CCM2

Summary

CCM2 (CCM2 scaffold protein, HGNC:21708) is a protein-coding gene on chromosome 7p13, encoding Cerebral cavernous malformations 2 protein (Q9BSQ5). Component of the CCM signaling pathway which is a crucial regulator of heart and vessel formation and integrity.

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.

Source: NCBI Gene 83605 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cerebral cavernous malformation 2 (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 20
• Clinical variants (ClinVar): 521 total — 93 pathogenic, 26 likely-pathogenic
• Phenotypes (HPO): 35
• MANE Select transcript: NM_031443

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21708
Approved symbol	CCM2
Name	CCM2 scaffold protein
Location	7p13
Locus type	gene with protein product
Status	Approved
Aliases	MGC4607, OSM
Ensembl gene	ENSG00000136280
Ensembl biotype	protein_coding
OMIM	607929
Entrez	83605

Gene structure

Transcript identifiers

Ensembl transcripts: 41 — 28 protein_coding, 6 protein_coding_CDS_not_defined, 5 retained_intron, 2 nonsense_mediated_decay

ENST00000258781, ENST00000381112, ENST00000461377, ENST00000470837, ENST00000472223, ENST00000474617, ENST00000475551, ENST00000476594, ENST00000477605, ENST00000478169, ENST00000478582, ENST00000480382, ENST00000480658, ENST00000481194, ENST00000482714, ENST00000488727, ENST00000492883, ENST00000541586, ENST00000544363, ENST00000648329, ENST00000860886, ENST00000860887, ENST00000860888, ENST00000860889, ENST00000860890, ENST00000860891, ENST00000860892, ENST00000860893, ENST00000860894, ENST00000938552, ENST00000938553, ENST00000938554, ENST00000956241, ENST00000956242, ENST00000956243, ENST00000956244, ENST00000956245, ENST00000956246, ENST00000956247, ENST00000956248, ENST00000956249

RefSeq mRNA: 6 — MANE Select: NM_031443 NM_001029835, NM_001167934, NM_001167935, NM_001363458, NM_001363459, NM_031443

CCDS: CCDS34630, CCDS5500, CCDS55108, CCDS55109

Canonical transcript exons

ENST00000258781 — 10 exons

Exon	Start	End
ENSE00001820070	45075777	45076453
ENSE00001947712	45000201	45000363
ENSE00003492752	45068443	45068579
ENSE00003496519	45069826	45069961
ENSE00003526601	45073460	45073571
ENSE00003550573	45063918	45064001
ENSE00003560977	45064463	45064646
ENSE00003564041	45072726	45072783
ENSE00003593170	45074270	45074408
ENSE00003596867	45038253	45038426

Expression profiles

Bgee: expression breadth ubiquitous, 243 present calls, max score 97.79.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 32.3274 / max 482.2196, expressed in 1822 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
78471	16.3224	1816
78470	7.7296	1749
78473	5.8870	309
78468	1.6843	999
78472	0.2950	109
78469	0.1997	68
78474	0.1060	42
204429	0.1035	42

Top tissues by expression

254 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
putamen	UBERON:0001874	97.79	gold quality
nucleus accumbens	UBERON:0001882	97.60	gold quality
anterior cingulate cortex	UBERON:0009835	97.37	gold quality
caudate nucleus	UBERON:0001873	97.35	gold quality
granulocyte	CL:0000094	97.31	gold quality
right frontal lobe	UBERON:0002810	97.13	gold quality
prefrontal cortex	UBERON:0000451	97.10	gold quality
Brodmann (1909) area 9	UBERON:0013540	96.80	gold quality
amygdala	UBERON:0001876	96.36	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	96.03	gold quality
frontal cortex	UBERON:0001870	95.87	gold quality
hypothalamus	UBERON:0001898	95.75	gold quality
neocortex	UBERON:0001950	95.74	gold quality
blood	UBERON:0000178	95.19	gold quality
right lobe of liver	UBERON:0001114	94.95	gold quality
right hemisphere of cerebellum	UBERON:0014890	94.91	gold quality
spleen	UBERON:0002106	94.81	gold quality
cerebellar hemisphere	UBERON:0002245	94.78	gold quality
cerebellar cortex	UBERON:0002129	94.74	gold quality
forebrain	UBERON:0001890	94.72	gold quality
cerebral cortex	UBERON:0000956	94.69	gold quality
substantia nigra	UBERON:0002038	94.69	gold quality
lymph node	UBERON:0000029	94.60	gold quality
brain	UBERON:0000955	94.45	gold quality
cerebellum	UBERON:0002037	94.27	gold quality
hindlimb stylopod muscle	UBERON:0004252	94.16	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	94.14	gold quality
midbrain	UBERON:0001891	94.13	gold quality
apex of heart	UBERON:0002098	93.84	gold quality
leukocyte	CL:0000738	93.82	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.06
E-GEOD-75367	no	663.20
E-MTAB-6379	no	330.99

