Cerebral cavernous malformation 1

Summary

Cerebral cavernous malformation 1 (MONDO:0020724) is a disease caused by KRIT1 (GenCC Definitive), with 2 cohort genes and 6 clinical trials. Top therapeutic interventions include propranolol.

At a glance

• Causal gene: KRIT1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 15
• Clinical trials: 6

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	cerebral cavernous malformation 1
Mondo ID	MONDO:0020724
OMIM	116860
DOID	DOID:0080491
UMLS	C1366911
MedGen	237128
GARD	0025224
Is cancer (heuristic)	no

Also known as: CCM · cerebral cavernous malformation 1 · cerebral cavernous malformations · cerebral cavernous malformations-1 · familial cerebral cavernous malformation 1

Data availability: 15 ClinVar variants · 5 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 1

Related subtypes (4): cerebral cavernous malformation 2, cerebral cavernous malformation 3, 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

15 retrieved; paginated sample, class counts are floors:

13 pathogenic, 1 pathogenic/likely pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1678641	NM_194454.3(KRIT1):c.1561C>T (p.Gln521Ter)	KRIT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1805590	NM_194454.3(KRIT1):c.857G>A (p.Trp286Ter)	KRIT1	Pathogenic	criteria provided, single submitter
1805790	NM_194454.3(KRIT1):c.953_956del (p.Asp318fs)	KRIT1	Pathogenic	criteria provided, single submitter
2102716	NM_194454.3(KRIT1):c.150_151del (p.Lys51fs)	KRIT1	Pathogenic	criteria provided, multiple submitters, no conflicts
279827	NM_194454.3(KRIT1):c.151_154del (p.Lys51fs)	KRIT1	Pathogenic	criteria provided, multiple submitters, no conflicts
468207	NM_194454.3(KRIT1):c.1362_1363del (p.Gln455fs)	KRIT1	Pathogenic	criteria provided, multiple submitters, no conflicts
5718	NM_194454.3(KRIT1):c.1879C>T (p.Gln627Ter)	KRIT1	Pathogenic	criteria provided, single submitter
5719	NM_194454.3(KRIT1):c.1940del (p.Lys647fs)	KRIT1	Pathogenic	no assertion criteria provided
5720	NM_194454.3(KRIT1):c.1867dup (p.Arg623fs)	KRIT1	Pathogenic	criteria provided, single submitter
5721	NM_194454.3(KRIT1):c.1363C>T (p.Gln455Ter)	KRIT1	Pathogenic	criteria provided, multiple submitters, no conflicts
5723	NM_194454.3(KRIT1):c.845+2T>C	KRIT1	Pathogenic	no assertion criteria provided
5726	NM_194454.3(KRIT1):c.601C>G (p.Gln201Glu)	KRIT1	Pathogenic	criteria provided, multiple submitters, no conflicts
5728	NM_194454.3(KRIT1):c.987C>A (p.Cys329Ter)	KRIT1	Pathogenic	no assertion criteria provided
1338866	NM_007217.4(PDCD10):c.131dup (p.Arg45fs)	PDCD10	Pathogenic	criteria provided, single submitter
5725	NM_194454.3(KRIT1):c.410A>G (p.Asp137Gly)	KRIT1	Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
KRIT1	Definitive	Autosomal dominant	cerebral cavernous malformation 1	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KRIT1	Orphanet:221061	Familial cerebral cavernous malformation
PDCD10	Orphanet:221061	Familial cerebral cavernous malformation

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
KRIT1	HGNC:1573	ENSG00000001631	O00522	Krev interaction trapped protein 1	gencc,clinvar
PDCD10	HGNC:8761	ENSG00000114209	Q9BUL8	Programmed cell death protein 10	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KRIT1	Krev interaction trapped protein 1	Component of the CCM signaling pathway which is a crucial regulator of heart and vessel formation and integrity.
PDCD10	Programmed cell death protein 10	Promotes cell proliferation.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.0

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
Scaffold/PPI	1	8.6×	0.225
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KRIT1	Scaffold/PPI	no		FERM_domain, Ankyrin_rpt, PH-like_dom_sf
PDCD10	Other/Unknown	no		PDCD10, PDC10_dimerisation_sf, PDCD10_N

