GeneBe

CCM2

protein-coding

CCM2 scaffold protein, the group of CCM adhesion complex

Gene summary

This gene encodes a scaffold protein that functions in the stress-activated p38 Mitogen-activated protein kinase (MAPK) signaling cascade. The protein interacts with SMAD specific E3 ubiquitin protein ligase 1 (also known as SMURF1) via a phosphotyrosine binding domain to promote RhoA degradation. The protein is required for normal cytoskeletal structure, cell-cell interactions, and lumen formation in endothelial cells. Mutations in this gene result in cerebral cavernous malformations. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Nov 2009]

Previous symbols:
  • C7orf22

MANE transcript

NM_031443.4

Inheritance

AD

ClinVar variants

P:126U:153B:91

Top phenotype

Cerebral cavernous malformations 2

gnomAD constraint

pLI —, LoF o/e 0.35

Max pathogenic AF

—

Genomic locus

chr7:44,999,475-45,076,469

External References & Databases

Ensembl (ENSG00000136280)NCBI Gene (83605)OMIM (607929)HGNC:21708GenCCUniProt (Q9BSQ5)AlphaFoldClinVar (CCM2)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~77.0 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

cerebral cavernous malformation 2DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011304

Submitter: ClinGen

CCM2 scaffold protein (*CCM2*) was first reported in relation to autosomal dominant cerebral cavernous malformation 2 in 2003 (Liquori et al., PMID: 14624391). Germline variation in *CCM2* accounts for approximately 20% of familial cerebral cavernous malformations (CCM) and is associated with less severe disease (PMID 39740786). *CCM2* related CCMs are typically adult-onset but there is at least one reported case of onset in childhood (PMID 31937560). 20 variants (6 missense, 4 nonsense, 6 frameshift, and 4 splice site) that have been reported in 24 probands in 4 publications (PMIDs 14624391, 39181174, 31937560, 14740320) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence has been reached. The mechanism of pathogenicity appears to be a two-hit mechanism, with a germline LOF variant and somatic variation in the wildtype allele at the site of lesion formation (PMIDs 19088123, 31446422). This gene-disease relationship is also supported by coimmunoprecipitation data and animal models (PMIDs 18981891, 17900104, 21596842). Experimental data confirm that *CCM2* interacts with KRIT1, and PDCD10 which are both associated with monogenic CCM. Further, two mouse models support the two-hit mechanism of pathogenesis. In summary, there is definitive evidence supporting the relationship between *CCM2* and autosomal dominant cerebral cavernous malformation 2. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Neurovascular Disorders GCEP on May 27, 2025 (SOP Version 11).

cerebral cavernous malformation 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011304

Submitter: Genomics England PanelApp

famililal cerebral cavernous malformationsSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0031037

Submitter: Orphanet

cerebral cavernous malformation 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011304

Submitter: Labcorp Genetics (formerly Invitae)

cerebral cavernous malformation 2DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011304

Submitter: G2P

Clinical Genomic Database (CGD)

Cerebral cavernous malformations 2AD

Manifestation: Cardiovascular; Neurologic

Intervention: Cardiovascular; Neurologic; Pharmacogenomic

Rationale: Surveillance measures (eg, spinal cord MRI, annual brain gradient echo or susceptibility-weighted imaging) has been advocated; Agents that increase risk of hemorrhage should be avoided (eg, aspirin, NSAIDs, heparin, warfarin).

Refs: 14624391; 17211633; 17160895; 18060436; 18779516; 19088123; 21543988; 20301470Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CCM2 variants in ClinVar

11 Conditions Cataloged
Cerebral cavernous malformation 2Total: 238
not providedTotal: 123
Inborn genetic diseasesTotal: 113
CCM2-related disorderTotal: 45
not specifiedTotal: 45
Cerebral cavernous malformationTotal: 4
Vascular dementiaTotal: 2
VasculitisTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_031443.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
2
clinvar
3
clinvar
68
clinvar
3
clinvar
 76
missense
5
clinvar
3
clinvar
145
clinvar
18
clinvar
2
clinvar
 173
nonsense
16
clinvar
6
clinvar
 22
start loss
1
clinvar
1
clinvar
 2
frameshift
44
clinvar
23
clinvar
1
clinvar
 68
splice donor/acceptor (+/-2bp)
13
clinvar
12
clinvar
4
clinvar
 29
Total7947153865370

Highest pathogenic variant AF is 0.000025369043

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 112 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_031443.4RefSeqNP_113631.110MANE Select
ENST00000258781.11EnsemblENSP00000258781.710MANE Select
NM_001029835.2RefSeqNP_001025006.110Standard
NM_001167934.2RefSeqNP_001161406.19Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
ccm2Danio rerio

Structure: blood vessel endothelial cell

Quality: decreased length

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Regulation of p38-alpha and p38-beta
  • p38 MAPK signaling pathway

Biological Process

  • vasculogenesis
  • in utero embryonic development
  • endothelial cell development
  • integrin-mediated signaling pathway
  • multicellular organism growth

Molecular Function

  • protein binding

Cellular Component

  • cytoplasm
  • mitochondrion
  • protein-containing complex

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000381112
Coding exons
10
Length
76995
Individuals with no LoFs
125737
Homozygous LoFs
0
Heterozygous LoFs
11
Defined
125748
p
0.0000437
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.5182442680.9110.00001773042
Missense (PolyPhen)74107.670.687281166
Synonymous-0.9571301171.110.00000863924
Loss of Function2.68719.90.3519.70e-7243

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)0.0000440.000044rare
South Asian0.000160.00016rare
Other0.000160.00016rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Component of the CCM signaling pathway which is a crucial regulator of heart and vessel formation and integrity. May act through the stabilization of endothelial cell junctions (By similarity). May function as a scaffold protein for MAP2K3-MAP3K3 signaling. Seems to play a major role in the modulation of MAP3K3- dependent p38 activation induced by hyperosmotic shock (By similarity). {ECO:0000250}.;
Disease
DISEASE: Cerebral cavernous malformations 2 (CCM2) [MIM:603284]: A congenital vascular anomaly of the central nervous system that can result in hemorrhagic stroke, seizures, recurrent headaches, and focal neurologic deficits. The lesions are characterized by grossly enlarged blood vessels consisting of a single layer of endothelium and without any intervening neural tissue, ranging in diameter from a few millimeters to several centimeters. {ECO:0000269|PubMed:14624391, ECO:0000269|PubMed:14740320, ECO:0000269|PubMed:22415356}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.116

Intolerance Scores

LoFtool
0.292
RVIS EVS
-0.38
RVIS percentile EVS
28.11

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.700

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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