Neurocutaneous melanocytosis

Summary

Neurocutaneous melanocytosis (MONDO:0009578) is a disease with 1 cohort gene and 1 clinical trial.

At a glance

• Prevalence: 1-9 / 100 000 (Europe) [Orphanet-validated]
• Cohort genes: 1
• ClinVar variants: 3
• Phenotypes (HPO): 46
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	1.25	Europe	Validated

Signs & symptoms

Clinical features (HPO)

46 HPO clinical features (Orphanet curated; top 46 by frequency):

HPO ID	Term	Frequency
HP:0000995	Melanocytic nevus	Very frequent (80-99%)
HP:0001072	Thickened skin	Very frequent (80-99%)
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001250	Seizure	Very frequent (80-99%)
HP:0002230	Generalized hirsutism	Very frequent (80-99%)
HP:0002516	Increased intracranial pressure	Very frequent (80-99%)
HP:0002922	Increased CSF protein concentration	Very frequent (80-99%)
HP:0005603	Numerous congenital melanocytic nevi	Very frequent (80-99%)
HP:0007440	Generalized hyperpigmentation	Very frequent (80-99%)
HP:0000238	Hydrocephalus	Frequent (30-79%)
HP:0001085	Papilledema	Frequent (30-79%)
HP:0002353	EEG abnormality	Occasional (5-29%)
HP:0002381	Aphasia	Occasional (5-29%)
HP:0002383	Infectious encephalitis	Occasional (5-29%)
HP:0002435	Meningocele	Occasional (5-29%)
HP:0002664	Neoplasm	Occasional (5-29%)
HP:0002861	Melanoma	Occasional (5-29%)
HP:0003396	Syringomyelia	Occasional (5-29%)
HP:0004936	Venous thrombosis	Occasional (5-29%)
HP:0006824	Cranial nerve paralysis	Occasional (5-29%)
HP:0006979	Sleep-wake cycle disturbance	Occasional (5-29%)
HP:0007360	Aplasia/Hypoplasia of the cerebellum	Occasional (5-29%)
HP:0007703	Abnormality of retinal pigmentation	Occasional (5-29%)
HP:0008678	Renal hypoplasia/aplasia	Occasional (5-29%)
HP:0011972	Hypoglycorrhachia	Occasional (5-29%)
HP:0012470	Setting-sun eye phenomenon	Occasional (5-29%)
HP:0000009	Functional abnormality of the bladder	Occasional (5-29%)
HP:0000505	Visual impairment	Occasional (5-29%)
HP:0000567	Chorioretinal coloboma	Occasional (5-29%)
HP:0000603	Central scotoma	Occasional (5-29%)
HP:0000648	Optic atrophy	Occasional (5-29%)
HP:0000708	Atypical behavior	Occasional (5-29%)
HP:0000709	Psychosis	Occasional (5-29%)
HP:0000737	Irritability	Occasional (5-29%)
HP:0001268	Mental deterioration	Occasional (5-29%)
HP:0001269	Hemiparesis	Occasional (5-29%)
HP:0001305	Dandy-Walker malformation	Occasional (5-29%)
HP:0001522	Death in infancy	Occasional (5-29%)
HP:0002015	Dysphagia	Occasional (5-29%)
HP:0002119	Ventriculomegaly	Occasional (5-29%)
HP:0002170	Intracranial hemorrhage	Occasional (5-29%)
HP:0002176	Spinal cord compression	Occasional (5-29%)
HP:0002269	Abnormality of neuronal migration	Occasional (5-29%)
HP:0002308	Chiari malformation	Occasional (5-29%)
HP:0002315	Headache	Occasional (5-29%)
HP:0000989	Pruritus	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	neurocutaneous melanocytosis
Mondo ID	MONDO:0009578
MeSH	C537387
OMIM	249400
Orphanet	2481
ICD-11	403221860
NCIT	C175215
UMLS	C0544862
MedGen	154259
GARD	0007186
Is cancer (heuristic)	no

Also known as: melanosis, neurocutaneous · NCM · NCMS · neurocutaneous melanosis · neurocutaneous melanosis syndrome · neurocutaneous melanosis, somatic

Data availability: 3 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › cancer or benign tumor › neoplastic disease or syndrome › neoplasm › benign neoplasm › nervous system benign neoplasm › neurocutaneous melanocytosis

Related subtypes (4): central nervous system organ benign neoplasm, sensory organ benign neoplasm, hemangioblastoma, phakomatosis pigmentokeratotica

