Cardiofaciocutaneous syndrome 2

Summary

Cardiofaciocutaneous syndrome 2 (MONDO:0014112) is a disease caused by KRAS (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: KRAS (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 35

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	cardiofaciocutaneous syndrome 2
Mondo ID	MONDO:0014112
OMIM	615278
DOID	DOID:0111461
UMLS	C3809005
MedGen	815335
GARD	0015935
Is cancer (heuristic)	no

Also known as: cardiofaciocutaneous syndrome 2 · cardiofaciocutaneous syndrome caused by mutation in KRAS · cardiofaciocutaneous syndrome caused by mutation in kras · cardiofaciocutaneous syndrome type 2 · CFC2 · KRAS cardiofaciocutaneous syndrome · kras cardiofaciocutaneous syndrome

Data availability: 35 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 2

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

35 retrieved; paginated sample, class counts are floors:

9 uncertain significance, 8 pathogenic, 6 conflicting classifications of pathogenicity, 4 pathogenic/likely pathogenic, 4 likely benign, 2 likely pathogenic, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
12582	NM_004985.5(KRAS):c.35G>A (p.Gly12Asp)	KRAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12584	NM_004985.5(KRAS):c.34G>A (p.Gly12Ser)	KRAS	Pathogenic	criteria provided, multiple submitters, no conflicts
12586	NM_004985.5(KRAS):c.178G>C (p.Gly60Arg)	KRAS	Pathogenic	reviewed by expert panel
12587	NM_004985.5(KRAS):c.458A>T (p.Asp153Val)	KRAS	Pathogenic	reviewed by expert panel
12590	NM_004985.5(KRAS):c.101C>G (p.Pro34Arg)	KRAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12594	NM_033360.4(KRAS):c.15A>T (p.Lys5Asn)	KRAS	Pathogenic	reviewed by expert panel
12595	NM_033360.4(KRAS):c.*22C>G	KRAS	Pathogenic	criteria provided, multiple submitters, no conflicts
12597	NM_033360.4(KRAS):c.178G>A (p.Gly60Ser)	KRAS	Pathogenic	criteria provided, multiple submitters, no conflicts
31940	NM_033360.4(KRAS):c.211T>C (p.Tyr71His)	KRAS	Pathogenic	no assertion criteria provided
31941	NM_033360.4(KRAS):c.439A>G (p.Lys147Glu)	KRAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
40452	NM_004985.5(KRAS):c.65A>G (p.Gln22Arg)	KRAS	Pathogenic	reviewed by expert panel
45122	NM_004985.5(KRAS):c.35G>C (p.Gly12Ala)	KRAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2431456	NM_004985.5(KRAS):c.175_176delinsTT (p.Ala59Leu)	KRAS	Likely pathogenic	criteria provided, single submitter
40460	NM_033360.4(KRAS):c.355G>A (p.Asp119Asn)	KRAS	Likely pathogenic	criteria provided, multiple submitters, no conflicts
180857	NM_004985.5(KRAS):c.184GAG[1] (p.Glu63del)	KRAS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
197243	NM_004985.5(KRAS):c.436G>A (p.Ala146Thr)	KRAS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2454057	NM_004985.5(KRAS):c.168C>T (p.Leu56=)	KRAS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
503538	NM_004985.5(KRAS):c.407G>A (p.Ser136Asn)	KRAS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
620625	NM_033360.4(KRAS):c.*101_*106del	KRAS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
626130	NM_033360.4(KRAS):c.112-5C>T	KRAS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1046139	NM_004985.5(KRAS):c.388_389delinsAT (p.Ala130Ile)	KRAS	Uncertain significance	criteria provided, multiple submitters, no conflicts
1047419	NM_004985.5(KRAS):c.352T>C (p.Cys118Arg)	KRAS	Uncertain significance	criteria provided, multiple submitters, no conflicts
1098601	NM_004985.5(KRAS):c.58A>G (p.Thr20Ala)	KRAS	Uncertain significance	criteria provided, single submitter
1717054	NM_004985.5(KRAS):c.365C>G (p.Ser122Cys)	KRAS	Uncertain significance	criteria provided, multiple submitters, no conflicts
180861	NM_033360.4(KRAS):c.389C>T (p.Ala130Val)	KRAS	Uncertain significance	criteria provided, multiple submitters, no conflicts
1915455	NM_004985.5(KRAS):c.450+5G>A	KRAS	Uncertain significance	criteria provided, multiple submitters, no conflicts
2909102	NM_004985.5(KRAS):c.331A>G (p.Met111Val)	KRAS	Uncertain significance	criteria provided, multiple submitters, no conflicts
3574545	NM_004985.5(KRAS):c.451-6T>C	KRAS	Uncertain significance	criteria provided, single submitter
935432	NM_004985.5(KRAS):c.487A>G (p.Ile163Val)	KRAS	Uncertain significance	criteria provided, multiple submitters, no conflicts
138061	NM_033360.4(KRAS):c.90C>T (p.Asp30=)	KRAS	Likely benign	reviewed by expert panel