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GATA2

miRNA regulators (miRDB)

28 targeting CCM2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-205-5P	99.81	70.05	1557
HSA-MIR-7856-5P	99.75	69.99	2901
HSA-MIR-6132	99.60	65.83	1554
HSA-MIR-6836-5P	99.60	65.62	1538
HSA-MIR-4251	99.40	69.19	3363
HSA-MIR-593-3P	99.22	67.28	1327
HSA-MIR-146A-3P	99.13	68.99	1881
HSA-MIR-6761-5P	98.71	68.03	1504
HSA-MIR-6516-5P	98.42	70.19	1551
HSA-MIR-3921	97.81	67.45	1431
HSA-MIR-1285-3P	97.72	67.02	1932
HSA-MIR-5189-5P	97.72	66.96	1814
HSA-MIR-4329	97.68	66.26	1003
HSA-MIR-4456	97.50	64.88	1678
HSA-MIR-612	97.26	65.95	1597
HSA-MIR-4653-5P	97.22	67.72	1429
HSA-MIR-4448	97.04	66.22	752
HSA-MIR-301A-5P	96.88	68.07	931
HSA-MIR-301B-5P	96.88	67.75	946
HSA-MIR-8071	95.69	64.93	484

Literature-anchored findings (GeneRIF, showing 40)

