Cerebral cavernous malformation

Summary

Cerebral cavernous malformation (MONDO:0000820) is a disease with 7 cohort genes and 9 clinical trials. Top therapeutic interventions include atorvastatin.

At a glance

• Cohort genes: 7
• ClinVar variants: 574
• Clinical trials: 9

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	cerebral cavernous malformation
Mondo ID	MONDO:0000820
Orphanet	164
DOID	DOID:0060669
ICD-11	916773262
NCIT	C84626
UMLS	C2919945
MedGen	418825
Is cancer (heuristic)	no

Also known as: brain cavernous hemangioma · CCM · cerebral cavernous malformation

Data availability: 574 ClinVar variants · 7 cell lines.

Disease family

An umbrella term covering 1 Mondo subtype.

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

Related subtypes (216): polymicrogyria, congenital myasthenic syndrome with tubular aggregates, prenatal-onset spinal muscular atrophy with congenital bone fractures, anencephaly, meningocele, progressive external ophthalmoplegia, congenital nystagmus, congenital toxoplasmosis, congenital contractural arachnodactyly, congenital trigeminal anesthesia, familial congenital palsy of trochlear nerve, Myhre syndrome, Aase-Smith syndrome, KBG syndrome, autosomal dominant primary microcephaly, Mobius syndrome, MYH7-related skeletal myopathy, congenital stationary night blindness autosomal dominant 2, Prader-Willi syndrome, congenital myopathy 7A, myosin storage, autosomal dominant, Smith-Magenis syndrome, spina bifida, Freeman-Sheldon syndrome, isolated cerebellar hypoplasia/agenesis, Chediak-Higashi syndrome, Cohen syndrome, multiple pterygium-malignant hyperthermia syndrome, corpus callosum, agenesis of, congenital lactic acidosis, Saguenay-Lac-Saint-Jean type, facial dysmorphism-macrocephaly-myopia-Dandy-Walker malformation syndrome, diastematomyelia, EEM syndrome, Mowat-Wilson syndrome, Johanson-Blizzard syndrome, intellectual disability, Buenos-Aires type, myasthenia, congenital, refractory to acetylcholinesterase inhibitors, congenital myasthenic syndrome 6, Bailey-Bloch congenital myopathy, congenital stationary night blindness 1B, radioulnar synostosis-developmental delay-hypotonia syndrome, Schinzel-Giedion syndrome, schizencephaly, intellectual disability, Wolff type, X-linked intellectual disability-plagiocephaly syndrome, X-linked adrenal hypoplasia congenita, syndromic X-linked intellectual disability 7, syndromic X-linked intellectual disability Shashi type, syndromic X-linked intellectual disability Lubs type, syndromic X-linked intellectual disability Abidi type, syndromic X-linked intellectual disability Siderius type, X-linked intellectual disability, Cabezas type, X-linked intellectual disability-cubitus valgus-dysmorphism syndrome, syndromic X-linked intellectual disability Claes-Jensen type, moyamoya angiopathy-short stature-facial dysmorphism-hypergonadotropic hypogonadism syndrome, multiple congenital anomalies-hypotonia-seizures syndrome 2, developmental and epileptic encephalopathy, 36, blepharophimosis - intellectual disability syndrome, MKB type, X-linked intellectual disability-short stature-overweight syndrome, intellectual disability, X-linked, syndromic 33, syndromic X-linked intellectual disability 34, infantile-onset X-linked spinal muscular atrophy, syndromic X-linked intellectual disability 5, holoprosencephaly-hypokinesia-congenital contractures syndrome, X-linked intellectual disability with marfanoid habitus, Wieacker-Wolff syndrome, MERRF syndrome, macrocephaly-spastic paraplegia-dysmorphism syndrome, intellectual