LEOPARD syndrome 3

Summary

LEOPARD syndrome 3 (MONDO:0013380) is a disease caused by BRAF (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: BRAF (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 128

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	LEOPARD syndrome 3
Mondo ID	MONDO:0013380
OMIM	613707
DOID	DOID:0080550
UMLS	C3150971
MedGen	462321
GARD	0015694
Is cancer (heuristic)	no

Also known as: BRAF Noonan syndrome with multiple lentigines · LEOPARD syndrome 3 · leopard syndrome 3 · Leopard syndrome type 3 · LPRD3 · Noonan syndrome with multiple lentigines caused by mutation in BRAF

Data availability: 128 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › Noonan syndrome with multiple lentigines › LEOPARD syndrome 3

Related subtypes (2): LEOPARD syndrome 2, LEOPARD syndrome 1

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

128 retrieved; paginated sample, class counts are floors:

55 uncertain significance, 18 conflicting classifications of pathogenicity, 16 benign/likely benign, 14 likely benign, 12 benign, 7 pathogenic/likely pathogenic, 5 pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
13969	NM_004333.6(BRAF):c.1789C>G (p.Leu597Val)	BRAF	Pathogenic	criteria provided, multiple submitters, no conflicts
13973	NM_004333.6(BRAF):c.770A>G (p.Gln257Arg)	BRAF	Pathogenic	reviewed by expert panel
13976	NM_004333.6(BRAF):c.1495A>G (p.Lys499Glu)	BRAF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13979	NM_004333.6(BRAF):c.1741A>G (p.Asn581Asp)	BRAF	Pathogenic	reviewed by expert panel
13981	NM_004333.6(BRAF):c.1914T>A (p.Asp638Glu)	BRAF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
162795	NM_004333.6(BRAF):c.2135C>A (p.Ala712Asp)	BRAF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
222077	NM_004333.6(BRAF):c.1574T>C (p.Leu525Pro)	BRAF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
29805	NM_004333.6(BRAF):c.722C>T (p.Thr241Met)	BRAF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
29807	NM_004333.6(BRAF):c.721A>C (p.Thr241Pro)	BRAF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
40347	NM_004333.6(BRAF):c.735A>C (p.Leu245Phe)	BRAF	Pathogenic	reviewed by expert panel
41446	NM_004333.6(BRAF):c.1801A>C (p.Lys601Gln)	BRAF	Pathogenic	criteria provided, multiple submitters, no conflicts
44811	NM_004333.6(BRAF):c.1743T>A (p.Asn581Lys)	BRAF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
40370	NM_004333.6(BRAF):c.1454T>C (p.Leu485Ser)	BRAF	Likely pathogenic	reviewed by expert panel
1050230	NM_004333.6(BRAF):c.1789C>T (p.Leu597=)	BRAF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1091347	NM_004333.6(BRAF):c.915G>A (p.Ala305=)	BRAF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1130636	NM_004333.6(BRAF):c.1797A>G (p.Thr599=)	BRAF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1318788	NM_004333.6(BRAF):c.52C>G (p.Leu18Val)	BRAF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
133720	NM_004333.6(BRAF):c.72G>C (p.Glu24Asp)	BRAF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1339665	NM_004333.6(BRAF):c.1690A>G (p.Met564Val)	BRAF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2167103	NM_004333.6(BRAF):c.505-20A>G	BRAF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2722508	NM_004333.6(BRAF):c.1433-11T>A	BRAF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2977730	NM_004333.6(BRAF):c.1365G>T (p.Gly455=)	BRAF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3481744	NM_004333.6(BRAF):c.45C>T (p.Gly15=)	BRAF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
359049	NM_004333.6(BRAF):c.981-14C>A	BRAF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
372564	NM_004333.6(BRAF):c.437G>A (p.Arg146Gln)	BRAF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
417227	NM_004333.6(BRAF):c.2196C>G (p.Ser732=)	BRAF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
44809	NM_004333.6(BRAF):c.1694+14G>A	BRAF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
500454	NM_004333.6(BRAF):c.1207C>G (p.Pro403Ala)	BRAF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
512959	NM_004333.6(BRAF):c.1023A>G (p.Pro341=)	BRAF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
633085	NM_004333.6(BRAF):c.995C>T (p.Thr332Ile)	BRAF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 23 · Orphanet: 11 · 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
BRAF	Definitive	Autosomal dominant	LEOPARD syndrome 3	23

