Cardiofaciocutaneous syndrome 3

Summary

Cardiofaciocutaneous syndrome 3 (MONDO:0014113) is a disease caused by MAP2K1 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: MAP2K1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 69

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	cardiofaciocutaneous syndrome 3
Mondo ID	MONDO:0014113
OMIM	615279
DOID	DOID:0111462
UMLS	C3809006
MedGen	815336
GARD	0015936
Is cancer (heuristic)	no

Also known as: cardiofaciocutaneous syndrome 3 · cardiofaciocutaneous syndrome caused by mutation in MAP2K1 · cardiofaciocutaneous syndrome type 3 · CFC3 · MAP2K1 cardiofaciocutaneous syndrome

Data availability: 69 ClinVar variants · 5 GenCC gene-disease records.

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 3

Related subtypes (3): cardiofaciocutaneous syndrome 1, cardiofaciocutaneous syndrome 2, cardiofaciocutaneous syndrome 4

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

69 retrieved; paginated sample, class counts are floors:

31 uncertain significance, 12 likely pathogenic, 10 pathogenic, 7 conflicting classifications of pathogenicity, 3 pathogenic/likely pathogenic, 3 likely benign, 2 benign, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1297058	NM_002755.4(MAP2K1):c.383G>C (p.Gly128Ala)	MAP2K1	Pathogenic	criteria provided, single submitter
1328146	NM_002755.4(MAP2K1):c.607G>C (p.Glu203Gln)	MAP2K1	Pathogenic	criteria provided, single submitter
13351	NM_002755.4(MAP2K1):c.389A>G (p.Tyr130Cys)	MAP2K1	Pathogenic	reviewed by expert panel
13352	NM_002755.4(MAP2K1):c.383G>T (p.Gly128Val)	MAP2K1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
190378	NM_002755.4(MAP2K1):c.305A>G (p.Glu102Gly)	MAP2K1	Pathogenic	criteria provided, single submitter
228273	NM_002755.4(MAP2K1):c.364A>G (p.Asn122Asp)	MAP2K1	Pathogenic	reviewed by expert panel
375981	NM_002755.4(MAP2K1):c.370C>T (p.Pro124Ser)	MAP2K1	Pathogenic	reviewed by expert panel
3897831	NM_002755.4(MAP2K1):c.527G>T (p.Gly176Val)	MAP2K1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
40743	NM_002755.4(MAP2K1):c.371C>A (p.Pro124Gln)	MAP2K1	Pathogenic	no assertion criteria provided
40744	NM_002755.4(MAP2K1):c.371C>T (p.Pro124Leu)	MAP2K1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
40781	NM_002755.4(MAP2K1):c.199G>A (p.Asp67Asn)	MAP2K1	Pathogenic	reviewed by expert panel
44587	NM_002755.4(MAP2K1):c.124C>T (p.Leu42Phe)	MAP2K1	Pathogenic	reviewed by expert panel
636238	NM_002755.4(MAP2K1):c.388T>A (p.Tyr130Asn)	MAP2K1	Pathogenic	criteria provided, single submitter
1299563	NM_002755.4(MAP2K1):c.265C>A (p.Pro89Thr)	MAP2K1	Likely pathogenic	criteria provided, single submitter
13350	NM_002755.4(MAP2K1):c.158T>C (p.Phe53Ser)	MAP2K1	Likely pathogenic	reviewed by expert panel
1697313	NM_002755.4(MAP2K1):c.370C>G (p.Pro124Ala)	MAP2K1	Likely pathogenic	criteria provided, single submitter
222074	NM_002755.4(MAP2K1):c.175_177del (p.Lys59del)	MAP2K1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2572546	NM_002755.4(MAP2K1):c.767T>C (p.Met256Thr)	MAP2K1	Likely pathogenic	criteria provided, single submitter
280446	NM_002755.4(MAP2K1):c.323G>T (p.Arg108Leu)	MAP2K1	Likely pathogenic	reviewed by expert panel
3256896	NM_002755.4(MAP2K1):c.147_149dup (p.Leu50_Glu51insLeu)	MAP2K1	Likely pathogenic	criteria provided, single submitter
3577599	NM_002755.4(MAP2K1):c.200A>G (p.Asp67Gly)	MAP2K1	Likely pathogenic	criteria provided, single submitter
375982	NM_002755.4(MAP2K1):c.607G>A (p.Glu203Lys)	MAP2K1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3775508	NM_002755.4(MAP2K1):c.385T>C (p.Phe129Leu)	MAP2K1	Likely pathogenic	criteria provided, single submitter
4280604	NM_002755.4(MAP2K1):c.154G>C (p.Ala52Pro)	MAP2K1	Likely pathogenic	criteria provided, single submitter
4814140	NM_002755.4(MAP2K1):c.158T>A (p.Phe53Tyr)	MAP2K1	Likely pathogenic	criteria provided, single submitter
1138943	NM_002755.4(MAP2K1):c.961-10G>C	MAP2K1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1334255	NM_002755.4(MAP2K1):c.1138G>A (p.Gly380Ser)	MAP2K1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
180896	NM_002755.4(MAP2K1):c.277G>A (p.Val93Ile)	MAP2K1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2672171	NM_002755.4(MAP2K1):c.1023-4T>A	MAP2K1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3577604	NM_002755.4(MAP2K1):c.528C>T (p.Gly176=)	MAP2K1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · 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
MAP2K1	Definitive	Autosomal dominant	cardiofaciocutaneous syndrome	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MAP2K1	Orphanet:1340	Cardiofaciocutaneous syndrome
MAP2K1	Orphanet:389	Langerhans cell histiocytosis