disability-sparse hair-brachydactyly syndrome, myofibrillar myopathy 1, isolated hereditary congenital facial paralysis, fibrosis of extraocular muscles, congenital, 2, Pierpont syndrome, congenital cataracts-facial dysmorphism-neuropathy syndrome, Bohring-Opitz syndrome, PHACE syndrome, B4GALT1-congenital disorder of glycosylation, developmental malformations-deafness-dystonia syndrome, sensory ataxic neuropathy, dysarthria, and ophthalmoparesis, AICA-ribosiduria, myofibrillar myopathy 3, fibrosis of extraocular muscles, congenital, 3c, myofibrillar myopathy 4, myofibrillar myopathy 5, cone-rod synaptic disorder, congenital nonprogressive, congenital stationary night blindness autosomal dominant 3, congenital stationary night blindness autosomal dominant 1, intellectual disability, autosomal recessive 12, progressive myoclonic epilepsy type 3, chromosome 15q13.3 microdeletion syndrome, combined pituitary hormone deficiencies, genetic form, congenital stationary night blindness 1D, DYRK1A-related intellectual disability syndrome, Pitt-Hopkins-like syndrome 2, developmental and epileptic encephalopathy, 15, Schuurs-Hoeijmakers syndrome, severe intellectual disability-poor language-strabismus-grimacing face-long fingers syndrome, severe intellectual disability-progressive spastic diplegia syndrome, hypotonia, infantile, with psychomotor retardation and characteristic facies, developmental and epileptic encephalopathy, 18, CTCF-related neurodevelopmental disorder, autism spectrum disorder due to AUTS2 deficiency, developmental and epileptic encephalopathy, 23, ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder, Bardet-Biedl syndrome 11, cerebellar-facial-dental syndrome, fibrosis of extraocular muscles, congenital, 5, congenital myasthenic syndrome 15, lethal fetal cerebrorenogenitourinary agenesis/hypoplasia syndrome, autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome, congenital myasthenic syndrome 18, autosomal recessive spinocerebellar ataxia 20, Houge-Janssens syndrome 1, intellectual disability-microcephaly-strabismus-behavioral abnormalities syndrome, congenital stationary night blindness 1G, hypomyelinating leukodystrophy 10, developmental and epileptic encephalopathy, 50, congenital insensitivity to pain-hypohidrosis syndrome, macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome, SLC39A8-CDG, spastic paraplegia-severe developmental delay-epilepsy syndrome, cardiac anomalies - developmental delay - facial dysmorphism syndrome, severe intellectual disability-corpus callosum agenesis-facial dysmorphism-cerebellar ataxia syndrome, intellectual disability, autosomal recessive 53, TELO2-related intellectual disability-neurodevelopmental disorder, micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome, autosomal recessive limb-girdle muscular dystrophy type 2Y, myofibrillar myopathy 7, short stature-brachydactyly-obesity-global developmental delay syndrome, autosomal recessive limb-girdle muscular dystrophy type 2R1, severe microbrachycephaly-intellectual disability-athetoid cerebral palsy syndrome, congenital laryngeal palsy, congenital or early infantile CACH syndrome, congenital epulis, severe congenital nemaline myopathy, intermediate nemaline myopathy, typical nemaline myopathy, childhood-onset nemaline myopathy, adult-onset nemaline myopathy, qualitative or quantitative defects of protein involved in O-glycosylation of alpha-dystroglycan, holoprosencephaly, congenital insensitivity to pain with hyperhidrosis, congenital hydrocephalus, familial