Cardiofaciocutaneous syndrome 4

Summary

Cardiofaciocutaneous syndrome 4 (MONDO:0014114) is a disease caused by MAP2K2 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: MAP2K2 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 116

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	cardiofaciocutaneous syndrome 4
Mondo ID	MONDO:0014114
OMIM	615280
DOID	DOID:0111463
UMLS	C3809007
MedGen	815337
GARD	0015937
Is cancer (heuristic)	no

Also known as: cardiofaciocutaneous syndrome 4 · cardiofaciocutaneous syndrome caused by mutation in MAP2K2 · cardiofaciocutaneous syndrome type 4 · CFC4 · MAP2K2 cardiofaciocutaneous syndrome

Data availability: 116 ClinVar variants · 5 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › disorder of development or morphogenesis › developmental defect during embryogenesis › multiple congenital anomalies/dysmorphic syndrome › multiple congenital anomalies/dysmorphic syndrome-intellectual disability › cardiofaciocutaneous syndrome › cardiofaciocutaneous syndrome 4

Related subtypes (3): cardiofaciocutaneous syndrome 1, cardiofaciocutaneous syndrome 2, cardiofaciocutaneous syndrome 3

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

116 retrieved; paginated sample, class counts are floors:

64 uncertain significance, 16 benign, 14 conflicting classifications of pathogenicity, 6 likely benign, 6 pathogenic/likely pathogenic, 4 pathogenic, 3 benign/likely benign, 3 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
180911	NM_030662.4(MAP2K2):c.169T>C (p.Phe57Leu)	MAP2K2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
279998	NM_030662.4(MAP2K2):c.183A>C (p.Lys61Asn)	MAP2K2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
30170	NM_030662.4(MAP2K2):c.395G>A (p.Gly132Asp)	MAP2K2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
376176	NM_030662.4(MAP2K2):c.376A>G (p.Asn126Asp)	MAP2K2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
40769	NM_030662.4(MAP2K2):c.181A>G (p.Lys61Glu)	MAP2K2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
666272	NM_030662.4(MAP2K2):c.383C>T (p.Pro128Leu)	MAP2K2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
8272	NM_030662.4(MAP2K2):c.170T>G (p.Phe57Cys)	MAP2K2	Pathogenic	reviewed by expert panel
8273	NM_030662.4(MAP2K2):c.169T>G (p.Phe57Val)	MAP2K2	Pathogenic	reviewed by expert panel
8274	NM_030662.4(MAP2K2):c.400T>C (p.Tyr134His)	MAP2K2	Pathogenic	reviewed by expert panel
8275	NM_030662.4(MAP2K2):c.383C>A (p.Pro128Gln)	MAP2K2	Pathogenic	reviewed by expert panel
2444198	NM_030662.4(MAP2K2):c.167C>A (p.Ala56Asp)	MAP2K2	Likely pathogenic	criteria provided, single submitter
4294094	NM_030662.4(MAP2K2):c.180G>C (p.Gln60His)	MAP2K2	Likely pathogenic	criteria provided, single submitter
431174	NM_030662.4(MAP2K2):c.191T>G (p.Val64Gly)	MAP2K2	Likely pathogenic	no assertion criteria provided
1747506	NM_030662.4(MAP2K2):c.1017C>T (p.Thr339=)	MAP2K2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
180903	NM_030662.4(MAP2K2):c.913G>A (p.Val305Ile)	MAP2K2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1989641	NM_030662.4(MAP2K2):c.925G>A (p.Gly309Arg)	MAP2K2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2055907	NM_030662.4(MAP2K2):c.335G>A (p.Arg112Gln)	MAP2K2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2548628	NM_030662.4(MAP2K2):c.1198G>T (p.Val400Leu)	MAP2K2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
280819	NM_030662.4(MAP2K2):c.536G>A (p.Arg179Gln)	MAP2K2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
285121	NM_030662.4(MAP2K2):c.890G>A (p.Arg297Gln)	MAP2K2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3061850	NM_030662.4(MAP2K2):c.404G>T (p.Gly135Val)	MAP2K2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
40829	NM_030662.4(MAP2K2):c.856G>A (p.Gly286Arg)	MAP2K2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
40830	NM_030662.4(MAP2K2):c.884C>T (p.Ser295Leu)	MAP2K2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
40839	NM_030662.4(MAP2K2):c.938G>A (p.Arg313Gln)	MAP2K2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
424075	NM_030662.4(MAP2K2):c.814G>A (p.Ala272Thr)	MAP2K2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
496476	NM_030662.4(MAP2K2):c.847G>A (p.Val283Met)	MAP2K2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
837201	NM_030662.4(MAP2K2):c.335G>T (p.Arg112Leu)	MAP2K2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3375926	NM_030662.4(MAP2K2):c.47C>G (p.Pro16Arg)	LOC130063193	Uncertain significance	criteria provided, multiple submitters, no conflicts
620595	NM_030662.4(MAP2K2):c.46C>A (p.Pro16Thr)	LOC130063193	Uncertain significance	criteria provided, multiple submitters, no conflicts
636574	NM_030662.4(MAP2K2):c.7G>T (p.Ala3Ser)	LOC130063193	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 2 · 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
MAP2K2	Definitive	Autosomal dominant	cardiofaciocutaneous syndrome	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MAP2K2	Orphanet:1340	Cardiofaciocutaneous syndrome
MAP2K2	Orphanet:638	Neurofibromatosis-Noonan syndrome