• MGC4607 encodes a protein with a phosphotyrosine-binding domain that may be part of the complex pathway of integrin signaling that, when perturbed, causes abnormal vascular morphogenesis in the brain, leading to CCM formation. (PMID:14624391)
• KRIT1, Malcavernin, and PDCD10 are differentially expressed in cerebral venous malformations and cerebral cavernous malformations (PMID:16239636)
• CCM1 and CCM2 have similar expression patterns during development and are involved in the same pathway important for central nervous system vascular development (PMID:16373645)
• Five percent of patients with familial cerebral cavernomas have retinal cavernomas. These lesions are clinically asymptomatic. They can be associated with any of the 3 cerebral cavernous malformation genes. (PMID:16769843)
• The prevalence of CCM2 is much higher than previously predicted, nearly equal to CCM1, and that large genomic deletions in the CCM2 gene represent a major component of this disease. (PMID:17160895)
• Through its NPXY motifs, Krit1 interacts with malcavernin and may shuttle it through the nucleus via its nuclear localization signal and nuclear export signals, thereby regulating its cellular function. (PMID:17290187)
• In a CCM2 affected family, we report a novel causative mutation, (54_55delAC) in exon 2 of the MGC4607 gene, that produces a truncated protein containing only 22 amino acids (PMID:17440989)
• CCM3 (PDCD10) coprecipitates and colocalizes with CCM2. CCM3 directly binds to serine/threonine kinase 25 (STK25, YSK1, SOK1) and the phosphatase domain of Fas-associated phosphatase-1 (FAP-1, PTPN13, PTP-Bas, PTP-BL). (PMID:17657516)
• data are in agreement with a loss-of-function mechanism for CCM mutations, uncover an N-terminal CCM2 domain required for CCM1 binding, and demonstrate full-length CCM2 as the essential core protein in the CCM1/CCM2/CCM3 complex (PMID:18300272)
• Biallelic germline and somatic mutations were identified in CCM1, CCM2 or PDCD10 from all forms of inherited cerebral cavernous malformations. (PMID:19088123)
• Complete localized loss of either CCM1, CCM2 or CCM3 protein expression depend on the inherited mutation in cerebral cavernous malformations. (PMID:19088124)
• CCM2 regulates endothelial cytoskeletal architecture, cell-to-cell interactions and lumen formation. Heterozygosity at Ccm2, a genotype equivalent to that in human CCM, results in impaired endothelial barrier function (PMID:19151728)
• Methods Multiplex Ligation-dependent Probe Amplification analysis integrates the consecutive sequence analysis of the 3 genes (Krit1/CCM1, MGC4607/CCM2, and PDCD10/CCM3) known to be responsible for cerebral cavernous malformation lesions. (PMID:19199464)
• a molecular mechanism for the pathogenesis of cerebral cavernous malformations (CCM) resulting from loss of CCM2-mediated localization of Smurf1, which controls RhoA degradation required for maintenance of normal endothelial cell physiology. (PMID:19318350)
• Aberrant splicing due to a silent nucleotide change in CCM2 gene in a family with cerebral cavernous malformation (PMID:19475721)
• CCM2 protein contributes to vasculogenesis and angiogenesis in human placenta. (PMID:19688696)
• CCM2 is a key mediator of TrkA-dependent cell death in pediatric neuroblastic tumors (PMID:19755102)
• The KRIT1-CCM2 interaction regulates endothelial junctional stability and vascular barrier function by suppressing activation of the RhoA/ROCK signaling pathway. This pathway is dysregulated in human cerebral cavernous malformation endothelium. (PMID:20308363)
• Genetic variations could interfere with the proper CCM1/CCM2/CCM3 protein complex thus explaining the observed clinical variability in cerebral cavernous malformations in a large family. (PMID:20419355)
• Among familial cases of Cerebral cavernous malformations 67% had a mutation in CCM1, 5.5% in CCM2, and 5.5% in CCM3 (PMID:21029238)
• Data suggest that the two base pair change in CCM2 has the potential to simplify genetic testing for cerebral cavernous malformation in the Ashkenazi Jewish population. (PMID:21543988)
• This study shows for the first time that CCM2 is present in the developing human neocortex. (PMID:21569831)
• The possible association of CCM2 polymorphisms with sporadic cerebral cavernous malformation, was investigated. (PMID:22378217)
• Here we describe the molecular characterization of an Italian child, a symptomatic patient, affected by multiple cerebral cavernous malformations, without a family history of the disease and harbouring a new MGC4607 gene mutation. (PMID:22415356)
• Diffraction data were collected from native and selenomethionine-substituted crystals of CCM2-Ct to resolutions of 2.9 and 2.7 A, respectively (PMID:22684070)
• Down-modulation of STK25, but not STK24, rescued medulloblastoma cells from NGF-induced TrkA-dependent cell death, suggesting that STK25 is part of the death-signaling pathway initiated by TrkA and CCM2. (PMID:22782892)
• A previously undescribed deletion mutation in CCM2 gene exon 5 is described in an Italian family with multiple cerebral cavernous malformations and epilepsy. (PMID:23000020)
• structural characterization of CCM2 (PMID:23266514)
• CCM2 mutations are associated with cerebral cavernous malformation in some Japanese patients. (PMID:23485406)
• DNA sequencing and deletion/duplication testing of the CCM1, CCM2, and CCM3 genes in the proband revealed a CCM1 c.601CNG mutation. (PMID:24007869)
• The identification of other four new mutations in 40 sporadic patients with either single or multiple cerebral cavernous malformations, is reported. (PMID:24058906)
• Prevalence, frequency and characterization of CCM1, CCM2 and CCM3 variants in cerebral cavernous malformation Spanish patients. (PMID:24466005)
• Cerebral cavernous malformation(CCM)s develop because of loss of heart of glass (HEG)-independent CCM2 signaling in murine transgenic endothelium of central nervous system after birth. (PMID:24643410)
• Data find that several disease-associated missense mutations in CCM2 have the potential to interrupt the KRIT1-CCM2 interaction by destabilizing the CCM2 PTB domain and that a KRIT1 mutation also disrupts this interaction (PMID:25525273)
• both CCM2 and CCM3 are required for normal endothelial cell network formation. (PMID:25825518)
• a new mutation in MGC4607/CCM2 was identified in several family members with spinal and cutaneous angiomas. (PMID:25869611)
• Studies suggest that the 3 proteins of the Cerebral Cavernous Malformations (CCM) complex KRIT1/CCM1, CCM2/malcavernin and CCM3/PDCD10 not only require one another for reciprocal stabilization, but also act as a platform for signal transduction. (PMID:26356566)
• A novel missense mutation in CCM2 were detected in cerebral cavernous malformations patient. Several CCM2 gene polymorphisms in sporadic CCM patients were reported. (PMID:28000143)
• Data suggest that signaling via ANP/ANPR (atrial natriuretic factor/ANP receptor) in vascular endothelial cells activates PAK4 (p21-activated kinase 4) and CCM2 (cerebral cavernous malformation 2 protein), resulting in phosphorylation of MLC (myosin light chain), cytoskeletal reorganization, and cell spreading; kinase homology domain of ANPRA (guanylyl cyclase-A) activates downstream targets of ANP/ANPR signaling. (PMID:28432261)
• Case-control study to investigate the possible association of others polymorphisms (c.485+65 C/G, c.989+63 C/G, c.1980 A/G in CCM1 gene, c.472+127 C/T in CCM2 and c.150 G/A in CCM3) with cerebral cavernous malformations. The five polymorphisms were characterized in 64 sporadic patients and in 90 healthy controls by ASO-PCR. Results suggest that some polymorphisms in CCM genes could play an important role in the disease. (PMID:28870584)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	ccm2	ENSDARG00000013705
mus_musculus	Ccm2	ENSMUSG00000000378
rattus_norvegicus	Ccm2	ENSRNOG00000060825