congenital mirror movements, macrocephaly-short stature-paraplegia syndrome, cephalocele, mitochondrial neurogastrointestinal encephalomyopathy, X-linked intellectual disability-hypogonadism-ichthyosis-obesity-short stature syndrome, 7p22.1 microduplication syndrome, congenital achiasma, congenital retinal arteriovenous communication, 3q27.3 microdeletion syndrome, Prader-Willi-like syndrome, 9q31.1q31.3 microdeletion syndrome, congenital oculomotor nerve palsy, congenital abducens nerve palsy, neurodevelopmental disorder-craniofacial dysmorphism-cardiac defect-hip dysplasia syndrome, congenital insensitivity to pain with severe intellectual disability, X-linked intellectual disability-cerebellar hypoplasia-spondylo-epiphyseal dysplasia syndrome, global developmental delay-visual anomalies-progressive cerebellar atrophy-truncal hypotonia syndrome, lissencephaly spectrum disorders, hyaline body myopathy, 22q11.2 deletion syndrome, craniorachischisis, Leber congenital amaurosis, Ritscher-Schinzel syndrome, Rubinstein-Taybi syndrome, X-linked intellectual disability-hypogammaglobulinemia-progressive neurological deterioration syndrome, X-linked intellectual disability-epilepsy-progressive joint contractures-dysmorphism syndrome, X-linked intellectual disability, Pai type, X-linked intellectual disability, Stevenson type, X-linked intellectual disability, Stoll type, congenital muscular dystrophy, congenital vitreoretinal dysplasia, periventricular nodular heterotopia, postsynaptic congenital myasthenic syndrome, subcortical band heterotopia, congenital fibrosis of extraocular muscles type 1, Al Gazali Khidr Prem Chandran syndrome, distal arthrogryposis Moore weaver type, congenital myotonic dystrophy, myasthenic syndrome, congenital, 7B, presynaptic, autosomal recessive, intellectual disability, autosomal dominant 47, intellectual disability, autosomal dominant 48, spondyloepiphyseal dysplasia, sensorineural hearing loss, impaired intellectual development, and leber congenital amaurosis, myasthenic syndrome, congenital, 23, presynaptic, myasthenic syndrome, congenital, 24, presynaptic, myasthenic syndrome, congenital, 25, presynaptic, developmental and epileptic encephalopathy, 77, night blindness, congenital stationary, type1i, neuropathy, congenital hypomelinating, congenital axonal neuropathy with encephalopathy, developmental and epileptic encephalopathy, 73, PHIP-related behavioral problems-intellectual disability-obesity-dysmorphic features syndrome, isolated exencephaly, myasthenic syndrome, congenital, 22, intellectual developmental disorder with gastrointestinal difficulties and high pain threshold, intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomalies, 9q33.3q34.11 microdeletion syndrome, congenital labioscrotal agenesis-cerebellar malformation-corneal dystrophy-facial dysmorphism syndrome, early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome, SIN3A-related intellectual disability syndrome, childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder, X-linked congenital stationary night blindness, neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies, FOXG1 disorder, alpha-actinopathy, TPM3-related myopathy, X-linked recessive mitochondrial myopathy, RYR1-related myopathy, TTN-related myopathy, TPM2-related myopathy, myopathy caused by variation in POMGNT1, central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease, segmental spinal dysgenesis, myopathy, myofibrillar, 13, with rimmed vacuoles, congenital neuronal ceroid lipofuscinosis 10

