LEOPARD syndrome 2

Summary

LEOPARD syndrome 2 (MONDO:0012691) is a disease caused by RAF1 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: RAF1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 97

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	LEOPARD syndrome 2
Mondo ID	MONDO:0012691
MeSH	C537117
OMIM	611554
DOID	DOID:0080549
UMLS	C1969056
MedGen	370588
GARD	0015518
Is cancer (heuristic)	no

Also known as: LEOPARD syndrome 2 · leopard syndrome 2 · Leopard syndrome type 2 · LPRD2

Data availability: 97 ClinVar variants · 3 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 2

Related subtypes (2): LEOPARD syndrome 3, 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

97 retrieved; paginated sample, class counts are floors:

42 uncertain significance, 17 conflicting classifications of pathogenicity, 14 benign, 8 benign/likely benign, 8 likely benign, 4 pathogenic, 3 pathogenic/likely pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
13957	NM_002880.4(RAF1):c.770C>T (p.Ser257Leu)	RAF1	Pathogenic	reviewed by expert panel
13960	NM_002880.4(RAF1):c.1837C>G (p.Leu613Val)	RAF1	Pathogenic	reviewed by expert panel
265535	NM_002880.4(RAF1):c.505G>C (p.Gly169Arg)	RAF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
40605	NM_002880.4(RAF1):c.781C>G (p.Pro261Ala)	RAF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
40613	NM_002880.4(RAF1):c.1082G>C (p.Gly361Ala)	RAF1	Pathogenic	reviewed by expert panel
44633	NM_002880.4(RAF1):c.776C>A (p.Ser259Tyr)	RAF1	Pathogenic	reviewed by expert panel
496189	NM_002880.4(RAF1):c.788T>A (p.Val263Asp)	RAF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
801936	NM_002880.4(RAF1):c.773C>G (p.Thr258Arg)	RAF1	Likely pathogenic	criteria provided, single submitter
1100280	NM_002880.4(RAF1):c.192C>T (p.Asn64=)	RAF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1174673	NM_002880.4(RAF1):c.834+598G>A	RAF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
177842	NM_002880.4(RAF1):c.1721A>G (p.Tyr574Cys)	RAF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
220830	NM_002880.4(RAF1):c.462C>G (p.Ile154Met)	RAF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
343099	NM_002880.4(RAF1):c.*190G>A	RAF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
343104	NM_002880.4(RAF1):c.21T>C (p.Ala7=)	RAF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
376514	NM_002880.4(RAF1):c.770C>G (p.Ser257Trp)	RAF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
391813	NM_002880.4(RAF1):c.1871C>G (p.Ser624Cys)	RAF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
40577	NM_002880.4(RAF1):c.-201C>A	RAF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
40578	NM_002880.4(RAF1):c.-27+7G>A	RAF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
40586	NM_002880.4(RAF1):c.122G>A (p.Arg41Gln)	RAF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
432929	NM_002880.4(RAF1):c.601A>G (p.Ile201Val)	RAF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
477681	NM_002880.4(RAF1):c.933C>T (p.Pro311=)	RAF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
477682	NM_002880.4(RAF1):c.934G>A (p.Val312Met)	RAF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
508664	NM_002880.4(RAF1):c.600T>C (p.Thr200=)	RAF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
509193	NM_002880.4(RAF1):c.231C>T (p.Ser77=)	RAF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
899635	NM_002880.4(RAF1):c.654A>G (p.Arg218=)	RAF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1213769	NC_000003.12:g.12589035_12766981dup	LOC129389024	Uncertain significance	criteria provided, single submitter
902116	NM_002880.4(RAF1):c.*841C>T	MKRN2	Uncertain significance	criteria provided, single submitter
903003	NM_002880.4(RAF1):c.*840A>T	MKRN2	Uncertain significance	criteria provided, single submitter
1497149	NM_002880.4(RAF1):c.1A>G (p.Met1Val)	RAF1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1675117	NM_002880.4(RAF1):c.161C>A (p.Thr54Lys)	RAF1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 18 · Orphanet: 5 · 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
RAF1	Strong	Autosomal dominant	LEOPARD syndrome 2	18