Paralogs (1): CCM2L (ENSG00000101331)

Protein

Protein identifiers

Cerebral cavernous malformations 2 protein — Q9BSQ5 (reviewed: Q9BSQ5)

Alternative names: Malcavernin

All UniProt accessions (6): A0A0A0MT72, A0A3B3IRS0, C9JUH3, E9PEC4, Q9BSQ5, H7C516

UniProt curated annotations — full annotation on UniProt →

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. 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.

Subunit / interactions. Part of a complex with MAP2K3, MAP3K3 and RAC1. Binds RAC1 directly and independently of its nucleotide-bound state. Interacts with HEG1 and KRIT1; KRIT1 greatly facilitates the interaction with HEG1. Interacts with PDCD10.

Subcellular location. Cytoplasm.

Disease relevance. Cerebral cavernous malformations 2 (CCM2) [MIM:603284] A form of cerebral cavernous malformations, 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. CCM2 inheritance is autosomal dominant. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The C-terminal region constitutes an independently folded domain that has structural similarity with the USH1C (harmonin) N-terminus, despite very low sequence similarity.

Similarity. Belongs to the CCM2 family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q9BSQ5-1	1	yes
Q9BSQ5-2	2
Q9BSQ5-3	3
Q9BSQ5-4	4

RefSeq proteins (6): NP_001025006, NP_001161406, NP_001161407, NP_001350387, NP_001350388, NP_113631* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006020	PTB/PI_dom	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR026159	Malcavernin	Family
IPR032375	CCM2_C	Domain

Pfam: PF16545

UniProt features (47 total): helix 11, modified residue 7, strand 7, sequence variant 6, splice variant 3, region of interest 3, sequence conflict 3, turn 3, compositionally biased region 2, chain 1, domain 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
4FQN	X-RAY DIFFRACTION	1.9
4YKD	X-RAY DIFFRACTION	1.93
4YL6	X-RAY DIFFRACTION	2.1
4Y5O	X-RAY DIFFRACTION	2.35
4YKC	X-RAY DIFFRACTION	2.7
4WJ7	X-RAY DIFFRACTION	2.75
4TVQ	X-RAY DIFFRACTION	2.8
9PVG	X-RAY DIFFRACTION	3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BSQ5-F1	67.48	0.24

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (7): 393, 394, 396, 399, 15, 164, 384

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 531 (showing top): GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_DN, GSE45365_NK_CELL_VS_CD11B_DC_DN, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_ENDOTHELIAL_CELL_DEVELOPMENT, GOBP_HEMATOPOIETIC_PROGENITOR_CELL_DIFFERENTIATION, MODULE_92, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_REGULATION_OF_PHOSPHORYLATION, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE, GOBP_RESPONSE_TO_PEPTIDE, GOBP_EPITHELIAL_CELL_DEVELOPMENT, MODULE_64, GOBP_PEPTIDYL_SERINE_MODIFICATION