Subtypes (1): famililal cerebral cavernous malformations

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

574 retrieved; paginated sample, class counts are floors:

248 pathogenic, 134 uncertain significance, 67 likely benign, 29 conflicting classifications of pathogenicity, 28 pathogenic/likely pathogenic, 26 benign/likely benign, 25 likely pathogenic, 14 benign, 3 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1344507	NM_031443.4(CCM2):c.147del (p.Leu49fs)	CCM2	Pathogenic	criteria provided, single submitter
1068679	NM_194454.3(KRIT1):c.1333C>T (p.Gln445Ter)	KRIT1	Pathogenic	criteria provided, multiple submitters, no conflicts
1068705	NM_194454.3(KRIT1):c.1616T>G (p.Leu539Ter)	KRIT1	Pathogenic	criteria provided, single submitter
1069273	NM_194454.3(KRIT1):c.1297del (p.Ser433fs)	KRIT1	Pathogenic	criteria provided, single submitter
1070438	NM_194454.3(KRIT1):c.1446dup (p.His483fs)	KRIT1	Pathogenic	criteria provided, single submitter
1070522	NM_194454.3(KRIT1):c.206T>A (p.Leu69Ter)	KRIT1	Pathogenic	criteria provided, single submitter
1071790	NM_194454.3(KRIT1):c.1099dup (p.His367fs)	KRIT1	Pathogenic	criteria provided, single submitter
1071796	NM_194454.3(KRIT1):c.382G>T (p.Gly128Ter)	KRIT1	Pathogenic	criteria provided, single submitter
1072402	NC_000007.13:g.(?91829918)(91851387_?)del	KRIT1	Pathogenic	criteria provided, single submitter
1072403	NC_000007.13:g.(?91863743)(91871469_?)del	KRIT1	Pathogenic	criteria provided, single submitter
1073009	NM_194454.3(KRIT1):c.1162C>T (p.Gln388Ter)	KRIT1	Pathogenic	criteria provided, single submitter
1074210	NM_194454.3(KRIT1):c.250C>T (p.Gln84Ter)	KRIT1	Pathogenic	criteria provided, single submitter
1074229	NM_194454.3(KRIT1):c.2113A>T (p.Lys705Ter)	KRIT1	Pathogenic	criteria provided, single submitter
1074264	NC_000007.13:g.(?91851196)(91871469_?)del	KRIT1	Pathogenic	criteria provided, single submitter
1074265	NC_000007.13:g.(?91866961)(91871469_?)del	KRIT1	Pathogenic	criteria provided, single submitter
1074639	NM_194454.3(KRIT1):c.2049T>G (p.Tyr683Ter)	KRIT1	Pathogenic	criteria provided, single submitter
1074766	NM_194454.3(KRIT1):c.1389_1390del (p.Ile463fs)	KRIT1	Pathogenic	criteria provided, single submitter
1075474	NM_194454.3(KRIT1):c.1980_1981delinsGT (p.Gly661Ter)	KRIT1	Pathogenic	criteria provided, single submitter
1075800	NM_194454.3(KRIT1):c.1212G>A (p.Trp404Ter)	KRIT1	Pathogenic	criteria provided, single submitter
1187060	NM_194454.3(KRIT1):c.1146+1G>T	KRIT1	Pathogenic	criteria provided, multiple submitters, no conflicts
1252052	NM_194454.3(KRIT1):c.992A>G (p.Tyr331Cys)	KRIT1	Pathogenic	no assertion criteria provided
1299386	NM_194454.3(KRIT1):c.1664C>T (p.Ala555Val)	KRIT1	Pathogenic	criteria provided, multiple submitters, no conflicts
1320113	NM_194454.3(KRIT1):c.1444C>T (p.Gln482Ter)	KRIT1	Pathogenic	criteria provided, single submitter
1331022	NM_194454.3(KRIT1):c.1287dup (p.Ser430fs)	KRIT1	Pathogenic	criteria provided, multiple submitters, no conflicts
1333479	NM_194454.3(KRIT1):c.1097del (p.Gly366fs)	KRIT1	Pathogenic	criteria provided, single submitter
1355783	NC_000007.14:g.92201424dup	KRIT1	Pathogenic	criteria provided, single submitter
1358522	NM_194454.3(KRIT1):c.2100_2101dup (p.Ser701fs)	KRIT1	Pathogenic	criteria provided, single submitter
1365930	NM_194454.3(KRIT1):c.1400C>G (p.Ser467Ter)	KRIT1	Pathogenic	criteria provided, multiple submitters, no conflicts
1397943	NM_194454.3(KRIT1):c.1255_1270del16 (p.Glu420fs)	KRIT1	Pathogenic	criteria provided, single submitter
1422325	NM_194454.3(KRIT1):c.1927_1928del (p.Gln643fs)	KRIT1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 10 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KRIT1	Orphanet:221061	Familial cerebral cavernous malformation
CCM2	Orphanet:221061	Familial cerebral cavernous malformation
FGB	Orphanet:101041	Familial hypofibrinogenemia
FGB	Orphanet:248408	Familial hypodysfibrinogenemia
FGB	Orphanet:98880	Familial afibrinogenemia
FGB	Orphanet:98881	Familial dysfibrinogenemia
NOTCH3	Orphanet:136	Cerebral autosomal dominant arteriopathy-subcortical infarcts-leukoencephalopathy
NOTCH3	Orphanet:2591	Infantile myofibromatosis
NOTCH3	Orphanet:2789	Lateral meningocele syndrome
PDCD10	Orphanet:221061	Familial cerebral cavernous malformation