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
MAP2K1	HGNC:6840	ENSG00000169032	Q02750	Dual specificity mitogen-activated protein kinase kinase 1	gencc,clinvar
SNAPC5	HGNC:15484	ENSG00000174446	O75971	snRNA-activating protein complex subunit 5	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MAP2K1	Dual specificity mitogen-activated protein kinase kinase 1	Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway.
SNAPC5	snRNA-activating protein complex subunit 5	Part of the SNAPc complex required for the transcription of both RNA polymerase II and III small-nuclear RNA genes.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · 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
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MAP2K1	Kinase	yes	2.7.12.2	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
SNAPC5	Other/Unknown	no		SNAPC5

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
oocyte	1
orbitofrontal cortex	1
secondary oocyte	1
endothelial cell	1
middle temporal gyrus	1
sperm	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MAP2K1	298	ubiquitous	marker	secondary oocyte, oocyte, orbitofrontal cortex
SNAPC5	299	ubiquitous	marker	endothelial cell, middle temporal gyrus, sperm

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MAP2K1	5,944
SNAPC5	438

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MAP2K1	Q02750	94
SNAPC5	O75971	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 68. Enrichment computed across 2 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
Signaling by MAP2K mutants	1	1427.5×	0.018	MAP2K1
Negative feedback regulation of MAPK pathway	1	951.7×	0.018	MAP2K1
Prolonged ERK activation events	1	713.8×	0.018	MAP2K1
MAPK3 (ERK1) activation	1	519.1×	0.018	MAP2K1
Frs2-mediated activation	1	475.8×	0.018	MAP2K1
Uptake and function of anthrax toxins	1	475.8×	0.018	MAP2K1
Uptake and actions of bacterial toxins	1	407.9×	0.018	MAP2K1
MAP3K8 (TPL2)-dependent MAPK1/3 activation	1	356.9×	0.018	MAP2K1
RAF-independent MAPK1/3 activation	1	317.2×	0.018	MAP2K1
Signalling to ERKs	1	300.5×	0.018	MAP2K1
Signal transduction by L1	1	259.6×	0.018	MAP2K1
Signaling by RAS mutants	1	211.5×	0.018	MAP2K1
RNA Polymerase III Transcription Initiation From Type 3 Promoter	1	203.9×	0.018	SNAPC5
RAF activation	1	167.9×	0.018	MAP2K1
RNA Polymerase III Transcription Initiation	1	167.9×	0.018	SNAPC5
Bacterial Infection Pathways	1	167.9×	0.018	MAP2K1
RNA Polymerase III Transcription	1	163.1×	0.018	SNAPC5
Signaling by high-kinase activity BRAF mutants	1	158.6×	0.018	MAP2K1
MAP kinase activation	1	154.3×	0.018	MAP2K1
MAP2K and MAPK activation	1	142.8×	0.018	MAP2K1
RNA Polymerase III Abortive And Retractive Initiation	1	139.3×	0.018	SNAPC5
Signaling by RAF1 mutants	1	139.3×	0.018	MAP2K1
Interleukin-1 family signaling	1	135.9×	0.018	MAP2K1
Negative regulation of MAPK pathway	1	132.8×	0.018	MAP2K1
Interleukin-17 signaling	1	126.9×	0.018	MAP2K1
Signaling by moderate kinase activity BRAF mutants	1	126.9×	0.018	MAP2K1
Paradoxical activation of RAF signaling by kinase inactive BRAF	1	126.9×	0.018	MAP2K1
Signaling downstream of RAS mutants	1	126.9×	0.018	MAP2K1
Oncogenic MAPK signaling	1	124.1×	0.018	MAP2K1
Toll Like Receptor 10 (TLR10) Cascade	1	107.7×	0.018	MAP2K1

