Cafe au lait spots, multiple

Summary

Cafe au lait spots, multiple (MONDO:0007245) is a disease with 3 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide)
• Cohort genes: 3
• ClinVar variants: 25
• Phenotypes (HPO): 2

Clinical features

Signs & symptoms

Clinical features (HPO)

2 HPO clinical features (Orphanet curated; top 2 by frequency):

HPO ID	Term	Frequency
HP:0007565	Multiple cafe-au-lait spots	Very frequent (80-99%)
HP:0001480	Freckling	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	cafe au lait spots, multiple
Mondo ID	MONDO:0007245
MeSH	C537421
OMIM	114030
Orphanet	2678
UMLS	C1861975
MedGen	396266
GARD	0003967
Is cancer (heuristic)	no

Also known as: autosomal dominant café au lait spots · cafe-au-lait spots, multiple · familial cafe-au-lait spots · familial café-au-lait spots · multiple cafe-au-lait spots · multiple cafe-au-lait syndrome · multiple café-au-lait spots · multiple café-au-lait syndrome · neurofibromatosis type 6 · NF6

Data availability: 25 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by body system or component › integumentary system disorder › skin disorder › skin pigmentation disorder › hyperpigmentation of the skin › cafe au lait spots, multiple

Related subtypes (23): dyschromatosis universalis hereditaria, dermatopathia pigmentosa reticularis, dyschromatosis symmetrica hereditaria, extrasystoles-short stature-hyperpigmentation-microcephaly syndrome, gastrocutaneous syndrome, hyperkeratosis-hyperpigmentation syndrome, familial generalized lentiginosis, Naegeli-Franceschetti-Jadassohn syndrome, schwannomatosis, Dowling-Degos disease, H syndrome, Legius syndrome, familial progressive hyperpigmentation, linear and whorled nevoid hypermelanosis, reticulate acropigmentation of Kitamura, nail and teeth abnormalities-marginal palmoplantar keratoderma-oral hyperpigmentation syndrome, severe growth deficiency-strabismus-extensive dermal melanocytosis-intellectual disability syndrome, leukonychia totalis-acanthosis-nigricans-like lesions-abnormal hair syndrome, osteopathia striata-pigmentary dermopathy-white forelock syndrome, phakomatosis pigmentovascularis, acromelanosis, hyperpigmentation, progressive cribriform and zosteriform, mosaic Legius syndrome

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

25 retrieved; paginated sample, class counts are floors:

11 pathogenic, 6 uncertain significance, 6 pathogenic/likely pathogenic, 1 conflicting classifications of pathogenicity, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1321312	NM_001042492.3(NF1):c.4183_4186del (p.Gln1395fs)	NF1	Pathogenic	criteria provided, single submitter
220152	NM_001042492.3(NF1):c.4600C>T (p.Arg1534Ter)	NF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
280055	NM_001042492.3(NF1):c.2446C>T (p.Arg816Ter)	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
373947	NM_001042492.3(NF1):c.2410-1G>A	NF1	Pathogenic	criteria provided, multiple submitters, no conflicts
373973	NM_001042492.3(NF1):c.6904C>T (p.Gln2302Ter)	NF1	Pathogenic	criteria provided, multiple submitters, no conflicts
374022	NM_001042492.3(NF1):c.2252-3T>G	NF1	Pathogenic/Likely 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
40093	NM_001042492.3(NF1):c.574C>T (p.Arg192Ter)	NF1	Pathogenic	criteria provided, multiple submitters, no conflicts
431976	NM_001042492.3(NF1):c.1721G>A (p.Ser574Asn)	NF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
489188	NM_001042492.3(NF1):c.6225G>A (p.Trp2075Ter)	NF1	Pathogenic	criteria provided, multiple submitters, no conflicts
523344	NM_001042492.3(NF1):c.4875C>G (p.Tyr1625Ter)	NF1	Pathogenic	criteria provided, single submitter
523345	NM_001042492.3(NF1):c.4235G>C (p.Arg1412Thr)	NF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
523350	NM_001042492.3(NF1):c.6704+2del	NF1	Pathogenic	criteria provided, multiple submitters, no conflicts
803364	NM_001042492.3(NF1):c.5045_5046del (p.Asn1681_Cys1682insTer)	NF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
523263	GRCh37/hg19 17q11.2(chr17:29033882-30326958)	RAB11FIP4	Pathogenic	criteria provided, single submitter
523264	GRCh37/hg19 17q11.2(chr17:29033882-30326958)	RAB11FIP4	Pathogenic	criteria provided, single submitter
523349	NM_001042492.3(NF1):c.616_617insGG (p.Lys206fs)	NF1	Likely pathogenic	criteria provided, single submitter
523348	NM_001042492.3(NF1):c.6109G>A (p.Ala2037Thr)	NF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
267866	46;X;t(X;18)(p11.4;q12.2)dn		Uncertain significance	criteria provided, single submitter
523397	NM_001042492.3(NF1):c.3496+53T>C	NF1	Uncertain significance	criteria provided, single submitter
560363	NM_001042492.3(NF1):c.989C>A (p.Ala330Glu)	NF1	Uncertain significance	no assertion criteria provided
560364	NM_001042492.3(NF1):c.2800_2802del (p.Phe934del)	NF1	Uncertain significance	no assertion criteria provided
569677	NM_001042492.3(NF1):c.5935A>T (p.Ile1979Leu)	NF1	Uncertain significance	criteria provided, multiple submitters, no conflicts
180531	NM_005633.4(SOS1):c.1352C>A (p.Thr451Lys)	SOS1	Uncertain significance	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 11 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SOS1	Orphanet:2024	Hereditary gingival fibromatosis
SOS1	Orphanet:648	Noonan syndrome
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