Cohort genes → proteins

7 cohort genes, 7 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	7

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
KRIT1	HGNC:1573	ENSG00000001631	O00522	Krev interaction trapped protein 1	clinvar
CCM2	HGNC:21708	ENSG00000136280	Q9BSQ5	Cerebral cavernous malformations 2 protein	clinvar
ANKIB1	HGNC:22215	ENSG00000001629	Q9P2G1	Ankyrin repeat and IBR domain-containing protein 1	clinvar
LRRD1	HGNC:34300	ENSG00000240720	A4D1F6	Leucine-rich repeat and death domain-containing protein 1	clinvar
FGB	HGNC:3662	ENSG00000171564	P02675	Fibrinogen beta chain	clinvar
NOTCH3	HGNC:7883	ENSG00000074181	Q9UM47	Neurogenic locus notch homolog protein 3	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.
CCM2	Cerebral cavernous malformations 2 protein	Component of the CCM signaling pathway which is a crucial regulator of heart and vessel formation and integrity.
ANKIB1	Ankyrin repeat and IBR domain-containing protein 1	Might act as an E3 ubiquitin-protein ligase, or as part of E3 complex, which accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes and then transfers it to substrates.
FGB	Fibrinogen beta chain	Cleaved by the protease thrombin to yield monomers which, together with fibrinogen alpha (FGA) and fibrinogen gamma (FGG), polymerize to form an insoluble fibrin matrix.
NOTCH3	Neurogenic locus notch homolog protein 3	Functions as a receptor for membrane-bound ligands Jagged1, Jagged2 and Delta1 to regulate cell-fate determination.
PDCD10	Programmed cell death protein 10	Promotes cell proliferation.

Protein-family classification

Druggable: 0 · Difficult: 3 · Unknown: 4 · 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	2	4.9×	0.173
Transcription factor	1	1.2×	0.626
Other/Unknown	4	1.0×	0.626

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KRIT1	Scaffold/PPI	no		FERM_domain, Ankyrin_rpt, PH-like_dom_sf
CCM2	Other/Unknown	no		PTB/PI_dom, PH-like_dom_sf, Malcavernin
ANKIB1	Transcription factor	no		Znf_RING, Ankyrin_rpt, IBR_dom
LRRD1	Other/Unknown	no		Death_dom, Leu-rich_rpt, Leu-rich_rpt_typical-subtyp
FGB	Other/Unknown	no		Fibrinogen_a/b/g_C_dom, Fibrinogen_a/b/g_coil_dom, Fibrinogen_a/b/g_C_1
NOTCH3	Scaffold/PPI	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, Notch_dom
PDCD10	Other/Unknown	no		PDCD10, PDC10_dimerisation_sf, PDCD10_N

Expression context

Cohort genes with no expression data: 0.

7 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)	7
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	2
corpus callosum	2
colonic epithelium	1
anterior cingulate cortex	1
nucleus accumbens	1
putamen	1
kidney epithelium	1
left testis	1
male germ line stem cell (sensu Vertebrata) in testis	1
right testis	1
liver	1
right lobe of liver	1
type B pancreatic cell	1
popliteal artery	1
right coronary artery	1
tibial artery	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
CCM2	243	ubiquitous	marker	putamen, nucleus accumbens, anterior cingulate cortex
ANKIB1	261	ubiquitous	marker	corpus callosum, calcaneal tendon, kidney epithelium
LRRD1	74	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, left testis, right testis
FGB	159	broad	marker	right lobe of liver, liver, type B pancreatic cell
NOTCH3	273	ubiquitous	marker	popliteal artery, tibial artery, right coronary artery
PDCD10	295	ubiquitous	marker	jejunal mucosa, mucosa of sigmoid colon, colonic mucosa