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
calcaneal tendon	1
colonic epithelium	1
corpus callosum	1
colonic mucosa	1
jejunal mucosa	1
mucosa of sigmoid colon	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KRIT1	138	ubiquitous	marker	calcaneal tendon, colonic epithelium, corpus callosum
PDCD10	295	ubiquitous	marker	jejunal mucosa, mucosa of sigmoid colon, colonic mucosa

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PDCD10	1,792
KRIT1	1,290

Intra-cohort edges

A	B	Sources
KRIT1	PDCD10	intact, string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KRIT1	O00522	15
PDCD10	Q9BUL8	10

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 2 evidence-associated genes (0 with Reactome annotation).

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
endothelium development	2	1296.3×	2e-05	KRIT1, PDCD10
regulation of angiogenesis	2	421.3×	9e-05	KRIT1, PDCD10
angiogenesis	2	62.4×	0.003	KRIT1, PDCD10
intrinsic apoptotic signaling pathway in response to hydrogen peroxide	1	2808.7×	0.003	PDCD10
Golgi reassembly	1	1685.2×	0.004	PDCD10
negative regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis	1	1053.2×	0.005	PDCD10
establishment of Golgi localization	1	936.2×	0.005	PDCD10
integrin activation	1	702.2×	0.005	KRIT1
positive regulation of protein serine/threonine kinase activity	1	648.1×	0.005	PDCD10
wound healing, spreading of cells	1	561.7×	0.005	PDCD10
negative regulation of cell migration involved in sprouting angiogenesis	1	495.6×	0.005	PDCD10
regulation of establishment of cell polarity	1	468.1×	0.005	KRIT1
positive regulation of stress-activated MAPK cascade	1	401.2×	0.005	PDCD10
negative regulation of endothelial cell migration	1	383.0×	0.005	KRIT1
positive regulation of peptidyl-serine phosphorylation	1	383.0×	0.005	PDCD10
positive regulation of intracellular protein transport	1	337.0×	0.006	PDCD10
positive regulation of MAP kinase activity	1	324.1×	0.006	PDCD10
negative regulation of endothelial cell proliferation	1	271.8×	0.006	KRIT1
negative regulation of endothelial cell apoptotic process	1	247.8×	0.007	KRIT1
positive regulation of Notch signaling pathway	1	175.5×	0.009	PDCD10
cell redox homeostasis	1	172.0×	0.009	KRIT1
small GTPase-mediated signal transduction	1	91.6×	0.015	KRIT1
negative regulation of angiogenesis	1	84.3×	0.016	KRIT1
cellular response to leukemia inhibitory factor	1	79.5×	0.016	PDCD10
negative regulation of gene expression	1	34.5×	0.035	PDCD10
protein stabilization	1	33.4×	0.035	PDCD10
positive regulation of cell migration	1	30.9×	0.037	PDCD10
positive regulation of gene expression	1	19.4×	0.055	PDCD10
intracellular signal transduction	1	19.1×	0.055	PDCD10
negative regulation of apoptotic process	1	17.4×	0.059	PDCD10

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KRIT1	0	0
PDCD10	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
PDCD10	1	Binding:1

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

0 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.

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	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	KRIT1, PDCD10

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)
KRIT1	0	—
PDCD10	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 6.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	4
PHASE2	1
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03474614	PHASE2	TERMINATED	Effect of Oral Propranolol on mRNA Expresssion in Symptomatic Cavernous Malformation
NCT01764451	EARLY_PHASE1	TERMINATED	Permeability MRI in Cerebral Cavernous Malformations Type 1 in New Mexico: Effects of Statins
NCT01764529	Not specified	ACTIVE_NOT_RECRUITING	Modifiers of Disease Severity in Cerebral Cavernous Malformations
NCT06983132	Not specified	RECRUITING	Natural History of Familial Cerebral Cavernous Malformations: the CCM_Italia Cohort Study
NCT03467295	Not specified	UNKNOWN	Treatments and Outcomes of Untreated Cerebral Cavernous Malformations in CHina.
NCT03652181	Not specified	COMPLETED	CASH (Cavernous Angiomas With Symptomatic Hemorrhage) Trial Readiness

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
PROPRANOLOL	4	1