CCM2

Chr 7AD

CCM2 scaffold protein

Also known as: C7orf22, OSM, PP10187

NCBI Gene: 83605ENSG00000136280UniProt: Q9BSQ5

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]

Primary Disease Associations & Inheritance

Cerebral cavernous malformations-2MIM #603284
AD
Cerebral cavernous malformations-2MIM #603284
AD
454
ClinVar variants
151
Pathogenic / LP
0.01
pLI score
2
Active trials
Clinical Summary— CCM2
🧬
Gene-Disease Validity (ClinGen)
cerebral cavernous malformation 2 · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.01) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
151 Pathogenic / Likely Pathogenic· 146 VUS of 454 total submissions
💊
Clinical Trials
2 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.66LOEUF
pLI 0.009
Z-score 2.68
OE 0.35 (0.20–0.66)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.52Z-score
OE missense 0.91 (0.82–1.01)
244 obs / 267.9 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.35 (0.20–0.66)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.91 (0.82–1.01)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.11
0≤1.21.6
LoF obs/exp: 7 / 19.9Missense obs/exp: 244 / 267.9Syn Z: -0.96

ClinVar Variant Classifications

454 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic115
Likely Pathogenic36
VUS146
Likely Benign106
Benign37
Conflicting14
115
Pathogenic
36
Likely Pathogenic
146
VUS
106
Likely Benign
37
Benign
14
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
51
6
58
0
115
Likely Pathogenic
22
2
11
1
36
VUS
3
127
16
0
146
Likely Benign
0
7
36
63
106
Benign
0
4
29
4
37
Conflicting
—14
Total7614615068454

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

CCM2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

CCM2-related cerebral cavernous malformation

definitive
ADLoss Of FunctionAbsent Gene Product
Skin
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

2 OMIM entries

OMIM

Cerebral cavernous malformations-2

MIM #603284

Molecular basis of disorder known

Autosomal dominant

Cerebral cavernous malformations-2

MIM #603284

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — CCM2
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Convergence of coronary artery disease genes onto endothelial cell programs.
Schnitzler GR et al.·Nature
2024
Cerebral cavernous malformations - An overview on genetics, clinical aspects and therapeutic strategies.
Dulamea AO et al.·J Neurol Sci
2024Review
Epigenetic regulation by polycomb repressive complex 1 promotes cerebral cavernous malformations.
Pham VC et al.·EMBO Mol Med
2024
[Cerebral cavernous malformations].
Koht J et al.·Tidsskr Nor Laegeforen
2005Review
Pathology of cavernous malformations.
Cox EM et al.·Handb Clin Neurol
2017Review
Genetics of cavernous angiomas.
Labauge P et al.·Lancet Neurol
2007Review
Circulating biomarkers in familial cerebral cavernous malformation.
Lazzaroni F et al.·EBioMedicine
2024
KRIT1 in vascular biology and beyond.
Glading AJ·Biosci Rep
2024Review
Molecular diagnosis in cerebral cavernous malformations.
Mondejar R et al.·Neurologia
2017Review
Kinases in cerebral cavernous malformations: Pathogenesis and therapeutic targets.
Qi C et al.·Biochim Biophys Acta Mol Cell Res
2023Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Cavernous Angioma, FamilialCerebral Cavernous MalformationsCerebral Cavernous Hemangioma

Modifiers of Disease Severity in Cerebral Cavernous Malformations

ACTIVE NOT RECRUITING
NCT01764529University of California, San FranciscoStarted 2010-04-27
Cavernous Malformation, Cerebral

Daratumumab for Familial Cerebral Cavernous Malformations: A Single-Arm Safety and Efficacy Study

NOT YET RECRUITING
NCT07026604Phase EARLY_PHASE1Beijing Tiantan HospitalStarted 2025-07-01
Daratumumab

External Resources

Links to major genomics databases and tools