Protein interactions among cohort

Intra-cohort edges: 5.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NOTCH3	4,403
FGB	2,503
PDCD10	1,792
CCM2	1,600
KRIT1	1,290
ANKIB1	846
LRRD1	808

Intra-cohort edges

A	B	Sources
ANKIB1	LRRD1	string_interaction
CCM2	KRIT1	biogrid_interaction, intact, string_interaction
CCM2	PDCD10	intact, string_interaction
KRIT1	LRRD1	string_interaction
KRIT1	PDCD10	intact, string_interaction

Structural data

PDB: 5 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FGB	P02675	41
KRIT1	O00522	15
PDCD10	Q9BUL8	10
CCM2	Q9BSQ5	8
NOTCH3	Q9UM47	6

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
LRRD1	A4D1F6	81.53
ANKIB1	Q9P2G1	66.52

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 27. Enrichment computed across 7 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Aggregated β-amyloid interacts with fibrinogen	1	1427.5×	0.009	FGB
Defective LFNG causes SCDO3	1	1142.0×	0.009	NOTCH3
Pre-NOTCH Processing in the Endoplasmic Reticulum	1	951.7×	0.009	NOTCH3
Noncanonical activation of NOTCH3	1	713.8×	0.009	NOTCH3
Fibrin formation	1	439.2×	0.009	FGB
p130Cas linkage to MAPK signaling for integrins	1	380.7×	0.009	FGB
GRB2:SOS provides linkage to MAPK signaling for Integrins	1	356.9×	0.009	FGB
Pre-NOTCH Processing in Golgi	1	317.2×	0.009	NOTCH3
MyD88 deficiency (TLR2/4)	1	300.5×	0.009	FGB
IRAK4 deficiency (TLR2/4)	1	285.5×	0.009	FGB
Regulation of TLR by endogenous ligand	1	248.3×	0.009	FGB
NOTCH3 Activation and Transmission of Signal to the Nucleus	1	237.9×	0.009	NOTCH3
NOTCH3 Intracellular Domain Regulates Transcription	1	219.6×	0.009	NOTCH3
Integrin signaling	1	211.5×	0.009	FGB
Notch-HLH transcription pathway	1	203.9×	0.009	NOTCH3
Signaling by high-kinase activity BRAF mutants	1	158.6×	0.010	FGB
MAP2K and MAPK activation	1	142.8×	0.010	FGB
Signaling by RAF1 mutants	1	139.3×	0.010	FGB
Signaling by moderate kinase activity BRAF mutants	1	126.9×	0.010	FGB
Paradoxical activation of RAF signaling by kinase inactive BRAF	1	126.9×	0.010	FGB
Signaling downstream of RAS mutants	1	126.9×	0.010	FGB
Signaling by BRAF and RAF1 fusions	1	85.2×	0.014	FGB
MyD88:MAL(TIRAP) cascade initiated on plasma membrane	1	76.1×	0.015	FGB
Integrin cell surface interactions	1	67.2×	0.017	FGB
ER-Phagosome pathway	1	64.9×	0.017	FGB
Pre-NOTCH Transcription and Translation	1	61.4×	0.017	NOTCH3
Platelet degranulation	1	43.9×	0.023	FGB