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 17 · 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
KRAS	Definitive	Autosomal dominant	cardiofaciocutaneous syndrome 2	17

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KRAS	Orphanet:1333	Familial pancreatic carcinoma
KRAS	Orphanet:1340	Cardiofaciocutaneous syndrome
KRAS	Orphanet:144	Lynch syndrome
KRAS	Orphanet:146	Differentiated thyroid carcinoma
KRAS	Orphanet:2396	Encephalocraniocutaneous lipomatosis
KRAS	Orphanet:251615	Pilomyxoid astrocytoma
KRAS	Orphanet:2612	Linear nevus sebaceus syndrome
KRAS	Orphanet:268114	RAS-associated autoimmune leukoproliferative disease
KRAS	Orphanet:3339	Oculoectodermal syndrome
KRAS	Orphanet:648	Noonan syndrome
KRAS	Orphanet:86834	Juvenile myelomonocytic leukemia

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
KRAS	HGNC:6407	ENSG00000133703	P01116	GTPase KRas	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KRAS	GTPase KRas	Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.

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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KRAS	Enzyme (other)	yes	3.6.5.2	Small_GTPase, Small_GTP-bd, Small_GTPase_Ras-type

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
nipple	1
pylorus	1
trigeminal ganglion	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KRAS	298	ubiquitous	marker	trigeminal ganglion, pylorus, nipple

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KRAS	14,509

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KRAS	P01116	511

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 71. 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 RAS GAP mutants	1	3806.7×	0.003	KRAS
Signaling by RAS GTPase mutants	1	3806.7×	0.003	KRAS
Activation of RAS in B cells	1	2284.0×	0.003	KRAS
RAS signaling downstream of NF1 loss-of-function variants	1	1631.4×	0.003	KRAS
Estrogen-stimulated signaling through PRKCZ	1	1631.4×	0.003	KRAS
SOS-mediated signalling	1	1427.5×	0.003	KRAS
Activated NTRK3 signals through RAS	1	1268.9×	0.003	KRAS
EGFR Transactivation by Gastrin	1	1142.0×	0.003	KRAS
SHC-related events triggered by IGF1R	1	1142.0×	0.003	KRAS
RUNX3 regulates p14-ARF	1	1142.0×	0.003	KRAS
Activated NTRK2 signals through RAS	1	1142.0×	0.003	KRAS
MET activates RAS signaling	1	1038.2×	0.003	KRAS
Signaling by FGFR4 in disease	1	951.7×	0.003	KRAS
Activated NTRK2 signals through FRS2 and FRS3	1	951.7×	0.003	KRAS
Constitutive Signaling by Overexpressed ERBB2	1	951.7×	0.003	KRAS
p38MAPK events	1	878.5×	0.003	KRAS
Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants	1	878.5×	0.003	KRAS
Signaling by PDGFRA extracellular domain mutants	1	878.5×	0.003	KRAS
PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases	1	815.7×	0.003	KRAS
GRB2 events in EGFR signaling	1	761.3×	0.003	KRAS
Erythropoietin activates RAS	1	761.3×	0.003	KRAS
Signaling by FLT3 ITD and TKD mutants	1	761.3×	0.003	KRAS
SHC1 events in ERBB4 signaling	1	713.8×	0.003	KRAS
SHC1 events in EGFR signaling	1	713.8×	0.003	KRAS
Constitutive Signaling by EGFRvIII	1	713.8×	0.003	KRAS
Signalling to RAS	1	671.8×	0.003	KRAS
Insulin receptor signalling cascade	1	671.8×	0.003	KRAS
Signaling by ERBB2 ECD mutants	1	671.8×	0.003	KRAS
GRB2 events in ERBB2 signaling	1	634.4×	0.003	KRAS
Tie2 Signaling	1	601.0×	0.003	KRAS