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SOS1	HGNC:11187	ENSG00000115904	Q07889	Son of sevenless homolog 1	clinvar
RAB11FIP4	HGNC:30267	ENSG00000131242	Q86YS3	Rab11 family-interacting protein 4	clinvar
NF1	HGNC:7765	ENSG00000196712	P21359	Neurofibromin	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SOS1	Son of sevenless homolog 1	Promotes the exchange of Ras-bound GDP by GTP.
RAB11FIP4	Rab11 family-interacting protein 4	Acts as a regulator of endocytic traffic by participating in membrane delivery.
NF1	Neurofibromin	Stimulates the GTPase activity of Ras.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 2 · 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	1	5.8×	0.327
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SOS1	Scaffold/PPI	no		DH_dom, Ras-like_Gua-exchang_fac_N, PH_domain
RAB11FIP4	Other/Unknown	no		EF_hand_dom, EF-hand-dom_pair, Rab-bd_FIP-RBD
NF1	Other/Unknown	no		CRAL-TRIO_dom, RasGAP_dom, Rho_GTPase_activation_prot

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
colonic epithelium	2
jejunal mucosa	1
tendon of biceps brachii	1
frontal cortex	1
left testis	1
prefrontal cortex	1
adrenal tissue	1
calcaneal tendon	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SOS1	289	ubiquitous	marker	colonic epithelium, jejunal mucosa, tendon of biceps brachii
RAB11FIP4	205	ubiquitous	marker	prefrontal cortex, frontal cortex, left testis
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
SOS1	3,625
RAB11FIP4	726

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SOS1	Q07889	91
NF1	P21359	26