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
MAP2K2	HGNC:6842	ENSG00000126934	P36507	Dual specificity mitogen-activated protein kinase kinase 2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MAP2K2	Dual specificity mitogen-activated protein kinase kinase 2	Catalyzes the concomitant phosphorylation of a threonine and a tyrosine residue in a Thr-Glu-Tyr sequence located in MAP kinases.

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)
MAP2K2	Kinase	yes	2.7.12.2	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf

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
left testis	1
mucosa of transverse colon	1
right testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MAP2K2	291	ubiquitous	marker	mucosa of transverse colon, right testis, left testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MAP2K2	3,789

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MAP2K2	P36507	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 36. 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 MAP2K mutants	1	2855.0×	0.006	MAP2K2
Negative feedback regulation of MAPK pathway	1	1903.3×	0.006	MAP2K2
Prolonged ERK activation events	1	1427.5×	0.006	MAP2K2
MAPK1 (ERK2) activation	1	1142.0×	0.006	MAP2K2
Frs2-mediated activation	1	951.7×	0.006	MAP2K2
Uptake and function of anthrax toxins	1	951.7×	0.006	MAP2K2
Uptake and actions of bacterial toxins	1	815.7×	0.006	MAP2K2
RAF-independent MAPK1/3 activation	1	634.4×	0.007	MAP2K2
Signalling to ERKs	1	601.0×	0.007	MAP2K2
Signal transduction by L1	1	519.1×	0.007	MAP2K2
Signaling by RAS mutants	1	423.0×	0.007	MAP2K2
RAF activation	1	335.9×	0.007	MAP2K2
Bacterial Infection Pathways	1	335.9×	0.007	MAP2K2
Signaling by high-kinase activity BRAF mutants	1	317.2×	0.007	MAP2K2
MAP2K and MAPK activation	1	285.5×	0.007	MAP2K2
Signaling by RAF1 mutants	1	278.5×	0.007	MAP2K2
Negative regulation of MAPK pathway	1	265.6×	0.007	MAP2K2
Signaling by moderate kinase activity BRAF mutants	1	253.8×	0.007	MAP2K2
Paradoxical activation of RAF signaling by kinase inactive BRAF	1	253.8×	0.007	MAP2K2
Signaling downstream of RAS mutants	1	253.8×	0.007	MAP2K2
Oncogenic MAPK signaling	1	248.3×	0.007	MAP2K2
Signaling by NTRK1 (TRKA)	1	196.9×	0.008	MAP2K2
Signaling by NTRKs	1	181.3×	0.009	MAP2K2
Signaling by BRAF and RAF1 fusions	1	170.4×	0.009	MAP2K2
MAPK1/MAPK3 signaling	1	131.3×	0.011	MAP2K2
L1CAM interactions	1	120.2×	0.012	MAP2K2
MAPK family signaling cascades	1	102.9×	0.013	MAP2K2
RAF/MAP kinase cascade	1	61.1×	0.021	MAP2K2
Diseases of signal transduction by growth factor receptors and second messengers	1	56.8×	0.022	MAP2K2
Signaling by Receptor Tyrosine Kinases	1	51.7×	0.023	MAP2K2