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RAF1	Orphanet:154	Familial isolated dilated cardiomyopathy
RAF1	Orphanet:251615	Pilomyxoid astrocytoma
RAF1	Orphanet:500	Noonan syndrome with multiple lentigines
RAF1	Orphanet:626	Large/giant congenital melanocytic nevus
RAF1	Orphanet:648	Noonan syndrome

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
RAF1	HGNC:9829	ENSG00000132155	P04049	RAF proto-oncogene serine/threonine-protein kinase	gencc,clinvar
MKRN2	HGNC:7113	ENSG00000075975	Q9H000	E3 ubiquitin-protein ligase makorin-2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RAF1	RAF proto-oncogene serine/threonine-protein kinase	Serine/threonine-protein kinase that acts as a regulatory link between the membrane-associated Ras GTPases and the MAPK/ERK cascade, and this critical regulatory link functions as a switch determining cell fate decisions including prolifer…
MKRN2	E3 ubiquitin-protein ligase makorin-2	E3 ubiquitin ligase catalyzing the covalent attachment of ubiquitin moieties onto substrate proteins.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.5

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	13.9×	0.142
Transcription factor	1	4.1×	0.228

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RAF1	Kinase	yes	2.7.10.2	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, PKC_DAG/PE
MKRN2	Transcription factor	no		Znf_CCCH, Znf_RING, Znf_RING/FYVE/PHD

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gastrocnemius	1
muscle of leg	1
ventricular zone	1
left testis	1
secondary oocyte	1
sperm	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RAF1	299	ubiquitous	marker	gastrocnemius, muscle of leg, ventricular zone
MKRN2	270	ubiquitous	marker	secondary oocyte, left testis, sperm

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RAF1	6,574
MKRN2	2,276

Intra-cohort edges

A	B	Sources
MKRN2	RAF1	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RAF1	P04049	76

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MKRN2	Q9H000	71.78

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 17. 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
Negative feedback regulation of MAPK pathway	1	1903.3×	0.003	RAF1
SHOC2 M1731 mutant abolishes MRAS complex function	1	1427.5×	0.003	RAF1
Gain-of-function MRAS complexes activate RAF signaling	1	1427.5×	0.003	RAF1
IFNG signaling activates MAPKs	1	1427.5×	0.003	RAF1
GP1b-IX-V activation signalling	1	951.7×	0.004	RAF1
Rap1 signalling	1	713.8×	0.004	RAF1
CD209 (DC-SIGN) signaling	1	519.1×	0.004	RAF1
RAF activation	1	335.9×	0.004	RAF1
Signaling by high-kinase activity BRAF mutants	1	317.2×	0.004	RAF1
MAP2K and MAPK activation	1	285.5×	0.004	RAF1
Signaling by RAF1 mutants	1	278.5×	0.004	RAF1
Negative regulation of MAPK pathway	1	265.6×	0.004	RAF1
Signaling by moderate kinase activity BRAF mutants	1	253.8×	0.004	RAF1
Paradoxical activation of RAF signaling by kinase inactive BRAF	1	253.8×	0.004	RAF1
Signaling downstream of RAS mutants	1	253.8×	0.004	RAF1
Signaling by BRAF and RAF1 fusions	1	170.4×	0.006	RAF1
Stimuli-sensing channels	1	135.9×	0.007	RAF1