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
BRAF	Orphanet:1340	Cardiofaciocutaneous syndrome
BRAF	Orphanet:146	Differentiated thyroid carcinoma
BRAF	Orphanet:251615	Pilomyxoid astrocytoma
BRAF	Orphanet:389	Langerhans cell histiocytosis
BRAF	Orphanet:500	Noonan syndrome with multiple lentigines
BRAF	Orphanet:54595	Craniopharyngioma
BRAF	Orphanet:58017	Classic hairy cell leukemia
BRAF	Orphanet:626	Large/giant congenital melanocytic nevus
BRAF	Orphanet:648	Noonan syndrome
BRAF	Orphanet:840	Syringocystadenoma papilliferum
BRAF	Orphanet:96253	Cushing disease

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
BRAF	HGNC:1097	ENSG00000157764	P15056	Serine/threonine-protein kinase B-raf	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
BRAF	Serine/threonine-protein kinase B-raf	Protein kinase involved in the transduction of mitogenic signals from the cell membrane to the nucleus.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Kinase	1	27.7×	0.036

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
BRAF	Kinase	yes	2.7.10.2	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, PKC_DAG/PE

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
buccal mucosa cell	1
calcaneal tendon	1
colonic epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
BRAF	265	ubiquitous	marker	buccal mucosa cell, colonic epithelium, calcaneal tendon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
BRAF	7,394

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
BRAF	P15056	131

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 39. 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 MRAS-complex mutants	1	2855.0×	0.004	BRAF
Signalling to p38 via RIT and RIN	1	2284.0×	0.004	BRAF
Negative feedback regulation of MAPK pathway	1	1903.3×	0.004	BRAF
ARMS-mediated activation	1	1631.4×	0.004	BRAF
Prolonged ERK activation events	1	1427.5×	0.004	BRAF
SHOC2 M1731 mutant abolishes MRAS complex function	1	1427.5×	0.004	BRAF
Gain-of-function MRAS complexes activate RAF signaling	1	1427.5×	0.004	BRAF
Signaling by FGFR3	1	1142.0×	0.004	BRAF
Signaling by FGFR4	1	1038.2×	0.004	BRAF
Frs2-mediated activation	1	951.7×	0.004	BRAF
Signaling by FGFR1	1	815.7×	0.004	BRAF
Spry regulation of FGF signaling	1	713.8×	0.005	BRAF
Signalling to ERKs	1	601.0×	0.005	BRAF
Negative regulation of FGFR3 signaling	1	439.2×	0.005	BRAF
Signaling by RAS mutants	1	423.0×	0.005	BRAF
Negative regulation of FGFR4 signaling	1	407.9×	0.005	BRAF
Signaling by FGFR2	1	407.9×	0.005	BRAF
Negative regulation of FGFR1 signaling	1	368.4×	0.005	BRAF
Negative regulation of FGFR2 signaling	1	368.4×	0.005	BRAF
Signaling by FGFR	1	346.1×	0.005	BRAF
RAF activation	1	335.9×	0.005	BRAF
Signaling by high-kinase activity BRAF mutants	1	317.2×	0.005	BRAF
MAP2K and MAPK activation	1	285.5×	0.005	BRAF
Signaling by RAF1 mutants	1	278.5×	0.005	BRAF
Negative regulation of MAPK pathway	1	265.6×	0.005	BRAF
Signaling by moderate kinase activity BRAF mutants	1	253.8×	0.005	BRAF
Paradoxical activation of RAF signaling by kinase inactive BRAF	1	253.8×	0.005	BRAF
Signaling downstream of RAS mutants	1	253.8×	0.005	BRAF
Oncogenic MAPK signaling	1	248.3×	0.005	BRAF
Signaling by NTRK1 (TRKA)	1	196.9×	0.007	BRAF