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 7 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	3	555.6×	1e-06	KRIT1, CCM2, PDCD10
regulation of angiogenesis	3	180.6×	2e-05	KRIT1, CCM2, PDCD10
negative regulation of endothelial cell apoptotic process	2	141.6×	0.002	KRIT1, FGB
intrinsic apoptotic signaling pathway in response to hydrogen peroxide	1	802.5×	0.019	PDCD10
glomerular capillary formation	1	802.5×	0.019	NOTCH3
endothelial cell development	1	601.9×	0.019	CCM2
blood vessel endothelial cell differentiation	1	481.5×	0.019	CCM2
Golgi reassembly	1	481.5×	0.019	PDCD10
induction of bacterial agglutination	1	401.2×	0.019	FGB
venous blood vessel morphogenesis	1	343.9×	0.019	CCM2
neuroblast differentiation	1	300.9×	0.019	NOTCH3
negative regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis	1	300.9×	0.019	PDCD10
establishment of Golgi localization	1	267.5×	0.019	PDCD10
pericardium development	1	267.5×	0.019	CCM2
endothelial tube morphogenesis	1	267.5×	0.019	CCM2
blood coagulation, fibrin clot formation	1	240.7×	0.019	FGB
cellular response to leptin stimulus	1	218.9×	0.019	FGB
positive regulation of peptide hormone secretion	1	218.9×	0.019	FGB
integrin activation	1	200.6×	0.019	KRIT1
plasminogen activation	1	185.2×	0.019	FGB
positive regulation of heterotypic cell-cell adhesion	1	185.2×	0.019	FGB
positive regulation of protein serine/threonine kinase activity	1	185.2×	0.019	PDCD10
angiogenesis	2	17.8×	0.019	KRIT1, PDCD10
wound healing, spreading of cells	1	160.5×	0.021	PDCD10
protein polymerization	1	141.6×	0.022	FGB
negative regulation of cell migration involved in sprouting angiogenesis	1	141.6×	0.022	PDCD10
regulation of establishment of cell polarity	1	133.8×	0.022	KRIT1
fibrinolysis	1	120.4×	0.023	FGB
positive regulation of stress-activated MAPK cascade	1	114.6×	0.023	PDCD10
neuron fate commitment	1	114.6×	0.023	NOTCH3

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 2 · Undrugged: 5

Druggability breadth: 3 of 7 evidence-associated genes (43%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FGB	1	2
NOTCH3	1	2
KRIT1	0	0
CCM2	0	0
ANKIB1	0	0
LRRD1	0	0
PDCD10	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
SANGUINARIUM	2	FGB
VAREGACESTAT	2	NOTCH3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
NOTCH3	3	Binding:3
FGB	2	Binding:2
PDCD10	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 7; 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)
SANGUINARIUM	2	FGB
VAREGACESTAT	2	NOTCH3

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	2	FGB, NOTCH3
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	5	KRIT1, CCM2, ANKIB1, LRRD1, PDCD10

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
KRIT1	0	—
CCM2	0	—
ANKIB1	0	—
LRRD1	0	—
PDCD10	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 9.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	6
PHASE2	2
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02603328	PHASE1/PHASE2	COMPLETED	Atorvastatin Treatment of Cavernous Angiomas With Symptomatic Hemorrhage Exploratory Proof of Concept (AT CASH EPOC) Trial
NCT03589014	PHASE2	COMPLETED	Treat_CCM: Propranolol in Familial Cerebral Cavernous Malformation
NCT05085561	PHASE2	COMPLETED	The Symptomatic Cerebral Cavernous Malformation Trial of REC-994
NCT04467489	Not specified	ACTIVE_NOT_RECRUITING	Biomarkers of CASH
NCT06983132	Not specified	RECRUITING	Natural History of Familial Cerebral Cavernous Malformations: the CCM_Italia Cohort Study
NCT02946866	Not specified	UNKNOWN	CoHOrt of Cerebral CavernOus maLformATion: multicEnter Prospective Observational Study
NCT03652181	Not specified	COMPLETED	CASH (Cavernous Angiomas With Symptomatic Hemorrhage) Trial Readiness
NCT05148663	Not specified	TERMINATED	CCM Blood Biomarker Validation Study
NCT05298709	Not specified	TERMINATED	Functional Magnetic Resonance Imaging (fMRI) Vascular Reactivity in Cerebral Cavernous Malformations (CCM)

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ATORVASTATIN	4	1