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
death-inducing signaling complex assembly	1	4213.0×	0.009	RAF1
ERBB2-ERBB3 signaling pathway	1	842.6×	0.009	RAF1
insulin secretion involved in cellular response to glucose stimulus	1	648.1×	0.009	RAF1
type II interferon-mediated signaling pathway	1	601.9×	0.009	RAF1
Schwann cell development	1	526.6×	0.009	RAF1
neurotrophin TRK receptor signaling pathway	1	526.6×	0.009	RAF1
intermediate filament cytoskeleton organization	1	468.1×	0.009	RAF1
type B pancreatic cell proliferation	1	443.5×	0.009	RAF1
face development	1	401.2×	0.009	RAF1
positive regulation of peptidyl-serine phosphorylation	1	383.0×	0.009	RAF1
response to muscle stretch	1	383.0×	0.009	RAF1
negative regulation of inflammatory response to antigenic stimulus	1	300.9×	0.009	MKRN2
negative regulation of extrinsic apoptotic signaling pathway via death domain receptors	1	290.6×	0.009	RAF1
thyroid gland development	1	271.8×	0.009	RAF1
regulation of Rho protein signal transduction	1	255.3×	0.009	RAF1
negative regulation of non-canonical NF-kappaB signal transduction	1	255.3×	0.009	MKRN2
insulin-like growth factor receptor signaling pathway	1	247.8×	0.009	RAF1
negative regulation of protein-containing complex assembly	1	227.7×	0.009	RAF1
regulation of cell differentiation	1	216.1×	0.009	RAF1
positive regulation of transcription by RNA polymerase II	2	14.9×	0.009	RAF1, MKRN2
extrinsic apoptotic signaling pathway via death domain receptors	1	200.6×	0.010	RAF1
thymus development	1	168.5×	0.011	RAF1
myelination	1	125.8×	0.014	RAF1
somatic stem cell population maintenance	1	123.9×	0.014	RAF1
wound healing	1	113.9×	0.014	RAF1
DNA-templated transcription	1	112.3×	0.014	MKRN2
insulin receptor signaling pathway	1	110.9×	0.014	RAF1
phosphatidylinositol 3-kinase/protein kinase B signal transduction	1	105.3×	0.014	MKRN2
MAPK cascade	1	76.6×	0.018	RAF1
protein polyubiquitination	1	57.7×	0.024	MKRN2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) 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
RAF1	VEMURAFENIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RAF1	31	4
MKRN2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VEMURAFENIB	4	RAF1
SORAFENIB	4	RAF1
REGORAFENIB	4	RAF1
DABRAFENIB	4	RAF1
NILOTINIB	4	RAF1
TOVORAFENIB	4	RAF1
PAZOPANIB	4	RAF1
DASATINIB	4	RAF1
ERLOTINIB	4	RAF1
IMATINIB	4	RAF1
PLINABULIN	3	RAF1
AVUTOMETINIB	3	RAF1
NAPORAFENIB	3	RAF1
MOTESANIB	3	RAF1
DORAMAPIMOD	2	RAF1
CI-1040	2	RAF1
FORETINIB	2	RAF1
REBASTINIB	2	RAF1
TOLONIUM CHLORIDE	2	RAF1
CEP-32496	2	RAF1
BELVARAFENIB	2	RAF1
R-406	2	RAF1
RISOVALISIB	2	RAF1
EXARAFENIB	2	RAF1
RAF-265	2	RAF1
BRIMARAFENIB	2	RAF1
OSI-930	1	RAF1
PLUMBAGIN	1	RAF1
LY-3009120	1	RAF1
XP-102	1	RAF1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
RAF1	839	Binding:803, Functional:31, ADMET:5

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
RAF1	2.7.10.2	non-specific protein-tyrosine kinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
RAF1	839

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).

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	RAF1
SORAFENIB	4	RAF1
REGORAFENIB	4	RAF1
DABRAFENIB	4	RAF1
NILOTINIB	4	RAF1
TOVORAFENIB	4	RAF1
PAZOPANIB	4	RAF1
DASATINIB	4	RAF1
ERLOTINIB	4	RAF1
IMATINIB	4	RAF1
PLINABULIN	3	RAF1
AVUTOMETINIB	3	RAF1
NAPORAFENIB	3	RAF1
MOTESANIB	3	RAF1
DORAMAPIMOD	2	RAF1
CI-1040	2	RAF1
FORETINIB	2	RAF1
REBASTINIB	2	RAF1
TOLONIUM CHLORIDE	2	RAF1
CEP-32496	2	RAF1
BELVARAFENIB	2	RAF1
R-406	2	RAF1
RISOVALISIB	2	RAF1
EXARAFENIB	2	RAF1
RAF-265	2	RAF1
BRIMARAFENIB	2	RAF1
OSI-930	1	RAF1
PLUMBAGIN	1	RAF1
LY-3009120	1	RAF1
XP-102	1	RAF1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	RAF1
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	MKRN2

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)
MKRN2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.