotic signaling pathway in absence of ligand	1	1532.0×	0.002	NF1
forebrain morphogenesis	1	1404.3×	0.002	NF1
regulation of cell-matrix adhesion	1	1296.3×	0.003	NF1
negative regulation of neuroblast proliferation	1	1203.7×	0.003	NF1

Therapeutics

Drugs indicated for this disease

No approved or late-stage (phase ≥3) drug is indicated for this disease; the following are in earlier-phase trials only.

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): PEGINTERFERON ALFA-2B, Selumetinib.

Drug target analysis

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

Druggability breadth: 0 of 1 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
NF1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

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	1	NF1

Undrugged target profiles

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

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

Clinical trials & evidence

Clinical trials

Clinical trials: 31.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	12
Not specified	9
PHASE3	4
PHASE1/PHASE2	3
PHASE1	3

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04924608	PHASE3	ACTIVE_NOT_RECRUITING	Efficacy and Safety of Selumetinib in Adults With NF1 Who Have Symptomatic, Inoperable Plexiform Neurofibromas
NCT05913037	PHASE3	ACTIVE_NOT_RECRUITING	FCN-159 in Adult Patients With Symptomatic, Inoperable Neurofibromatosis Type 1-Related Plexiform Neurofibromas
NCT07407803	PHASE3	RECRUITING	Evaluation of TQ-B3234 Capsules in Patients With Symptomatic, Non-Surgical Type 1 Neurofibromatosis-Associated Plexiform Neurofibromas
NCT02471339	PHASE3	COMPLETED	Acceptance and Commitment Training for Adolescents and Young Adults With Neurofibromatosis Type 1, Plexiform Neurofibromas, and Chronic Pain
NCT03363217	PHASE2	ACTIVE_NOT_RECRUITING	Trametinib for Pediatric Neuro-oncology Patients With Refractory Tumor and Activation of the MAPK/ERK Pathway.
NCT03962543	PHASE2	ACTIVE_NOT_RECRUITING	MEK Inhibitor Mirdametinib (PD-0325901) in Patients With Neurofibromatosis Type 1 Associated Plexiform Neurofibromas
NCT04954001	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Study to Evaluate the Safety, Tolerability, PK Characteristics and Anti-tumor Activity of FCN-159 in Adult and Pediatric Participants With Neurofibromatosis Type 1
NCT05331105	PHASE2	RECRUITING	HL-085 in Adults With Neurofibromatosis Type 1 (NF1) and Inoperable Plexiform Neurofibromas
NCT06188741	PHASE2	RECRUITING	Selumetinib for the Prevention of Plexiform Neurofibroma Growth in NF Type 1
NCT07024394	PHASE1/PHASE2	NOT_YET_RECRUITING	Follow-up Study to Evaluate the Safety and Efficacy of FCN-159 in Pediatric Participants With Neurofibromatosis Type 1
NCT00326872	PHASE2	TERMINATED	AZD2171 in Treating Patients With Neurofibromatosis Type 1 and Plexiform Neurofibroma and/or Neurofibroma Near the Spine
NCT00396019	PHASE2	COMPLETED	Study of PEG-Intron for Plexiform Neurofibromas
NCT01402817	PHASE2	TERMINATED	Study of Sutent®/Sunitinib (SU11248) in Subjects With NF-1 Plexiform Neurofibromas
NCT01412892	PHASE2	COMPLETED	Use of RAD001 as Monotherapy in the Treatment of Neurofibromatosis 1 Related Internal Plexiform Neurofibromas
NCT02101736	PHASE2	COMPLETED	Cabozantinib for Plexiform Neurofibromas (PN) in Subjects With NF1 in Children and Adults
NCT02177825	PHASE2	TERMINATED	Study of Imatinib Mesylate in Neurofibromatosis Type I Patients Aged 2 to 21 With Plexiform Neurofibromas
NCT03231306	PHASE2	COMPLETED	Phase II Study of Binimetinib in Children and Adults With NF1 Plexiform Neurofibromas
NCT03326388	PHASE1/PHASE2	COMPLETED	Intermittent Dosing Of Selumetinib In Childhood NF1 Associated Tumours
NCT05825365	PHASE2	WITHDRAWN	Selumetinib in Chinese Paediatric With Post-operative NF1-PNs, PhaseⅡ, Double-Blinded, Placebo-Controlled Study
NCT06104488	PHASE1	RECRUITING	A Study of Avutometinib for People With Solid Tumor Cancers
NCT06502171	PHASE1	NOT_YET_RECRUITING	Study of Cabozantinib With Selumetinib for Plexiform Neurofibromas
NCT00727233	PHASE1	COMPLETED	Sorafenib to Treat Children and Young Adults With Neurofibromatosis Type 1 and Inoperable Plexiform Neurofibromas
NCT00924196	Not specified	ACTIVE_NOT_RECRUITING	Natural History Study of Patients With Neurofibromatosis Type I
NCT02544022	Not specified	RECRUITING	Development and Validation of Patient Reported Outcome (PRO) Measures for Individuals With Neurofibromatosis 1 (NF1) and Plexiform Neurofibromas (pNFs)
NCT03820778	Not specified	ACTIVE_NOT_RECRUITING	Whole Body MRI to Identify Atypical Neurofibromas in Patients With NF1
NCT06515860	Not specified	RECRUITING	Neurofibromatosis Type 1 Tumor Early Detection Study
NCT00006435	Not specified	COMPLETED	Study of Plexiform Neurofibromas in Neurofibromatosis Type 1
NCT01800032	Not specified	COMPLETED	PET/MRI in CNS and Extra-CNS Tumors of Patients With Neurofibromatosis-1 (NF1)
NCT02777775	Not specified	COMPLETED	Targeting the Mechanisms Underlying Cutaneous Neurofibroma Formation in NF1: A Clinical Translational Approach.
NCT05683678	Not specified	TERMINATED	US Selumetinib Registry
NCT06379230	Not specified	UNKNOWN	A Retrospective Study on Epidemiological Characteristics of Chinese NF1 Patients in Real World (PROMISE)

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
SELUMETINIB	4	5
BINIMETINIB	4	1
CABOZANTINIB	4	1
PEGINTERFERON ALFA-2B	4	1
TRAMETINIB	4	1
AVUTOMETINIB	3	1
CEDIRANIB MALEATE	3	1
TUNLAMETINIB	3	1
LUVOMETINIB	2	2
MIRDAMETINIB	2	1
CHEMBL4463209	0	5
CHEMBL4215501	0	1
CHEMBL4849721	0	1
CHEMBL5433950	0	1
EXELIXIS	0	1

Precision-medicine subtype map (CIViC)

Drug × molecular subtype: 1 predictive associations from 3 curated evidence items.

Molecular subtype	Therapy	Effect	Level	CIViC
NF1 Mutation	Selumetinib	Sensitivity/Response	CIViC A	EID11176 +2