Cerebral cavernous malformation 2

Summary

Cerebral cavernous malformation 2 (MONDO:0011304) is a disease caused by CCM2 (GenCC Definitive), with 3 cohort genes and 1 clinical trial.

At a glance

• Causal gene: CCM2 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 252
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	cerebral cavernous malformation 2
Mondo ID	MONDO:0011304
MeSH	C566394
OMIM	603284
DOID	DOID:0060670
UMLS	C1864041
MedGen	400438
GARD	0018313
Is cancer (heuristic)	no

Also known as: CCM2 · CCM2 familial cerebral cavernous malformation · cerebral cavernous malformation 2 · cerebral cavernous malformation type 2 · cerebral cavernous malformations 2 · cerebral cavernous malformations type 2 · cerebral cavernous malformations-2 · familial cerebral cavernous malformation caused by mutation in CCM2

Data availability: 252 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › cerebral cavernous malformation › famililal cerebral cavernous malformations › cerebral cavernous malformation 2

Related subtypes (4): cerebral cavernous malformation 3, cerebral cavernous malformation 1, cerebral cavernous malformation 4, cerebral cavernous malformations 5

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

252 retrieved; paginated sample, class counts are floors:

72 pathogenic, 59 uncertain significance, 54 likely benign, 14 benign, 13 benign/likely benign, 12 conflicting classifications of pathogenicity, 11 likely pathogenic, 9 pathogenic/likely pathogenic, 8 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
3063593	NC_000007.14:g.45043702_46521017delins[AGAAGGAAATTT;45310743_46521014;45043709_45310738inv]	ADCY1	Pathogenic	criteria provided, single submitter
1030944	NM_031443.4(CCM2):c.643C>T (p.Gln215Ter)	CCM2	Pathogenic	criteria provided, multiple submitters, no conflicts
1070815	NM_031443.4(CCM2):c.228dup (p.Pro77fs)	CCM2	Pathogenic	criteria provided, single submitter
1076028	NM_031443.4(CCM2):c.151G>T (p.Glu51Ter)	CCM2	Pathogenic	criteria provided, single submitter
1076241	NC_000007.13:g.(?45067284)(45115676_?)del	CCM2	Pathogenic	criteria provided, single submitter
1330532	NM_031443.4(CCM2):c.305dup (p.His104fs)	CCM2	Pathogenic	criteria provided, single submitter
1355285	NC_000007.13:g.(?45109405)(45109580_?)del	CCM2	Pathogenic	criteria provided, single submitter
1366649	NM_031443.4(CCM2):c.298C>T (p.Gln100Ter)	CCM2	Pathogenic	criteria provided, single submitter
1383573	NM_031443.4(CCM2):c.93del (p.Ala32fs)	CCM2	Pathogenic	criteria provided, single submitter
1400162	NM_031443.4(CCM2):c.473-2A>G	CCM2	Pathogenic	criteria provided, single submitter
1415667	NM_031443.4(CCM2):c.528_532del (p.Leu177fs)	CCM2	Pathogenic	criteria provided, single submitter
1427461	NC_000007.13:g.(?45039933)(45039982_?)del	CCM2	Pathogenic	criteria provided, single submitter
1456955	NM_031443.4(CCM2):c.1071_1074dup (p.Glu359delinsProTer)	CCM2	Pathogenic	criteria provided, single submitter
1458144	NM_031443.4(CCM2):c.83_87del (p.Arg28fs)	CCM2	Pathogenic	criteria provided, single submitter