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
negative regulation of homotypic cell-cell adhesion	1	4213.0×	0.004	MAP2K1
Golgi inheritance	1	4213.0×	0.004	MAP2K1
cerebellar cortex formation	1	2808.7×	0.004	MAP2K1
positive regulation of endodermal cell differentiation	1	2808.7×	0.004	MAP2K1
regulation of Golgi inheritance	1	2106.5×	0.004	MAP2K1
regulation of vascular associated smooth muscle contraction	1	1685.2×	0.004	MAP2K1
epithelial cell proliferation involved in lung morphogenesis	1	1685.2×	0.004	MAP2K1
transcription initiation at RNA polymerase III promoter	1	1203.7×	0.004	SNAPC5
positive regulation of muscle contraction	1	1203.7×	0.004	MAP2K1
regulation of axon regeneration	1	1203.7×	0.004	MAP2K1
trachea formation	1	1203.7×	0.004	MAP2K1
labyrinthine layer development	1	1053.2×	0.004	MAP2K1
negative regulation of hypoxia-induced intrinsic apoptotic signaling pathway	1	1053.2×	0.004	MAP2K1
regulation of early endosome to late endosome transport	1	1053.2×	0.004	MAP2K1
regulation of stress-activated MAPK cascade	1	936.2×	0.004	MAP2K1
snRNA transcription by RNA polymerase III	1	936.2×	0.004	SNAPC5
ERBB2-ERBB3 signaling pathway	1	842.6×	0.004	MAP2K1
snRNA transcription by RNA polymerase II	1	766.0×	0.004	SNAPC5
Bergmann glial cell differentiation	1	766.0×	0.004	MAP2K1
placenta blood vessel development	1	702.2×	0.004	MAP2K1
positive regulation of protein serine/threonine kinase activity	1	648.1×	0.004	MAP2K1
positive regulation of ATP biosynthetic process	1	601.9×	0.004	MAP2K1
Schwann cell development	1	526.6×	0.005	MAP2K1
type B pancreatic cell proliferation	1	443.5×	0.005	MAP2K1
positive regulation of Ras protein signal transduction	1	443.5×	0.005	MAP2K1
vesicle transport along microtubule	1	443.5×	0.005	MAP2K1
regulation of neurotransmitter receptor localization to postsynaptic specialization membrane	1	443.5×	0.005	MAP2K1
face development	1	401.2×	0.005	MAP2K1
melanosome transport	1	383.0×	0.005	MAP2K1
central nervous system neuron differentiation	1	300.9×	0.006	MAP2K1

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
MAP2K1	VEMURAFENIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MAP2K1	54	4
SNAPC5	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VEMURAFENIB	4	MAP2K1
SELUMETINIB	4	MAP2K1
TRAMETINIB	4	MAP2K1
COBIMETINIB	4	MAP2K1
BINIMETINIB	4	MAP2K1
DASATINIB	4	MAP2K1
SORAFENIB	4	MAP2K1
FEDRATINIB	4	MAP2K1
AXITINIB	4	MAP2K1
RUXOLITINIB	4	MAP2K1
NERATINIB	4	MAP2K1
TOFACITINIB	4	MAP2K1
VANDETANIB	4	MAP2K1
BOSUTINIB	4	MAP2K1
GILTERITINIB	4	MAP2K1
NINTEDANIB	4	MAP2K1
SUNITINIB	4	MAP2K1
SARACATINIB	3	MAP2K1
AVUTOMETINIB	3	MAP2K1
LINSITINIB	3	MAP2K1
ORANTINIB	3	MAP2K1
CANERTINIB	3	MAP2K1
DOVITINIB	3	MAP2K1
LESTAURTINIB	3	MAP2K1
CI-1040	2	MAP2K1
MIRDAMETINIB	2	MAP2K1
E-6201	2	MAP2K1
FORETINIB	2	MAP2K1
REFAMETINIB	2	MAP2K1
TAK-733	2	MAP2K1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
MAP2K1	1,200	Binding:1150, Functional:47, ADMET:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MAP2K1	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
MAP2K1	1,200

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	MAP2K1
SELUMETINIB	4	MAP2K1
TRAMETINIB	4	MAP2K1
COBIMETINIB	4	MAP2K1
BINIMETINIB	4	MAP2K1
DASATINIB	4	MAP2K1
SORAFENIB	4	MAP2K1
FEDRATINIB	4	MAP2K1
AXITINIB	4	MAP2K1
RUXOLITINIB	4	MAP2K1
NERATINIB	4	MAP2K1
TOFACITINIB	4	MAP2K1
VANDETANIB	4	MAP2K1
BOSUTINIB	4	MAP2K1
GILTERITINIB	4	MAP2K1
NINTEDANIB	4	MAP2K1
SUNITINIB	4	MAP2K1
SARACATINIB	3	MAP2K1
AVUTOMETINIB	3	MAP2K1
LINSITINIB	3	MAP2K1
ORANTINIB	3	MAP2K1
CANERTINIB	3	MAP2K1
DOVITINIB	3	MAP2K1
LESTAURTINIB	3	MAP2K1
CI-1040	2	MAP2K1
MIRDAMETINIB	2	MAP2K1
E-6201	2	MAP2K1
FORETINIB	2	MAP2K1
REFAMETINIB	2	MAP2K1
TAK-733	2	MAP2K1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	MAP2K1
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	SNAPC5

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)
SNAPC5	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.