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
RAB11FIP4	Q86YS3	72.35

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 136. Enrichment computed across 3 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
MAPK1/MAPK3 signaling	2	131.3×	0.006	SOS1, NF1
MAPK family signaling cascades	2	102.9×	0.006	SOS1, NF1
Downstream signaling of activated FGFR2	1	2855.0×	0.008	SOS1
Downstream signaling of activated FGFR3	1	2855.0×	0.008	SOS1
Downstream signaling of activated FGFR4	1	1903.3×	0.008	SOS1
Signaling by ERBB2 in Cancer	1	1142.0×	0.008	SOS1
Signaling by EGFRvIII in Cancer	1	1142.0×	0.008	SOS1
Signaling by Ligand-Responsive EGFR Variants in Cancer	1	951.7×	0.008	SOS1
RAS signaling downstream of NF1 loss-of-function variants	1	815.7×	0.008	NF1
Signaling by NTRK2 (TRKB)	1	815.7×	0.008	SOS1
Signaling by PDGFR in disease	1	815.7×	0.008	SOS1
SOS-mediated signalling	1	713.8×	0.008	SOS1
IGF1R signaling cascade	1	713.8×	0.008	SOS1
Activated NTRK3 signals through RAS	1	634.4×	0.008	SOS1
Signaling by EGFR in Cancer	1	571.0×	0.008	SOS1
EGFR Transactivation by Gastrin	1	571.0×	0.008	SOS1
SHC-related events triggered by IGF1R	1	571.0×	0.008	SOS1
Signaling by FGFR3	1	571.0×	0.008	SOS1
Activated NTRK2 signals through RAS	1	571.0×	0.008	SOS1
Signaling by NTRK3 (TRKC)	1	571.0×	0.008	SOS1
Signaling by KIT in disease	1	571.0×	0.008	SOS1
FLT3 signaling in disease	1	571.0×	0.008	SOS1
IRS-mediated signalling	1	519.1×	0.008	SOS1
IRS-related events triggered by IGF1R	1	519.1×	0.008	SOS1
Signaling by FGFR4	1	519.1×	0.008	SOS1
Signal attenuation	1	519.1×	0.008	SOS1
MET activates RAS signaling	1	519.1×	0.008	SOS1
Signaling by Erythropoietin	1	519.1×	0.008	SOS1
Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R)	1	475.8×	0.008	SOS1
Signaling by FGFR4 in disease	1	475.8×	0.008	SOS1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
Schwann cell development	2	702.2×	3e-04	SOS1, NF1
positive regulation of mast cell apoptotic process	1	5617.3×	0.004	NF1
regulation of glial cell differentiation	1	5617.3×	0.004	NF1
observational learning	1	5617.3×	0.004	NF1
positive regulation of G1 to G0 transition	1	5617.3×	0.004	RAB11FIP4
Ras protein signal transduction	2	137.0×	0.004	SOS1, NF1
gamma-aminobutyric acid secretion, neurotransmission	1	2808.7×	0.005	NF1
Schwann cell proliferation	1	1872.4×	0.005	NF1
forebrain astrocyte development	1	1872.4×	0.005	NF1
Schwann cell migration	1	1872.4×	0.005	NF1
glutamate secretion, neurotransmission	1	1872.4×	0.005	NF1
negative regulation of mast cell proliferation	1	1872.4×	0.005	NF1
negative regulation of Schwann cell migration	1	1872.4×	0.005	NF1
vascular associated smooth muscle cell migration	1	1872.4×	0.005	NF1
mast cell apoptotic process	1	1404.3×	0.005	NF1
negative regulation of Rac protein signal transduction	1	1404.3×	0.005	NF1
myeloid leukocyte migration	1	1404.3×	0.005	NF1
midbrain morphogenesis	1	1404.3×	0.005	SOS1
vitellogenesis	1	1123.5×	0.006	SOS1
mast cell proliferation	1	1123.5×	0.006	NF1
regulation of pro-B cell differentiation	1	1123.5×	0.006	SOS1
cardiac atrium morphogenesis	1	936.2×	0.006	SOS1
amygdala development	1	936.2×	0.006	NF1
regulation of blood vessel endothelial cell migration	1	936.2×	0.006	NF1
vascular associated smooth muscle cell proliferation	1	936.2×	0.006	NF1
negative regulation of Schwann cell proliferation	1	802.5×	0.006	NF1
regulation of T cell differentiation in thymus	1	802.5×	0.006	SOS1
negative regulation of neurotransmitter secretion	1	802.5×	0.006	NF1
pericardium morphogenesis	1	702.2×	0.006	SOS1
hair follicle maturation	1	702.2×	0.006	NF1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
SOS1	IDARUBICIN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SOS1	5	4
RAB11FIP4	0	0
NF1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
IDARUBICIN	4	SOS1
DOXORUBICIN	4	SOS1
SOTORASIB	4	SOS1
ADAGRASIB	4	SOS1
MRTX-0902	1	SOS1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SOS1	421	Binding:409, Functional:12

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
SOS1	421

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

5 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)
IDARUBICIN	4	SOS1
DOXORUBICIN	4	SOS1
SOTORASIB	4	SOS1
ADAGRASIB	4	SOS1
MRTX-0902	1	SOS1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	SOS1
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	RAB11FIP4, 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)
RAB11FIP4	0	—
NF1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.