193463	NM_031443.4(CCM2):c.30+5_30+6delinsTT	CCM2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1978046	NM_031443.4(CCM2):c.43delinsATTTAAACGAGTATTTAAA (p.Ser15delinsIleTer)	CCM2	Pathogenic	criteria provided, single submitter
1998853	NM_031443.4(CCM2):c.199dup (p.Val67fs)	CCM2	Pathogenic	criteria provided, single submitter
2014757	NM_031443.4(CCM2):c.369dup (p.Trp124fs)	CCM2	Pathogenic	criteria provided, single submitter
2021487	NM_031443.4(CCM2):c.50_54del (p.Phe17fs)	CCM2	Pathogenic	criteria provided, single submitter
2109629	NM_031443.4(CCM2):c.663del (p.Val220_Tyr221insTer)	CCM2	Pathogenic	criteria provided, single submitter
2136535	NM_031443.4(CCM2):c.652del (p.Gln218fs)	CCM2	Pathogenic	criteria provided, single submitter
2426972	NC_000007.13:g.(?45039933)(45115674_?)del	CCM2	Pathogenic	criteria provided, single submitter
2426973	NC_000007.13:g.(?45103497)(45109580_?)del	CCM2	Pathogenic	criteria provided, single submitter
2426974	NC_000007.13:g.(?45077832)(45115674_?)del	CCM2	Pathogenic	criteria provided, single submitter
2574653	NM_031443.4(CCM2):c.338T>C (p.Leu113Pro)	CCM2	Pathogenic	criteria provided, single submitter
2574654	NM_031443.4(CCM2):c.593T>C (p.Leu198Pro)	CCM2	Pathogenic	no assertion criteria provided
2574656	NM_031443.4(CCM2):c.365T>G (p.Leu122Arg)	CCM2	Pathogenic	no assertion criteria provided
2574657	NM_031443.4(CCM2):c.367G>C (p.Ala123Pro)	CCM2	Pathogenic	no assertion criteria provided
2680	NM_031443.4(CCM2):c.23del (p.Gly8fs)	CCM2	Pathogenic	criteria provided, single submitter
2681	NM_031443.4(CCM2):c.319C>T (p.Gln107Ter)	CCM2	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
CCM2	Definitive	Autosomal dominant	cerebral cavernous malformation 2	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CCM2	Orphanet:221061	Familial cerebral cavernous malformation
ADCY1	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CCM2	HGNC:21708	ENSG00000136280	Q9BSQ5	Cerebral cavernous malformations 2 protein	gencc,clinvar
NACAD	HGNC:22196	ENSG00000136274	O15069	NAC-alpha domain-containing protein 1	clinvar
ADCY1	HGNC:232	ENSG00000164742	Q08828	Adenylate cyclase type 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CCM2	Cerebral cavernous malformations 2 protein	Component of the CCM signaling pathway which is a crucial regulator of heart and vessel formation and integrity.
NACAD	NAC-alpha domain-containing protein 1	May prevent inappropriate targeting of non-secretory polypeptides to the endoplasmic reticulum (ER).
ADCY1	Adenylate cyclase type 1	Catalyzes the formation of the signaling molecule cAMP in response to G-protein signaling.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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	4.0×	0.460
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CCM2	Other/Unknown	no		PTB/PI_dom, PH-like_dom_sf, Malcavernin
NACAD	Other/Unknown	no		Nas_poly-pep-assoc_cplx_dom, EGD2/NACA0like, NAC_A/B_dom_sf
ADCY1	Enzyme (other)	yes	4.6.1.1	A/G_cyclase, A/G_cyclase_CS, Nucleotide_cyclase