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
CD4-positive or CD8-positive, alpha-beta T cell lineage commitment	1	5617.3×	0.003	BRAF
positive regulation of axon regeneration	1	3370.4×	0.003	BRAF
negative regulation of synaptic vesicle exocytosis	1	3370.4×	0.003	BRAF
CD4-positive, alpha-beta T cell differentiation	1	2808.7×	0.003	BRAF
myeloid progenitor cell differentiation	1	2407.4×	0.003	BRAF
positive regulation of D-glucose transmembrane transport	1	2106.5×	0.003	BRAF
head morphogenesis	1	2106.5×	0.003	BRAF
establishment of protein localization to membrane	1	1872.4×	0.003	BRAF
negative regulation of fibroblast migration	1	1532.0×	0.003	BRAF
endothelial cell apoptotic process	1	1296.3×	0.003	BRAF
regulation of T cell differentiation	1	1203.7×	0.003	BRAF
face development	1	802.5×	0.003	BRAF
synaptic vesicle exocytosis	1	766.0×	0.003	BRAF
positive regulation of peptidyl-serine phosphorylation	1	766.0×	0.003	BRAF
stress fiber assembly	1	766.0×	0.003	BRAF
postsynaptic modulation of chemical synaptic transmission	1	674.1×	0.004	BRAF
positive regulation of axonogenesis	1	581.1×	0.004	BRAF
thyroid gland development	1	543.6×	0.004	BRAF
negative regulation of endothelial cell apoptotic process	1	495.6×	0.004	BRAF
T cell differentiation in thymus	1	411.0×	0.005	BRAF
positive regulation of substrate adhesion-dependent cell spreading	1	374.5×	0.005	BRAF
substrate adhesion-dependent cell spreading	1	343.9×	0.005	BRAF
thymus development	1	337.0×	0.005	BRAF
ERK1 and ERK2 cascade	1	318.0×	0.005	BRAF
positive regulation of stress fiber assembly	1	312.1×	0.005	BRAF
visual learning	1	306.4×	0.005	BRAF
long-term synaptic potentiation	1	280.9×	0.005	BRAF
epidermal growth factor receptor signaling pathway	1	247.8×	0.006	BRAF
somatic stem cell population maintenance	1	247.8×	0.006	BRAF
cellular response to xenobiotic stimulus	1	240.7×	0.006	BRAF

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · 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).

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
BRAF	VEMURAFENIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
BRAF	48	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VEMURAFENIB	4	BRAF
PONATINIB	4	BRAF
FEDRATINIB	4	BRAF
SORAFENIB	4	BRAF
DASATINIB ANHYDROUS	4	BRAF
RUXOLITINIB	4	BRAF
INFIGRATINIB PHOSPHATE	4	BRAF
INFIGRATINIB	4	BRAF
REGORAFENIB	4	BRAF
DABRAFENIB	4	BRAF
COBIMETINIB	4	BRAF
NILOTINIB	4	BRAF
ABEMACICLIB	4	BRAF
ENCORAFENIB	4	BRAF
TOVORAFENIB	4	BRAF
PAZOPANIB	4	BRAF
DASATINIB	4	BRAF
ERLOTINIB	4	BRAF
GEFITINIB	4	BRAF
IMATINIB	4	BRAF
MASITINIB	3	BRAF
AVUTOMETINIB	3	BRAF
NAPORAFENIB	3	BRAF
QUERCETIN	3	BRAF
MOTESANIB	3	BRAF
DORAMAPIMOD	2	BRAF
FORETINIB	2	BRAF
REBASTINIB	2	BRAF
CEP-32496	2	BRAF
BAFETINIB	2	BRAF

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
BRAF	1,442	Binding:1400, Functional:37, ADMET:5

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
BRAF	2.7.10.2, 2.7.11.1	non-specific protein-tyrosine kinase, non-specific serine/threonine protein kinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
BRAF	1,442

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

30 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)
VEMURAFENIB	4	BRAF
PONATINIB	4	BRAF
FEDRATINIB	4	BRAF
SORAFENIB	4	BRAF
DASATINIB ANHYDROUS	4	BRAF
RUXOLITINIB	4	BRAF
INFIGRATINIB PHOSPHATE	4	BRAF
INFIGRATINIB	4	BRAF
REGORAFENIB	4	BRAF
DABRAFENIB	4	BRAF
COBIMETINIB	4	BRAF
NILOTINIB	4	BRAF
ABEMACICLIB	4	BRAF
ENCORAFENIB	4	BRAF
TOVORAFENIB	4	BRAF
PAZOPANIB	4	BRAF
DASATINIB	4	BRAF
ERLOTINIB	4	BRAF
GEFITINIB	4	BRAF
IMATINIB	4	BRAF
MASITINIB	3	BRAF
AVUTOMETINIB	3	BRAF
NAPORAFENIB	3	BRAF
QUERCETIN	3	BRAF
MOTESANIB	3	BRAF
DORAMAPIMOD	2	BRAF
FORETINIB	2	BRAF
REBASTINIB	2	BRAF
CEP-32496	2	BRAF
BAFETINIB	2	BRAF

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	BRAF
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	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: 0.