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

3 retrieved; paginated sample, class counts are floors:

1 pathogenic, 1 uncertain significance, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
13900	NM_002524.5(NRAS):c.182A>G (p.Gln61Arg)	NRAS	Pathogenic	criteria provided, multiple submitters, no conflicts
73058	NM_002524.5(NRAS):c.181C>A (p.Gln61Lys)	NRAS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
477662	NM_002524.5(NRAS):c.25G>A (p.Val9Ile)	NRAS	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 7 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NRAS	Orphanet:146	Differentiated thyroid carcinoma
NRAS	Orphanet:2612	Linear nevus sebaceus syndrome
NRAS	Orphanet:268114	RAS-associated autoimmune leukoproliferative disease
NRAS	Orphanet:389	Langerhans cell histiocytosis
NRAS	Orphanet:626	Large/giant congenital melanocytic nevus
NRAS	Orphanet:648	Noonan syndrome
NRAS	Orphanet:86834	Juvenile myelomonocytic leukemia

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
NRAS	HGNC:7989	ENSG00000213281	P01111	GTPase NRas	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NRAS	GTPase NRas	Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.

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)
NRAS	Other/Unknown	no		Small_GTPase, Small_GTP-bd, Small_GTPase_Ras-type

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
epithelium of nasopharynx	1
gingival epithelium	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NRAS	278	ubiquitous	marker	gingival epithelium, epithelium of nasopharynx, secondary oocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NRAS	7,598

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NRAS	P01111	35

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 68. 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
Signaling by RAS GAP mutants	1	3806.7×	0.003	NRAS
Signaling by RAS GTPase mutants	1	3806.7×	0.003	NRAS
Activation of RAS in B cells	1	2284.0×	0.003	NRAS
RAS signaling downstream of NF1 loss-of-function variants	1	1631.4×	0.003	NRAS
Estrogen-stimulated signaling through PRKCZ	1	1631.4×	0.003	NRAS
SOS-mediated signalling	1	1427.5×	0.003	NRAS
Activated NTRK3 signals through RAS	1	1268.9×	0.003	NRAS
EGFR Transactivation by Gastrin	1	1142.0×	0.003	NRAS
SHC-related events triggered by IGF1R	1	1142.0×	0.003	NRAS
Activated NTRK2 signals through RAS	1	1142.0×	0.003	NRAS
MET activates RAS signaling	1	1038.2×	0.003	NRAS
Signaling by FGFR4 in disease	1	951.7×	0.003	NRAS
Activated NTRK2 signals through FRS2 and FRS3	1	951.7×	0.003	NRAS
Constitutive Signaling by Overexpressed ERBB2	1	951.7×	0.003	NRAS
p38MAPK events	1	878.5×	0.003	NRAS
Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants	1	878.5×	0.003	NRAS
Signaling by PDGFRA extracellular domain mutants	1	878.5×	0.003	NRAS
PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases	1	815.7×	0.003	NRAS
GRB2 events in EGFR signaling	1	761.3×	0.003	NRAS
Erythropoietin activates RAS	1	761.3×	0.003	NRAS
Signaling by FLT3 ITD and TKD mutants	1	761.3×	0.003	NRAS
SHC1 events in ERBB4 signaling	1	713.8×	0.003	NRAS
SHC1 events in EGFR signaling	1	713.8×	0.003	NRAS
Constitutive Signaling by EGFRvIII	1	713.8×	0.003	NRAS
Signalling to RAS	1	671.8×	0.003	NRAS
Insulin receptor signalling cascade	1	671.8×	0.003	NRAS
Signaling by ERBB2 ECD mutants	1	671.8×	0.003	NRAS
GRB2 events in ERBB2 signaling	1	634.4×	0.003	NRAS
Tie2 Signaling	1	601.0×	0.003	NRAS
SHC-mediated cascade:FGFR3	1	601.0×	0.003	NRAS

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 endothelial cell proliferation	1	230.8×	0.007	NRAS
Ras protein signal transduction	1	205.5×	0.007	NRAS
MAPK cascade	1	153.2×	0.007	NRAS

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NRAS	1	1

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
L-778123 FREE BASE	1	NRAS

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
NRAS	18	Binding:18

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

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)
L-778123 FREE BASE	1	NRAS

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

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04548817	Not specified	RECRUITING	Neurocutaneous Melanocytosis Registry