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
regulation of Golgi inheritance	1	4213.0×	0.002	MAP2K2
peptidyl-serine autophosphorylation	1	3370.4×	0.002	MAP2K2
epithelial cell proliferation involved in lung morphogenesis	1	3370.4×	0.002	MAP2K2
regulation of axon regeneration	1	2407.4×	0.002	MAP2K2
trachea formation	1	2407.4×	0.002	MAP2K2
regulation of early endosome to late endosome transport	1	2106.5×	0.002	MAP2K2
regulation of stress-activated MAPK cascade	1	1872.4×	0.002	MAP2K2
ERBB2-ERBB3 signaling pathway	1	1685.2×	0.002	MAP2K2
positive regulation of protein serine/threonine kinase activity	1	1296.3×	0.002	MAP2K2
Schwann cell development	1	1053.2×	0.002	MAP2K2
face development	1	802.5×	0.002	MAP2K2
positive regulation of cell motility	1	766.0×	0.002	MAP2K2
positive regulation of axonogenesis	1	581.1×	0.003	MAP2K2
thyroid gland development	1	543.6×	0.003	MAP2K2
insulin-like growth factor receptor signaling pathway	1	495.6×	0.003	MAP2K2
thymus development	1	337.0×	0.004	MAP2K2
ERK1 and ERK2 cascade	1	318.0×	0.004	MAP2K2
myelination	1	251.5×	0.005	MAP2K2
MAPK cascade	1	153.2×	0.008	MAP2K2
heart development	1	78.8×	0.014	MAP2K2
positive regulation of gene expression	1	38.7×	0.027	MAP2K2
positive regulation of DNA-templated transcription	1	27.9×	0.036	MAP2K2

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
MAP2K2	VEMURAFENIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MAP2K2	52	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VEMURAFENIB	4	MAP2K2
SELUMETINIB	4	MAP2K2
TRAMETINIB	4	MAP2K2
COBIMETINIB	4	MAP2K2
BINIMETINIB	4	MAP2K2
DASATINIB	4	MAP2K2
FEDRATINIB	4	MAP2K2
AXITINIB	4	MAP2K2
RUXOLITINIB	4	MAP2K2
NERATINIB	4	MAP2K2
VANDETANIB	4	MAP2K2
BOSUTINIB	4	MAP2K2
GILTERITINIB	4	MAP2K2
NINTEDANIB	4	MAP2K2
SUNITINIB	4	MAP2K2
SARACATINIB	3	MAP2K2
AVUTOMETINIB	3	MAP2K2
LINSITINIB	3	MAP2K2
LINIFANIB	3	MAP2K2
ORANTINIB	3	MAP2K2
CANERTINIB	3	MAP2K2
CEDIRANIB	3	MAP2K2
DOVITINIB	3	MAP2K2
LESTAURTINIB	3	MAP2K2
CI-1040	2	MAP2K2
MIRDAMETINIB	2	MAP2K2
FORETINIB	2	MAP2K2
REFAMETINIB	2	MAP2K2
TAK-733	2	MAP2K2
SU-014813	2	MAP2K2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
MAP2K2	615	Binding:581, Functional:33, ADMET:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MAP2K2	2.7.12.2	mitogen-activated protein kinase kinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
MAP2K2	615

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	MAP2K2
SELUMETINIB	4	MAP2K2
TRAMETINIB	4	MAP2K2
COBIMETINIB	4	MAP2K2
BINIMETINIB	4	MAP2K2
DASATINIB	4	MAP2K2
FEDRATINIB	4	MAP2K2
AXITINIB	4	MAP2K2
RUXOLITINIB	4	MAP2K2
NERATINIB	4	MAP2K2
VANDETANIB	4	MAP2K2
BOSUTINIB	4	MAP2K2
GILTERITINIB	4	MAP2K2
NINTEDANIB	4	MAP2K2
SUNITINIB	4	MAP2K2
SARACATINIB	3	MAP2K2
AVUTOMETINIB	3	MAP2K2
LINSITINIB	3	MAP2K2
LINIFANIB	3	MAP2K2
ORANTINIB	3	MAP2K2
CANERTINIB	3	MAP2K2
CEDIRANIB	3	MAP2K2
DOVITINIB	3	MAP2K2
LESTAURTINIB	3	MAP2K2
CI-1040	2	MAP2K2
MIRDAMETINIB	2	MAP2K2
FORETINIB	2	MAP2K2
REFAMETINIB	2	MAP2K2
TAK-733	2	MAP2K2
SU-014813	2	MAP2K2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	MAP2K2
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.