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
response to mineralocorticoid	1	16852.0×	0.002	KRAS
forebrain astrocyte development	1	5617.3×	0.002	KRAS
response to isolation stress	1	4213.0×	0.002	KRAS
response to gravity	1	2808.7×	0.003	KRAS
type I pneumocyte differentiation	1	1532.0×	0.003	KRAS
myoblast proliferation	1	1404.3×	0.003	KRAS
positive regulation of cellular senescence	1	1296.3×	0.003	KRAS
negative regulation of epithelial cell differentiation	1	1203.7×	0.003	KRAS
regulation of synaptic transmission, GABAergic	1	1053.2×	0.003	KRAS
regulation of long-term neuronal synaptic plasticity	1	991.3×	0.003	KRAS
striated muscle cell differentiation	1	991.3×	0.003	KRAS
glial cell proliferation	1	887.0×	0.003	KRAS
epithelial tube branching involved in lung morphogenesis	1	842.6×	0.003	KRAS
positive regulation of glial cell proliferation	1	702.2×	0.003	KRAS
positive regulation of Rac protein signal transduction	1	648.1×	0.003	KRAS
cardiac muscle cell proliferation	1	581.1×	0.003	KRAS
Rac protein signal transduction	1	561.7×	0.003	KRAS
homeostasis of number of cells within a tissue	1	443.5×	0.004	KRAS
skeletal muscle cell differentiation	1	343.9×	0.005	KRAS
response to glucocorticoid	1	324.1×	0.005	KRAS
visual learning	1	306.4×	0.005	KRAS
liver development	1	221.7×	0.006	KRAS
female pregnancy	1	210.7×	0.006	KRAS
Ras protein signal transduction	1	205.5×	0.006	KRAS
neuron apoptotic process	1	185.2×	0.007	KRAS
MAPK cascade	1	153.2×	0.008	KRAS
cytokine-mediated signaling pathway	1	130.6×	0.009	KRAS
negative regulation of neuron apoptotic process	1	110.9×	0.010	KRAS
gene expression	1	79.9×	0.013	KRAS
actin cytoskeleton organization	1	79.1×	0.013	KRAS

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
KRAS	VEMURAFENIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KRAS	11	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VEMURAFENIB	4	KRAS
DABRAFENIB	4	KRAS
LONAFARNIB	4	KRAS
SOTORASIB	4	KRAS
ADAGRASIB	4	KRAS
OPNURASIB	3	KRAS
DIVARASIB	2	KRAS
GLECIRASIB	2	KRAS
BMS-214662	1	KRAS
LY-3009120	1	KRAS
MRTX-1133	1	KRAS

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
KRAS	861	Binding:829, Functional:32

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
KRAS	3.6.5.2	small monomeric GTPase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
KRAS	861

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

11 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	KRAS
DABRAFENIB	4	KRAS
LONAFARNIB	4	KRAS
SOTORASIB	4	KRAS
ADAGRASIB	4	KRAS
OPNURASIB	3	KRAS
DIVARASIB	2	KRAS
GLECIRASIB	2	KRAS
BMS-214662	1	KRAS
LY-3009120	1	KRAS
MRTX-1133	1	KRAS

Druggability pyramid

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

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