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
anterior cingulate cortex	1
nucleus accumbens	1
putamen	1
dorsal root ganglion	1
inferior vagus X ganglion	1
middle frontal gyrus	1
Brodmann (1909) area 23	1
middle temporal gyrus	1
orbitofrontal cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CCM2	243	ubiquitous	marker	putamen, nucleus accumbens, anterior cingulate cortex
NACAD	203	ubiquitous	marker	inferior vagus X ganglion, middle frontal gyrus, dorsal root ganglion
ADCY1	220	broad	marker	middle temporal gyrus, Brodmann (1909) area 23, orbitofrontal cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NACAD	1,732
ADCY1	1,731
CCM2	1,600

Structural data

PDB: 1 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CCM2	Q9BSQ5	8

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ADCY1	Q08828	78.34
NACAD	O15069	40.13

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 49. Enrichment computed across 3 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
Adenylate cyclase activating pathway	1	1142.0×	0.008	ADCY1
CREB1 phosphorylation through the activation of Adenylate Cyclase	1	878.5×	0.008	ADCY1
Adenylate cyclase inhibitory pathway	1	761.3×	0.008	ADCY1
PKA activation in glucagon signalling	1	671.8×	0.008	ADCY1
PKA activation	1	634.4×	0.008	ADCY1
Activation of GABAB receptors	1	601.0×	0.008	ADCY1
PKA-mediated phosphorylation of CREB	1	571.0×	0.008	ADCY1
GABA B receptor activation	1	543.8×	0.008	ADCY1
Anti-inflammatory response favouring Leishmania parasite infection	1	393.8×	0.008	ADCY1
Leishmania parasite growth and survival	1	393.8×	0.008	ADCY1
Calmodulin induced events	1	380.7×	0.008	ADCY1
CaM pathway	1	380.7×	0.008	ADCY1
Ca-dependent events	1	368.4×	0.008	ADCY1
Aquaporin-mediated transport	1	368.4×	0.008	ADCY1
Glucagon signaling in metabolic regulation	1	346.1×	0.008	ADCY1
G-protein mediated events	1	326.3×	0.008	ADCY1
DAG and IP3 signaling	1	317.2×	0.008	ADCY1
GABA receptor activation	1	317.2×	0.008	ADCY1
Response of endothelial cells to shear stress	1	300.5×	0.008	ADCY1
FCGR3A-mediated IL10 synthesis	1	292.8×	0.008	ADCY1
Opioid Signalling	1	265.6×	0.008	ADCY1
PLC beta mediated events	1	265.6×	0.008	ADCY1
Vasopressin regulates renal water homeostasis via Aquaporins	1	265.6×	0.008	ADCY1
Cellular responses to mechanical stimuli	1	259.6×	0.008	ADCY1
ADORA2B mediated anti-inflammatory cytokines production	1	253.8×	0.008	ADCY1
GPER1 signaling	1	248.3×	0.008	ADCY1
G alpha (z) signalling events	1	233.1×	0.008	ADCY1
Post NMDA receptor activation events	1	203.9×	0.009	ADCY1
Activation of NMDA receptors and postsynaptic events	1	184.2×	0.009	ADCY1
Signaling by Hedgehog	1	184.2×	0.009	ADCY1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
endothelial cell development	1	1404.3×	0.008	CCM2
blood vessel endothelial cell differentiation	1	1123.5×	0.008	CCM2
venous blood vessel morphogenesis	1	802.5×	0.008	CCM2
pericardium development	1	624.1×	0.008	CCM2
endothelial tube morphogenesis	1	624.1×	0.008	CCM2
obsolete positive regulation of CREB transcription factor activity	1	561.7×	0.008	ADCY1
neuroinflammatory response	1	510.7×	0.008	ADCY1
cAMP biosynthetic process	1	468.1×	0.008	ADCY1
endothelium development	1	432.1×	0.008	CCM2
cellular response to forskolin	1	374.5×	0.009	ADCY1
cellular response to glucagon stimulus	1	280.9×	0.010	ADCY1
vascular endothelial cell response to laminar fluid shear stress	1	244.2×	0.010	ADCY1
stress-activated MAPK cascade	1	234.1×	0.010	CCM2
positive regulation of long-term synaptic potentiation	1	224.7×	0.010	ADCY1
cell-cell junction organization	1	208.1×	0.011	CCM2
renal water homeostasis	1	170.2×	0.012	ADCY1
presynaptic modulation of chemical synaptic transmission	1	151.8×	0.012	ADCY1
long-term memory	1	140.4×	0.012	ADCY1
regulation of angiogenesis	1	140.4×	0.012	CCM2
inner ear development	1	124.8×	0.013	CCM2
protein targeting to membrane	1	98.5×	0.016	NACAD
regulation of circadian rhythm	1	86.4×	0.016	ADCY1
vasculogenesis	1	85.1×	0.016	CCM2
rhythmic process	1	83.8×	0.016	ADCY1
cellular response to calcium ion	1	66.9×	0.020	ADCY1
integrin-mediated signaling pathway	1	53.5×	0.023	CCM2
axonogenesis	1	53.5×	0.023	ADCY1
multicellular organism growth	1	45.7×	0.026	CCM2
adenylate cyclase-activating G protein-coupled receptor signaling pathway	1	37.7×	0.030	ADCY1
heart development	1	26.2×	0.041	CCM2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 2

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ADCY1	2	3
CCM2	0	0
NACAD	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
NB-001	3	ADCY1
COLFORSIN	2	ADCY1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
ADCY1	47	Binding:34, Functional:12, ADMET:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ADCY1	4.6.1.1	adenylate cyclase

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

2 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)
NB-001	3	ADCY1
COLFORSIN	2	ADCY1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	1	ADCY1
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	CCM2, NACAD

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
CCM2	0	—
NACAD	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03652181	Not specified	COMPLETED	CASH (Cavernous Angiomas With Symptomatic Hemorrhage) Trial Readiness