GO Biological Process (17): vasculogenesis (GO:0001570), in utero embryonic development (GO:0001701), endothelial cell development (GO:0001885), endothelium development (GO:0003158), integrin-mediated signaling pathway (GO:0007229), heart development (GO:0007507), multicellular organism growth (GO:0035264), cell-cell junction organization (GO:0045216), regulation of angiogenesis (GO:0045765), inner ear development (GO:0048839), venous blood vessel morphogenesis (GO:0048845), stress-activated MAPK cascade (GO:0051403), pericardium development (GO:0060039), blood vessel endothelial cell differentiation (GO:0060837), endothelial tube morphogenesis (GO:0061154), blood vessel development (GO:0001568), vasculature development (GO:0001944)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (3): cytoplasm (GO:0005737), mitochondrion (GO:0005739), protein-containing complex (GO:0032991)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
blood vessel morphogenesis	2
endothelial cell differentiation	2
epithelium development	2
circulatory system development	2
anatomical structure development	2
cell differentiation	1
chordate embryonic development	1
epithelial cell development	1
cell surface receptor signaling pathway	1
animal organ development	1
multicellular organismal process	1
developmental growth	1
cell junction organization	1
angiogenesis	1
regulation of anatomical structure morphogenesis	1
regulation of vasculature development	1
ear development	1
venous blood vessel development	1
MAPK cascade	1
stress-activated protein kinase signaling cascade	1
heart development	1
blood vessel development	1
morphogenesis of an endothelium	1
epithelial tube morphogenesis	1
vasculature development	1
system development	1
binding	1
intracellular anatomical structure	1
cellular anatomical structure	1
cytoplasm	1
intracellular membrane-bounded organelle	1
cellular_component	1

Protein interactions and networks

STRING

1484 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CCM2	KRIT1	O00522	998
CCM2	PDCD10	Q9BUL8	998
CCM2	MAP3K3	Q99759	984
CCM2	MAP2K3	P46734	975
CCM2	ITGB1BP1	O14713	962
CCM2	AKT1	P31749	853
CCM2	HEG1	Q9ULI3	837
CCM2	SMURF1	Q9HCE7	822
CCM2	STK25	O00506	804
CCM2	RHOA	P06749	742
CCM2	RAP1A	P10113	738
CCM2	MYL2	P10916	643
CCM2	CDH5	P33151	641
CCM2	ROCK2	O75116	640
CCM2	STK26	Q9P289	593

IntAct

57 interactions, top by confidence:

A	B	Type	Score
CCM2	KRIT1	psi-mi:“MI:0915”(physical association)	0.960
KRIT1	CCM2	psi-mi:“MI:0915”(physical association)	0.960
KRIT1	CCM2	psi-mi:“MI:0914”(association)	0.960
KRIT1	CCM2	psi-mi:“MI:0407”(direct interaction)	0.960
CCM2	KRIT1	psi-mi:“MI:0914”(association)	0.960
CCM2	TLNRD1	psi-mi:“MI:0915”(physical association)	0.740
PDCD10	CCM2	psi-mi:“MI:0915”(physical association)	0.680
PDCD10	CCM2	psi-mi:“MI:0403”(colocalization)	0.680
PDCD10	CCM2	psi-mi:“MI:0407”(direct interaction)	0.680
AP1S2	AP1G1	psi-mi:“MI:0914”(association)	0.670
RIN1	CCM2	psi-mi:“MI:0915”(physical association)	0.670
AP1S2	AP1G1	psi-mi:“MI:0914”(association)	0.660
DOK4	CCM2	psi-mi:“MI:0915”(physical association)	0.570
VSTM2L	CCM2	psi-mi:“MI:0915”(physical association)	0.570
CCM2	TWIST2	psi-mi:“MI:0915”(physical association)	0.570

BioGRID (59): TWIST2 (Two-hybrid), VSTM2L (Two-hybrid), CCM2 (Two-hybrid), KRIT1 (Two-hybrid), DOK4 (Affinity Capture-Luminescence), CCM2 (Affinity Capture-Luminescence), CCM2 (Affinity Capture-Luminescence), CCM2 (Two-hybrid), KRIT1 (Affinity Capture-MS), ITGB1BP1 (Affinity Capture-MS), RAD21 (Affinity Capture-MS), UBE3D (Affinity Capture-MS), CCM2 (Affinity Capture-MS), DDX19B (Affinity Capture-MS), STK26 (Affinity Capture-MS)

ESM2 similar proteins: A2A2Y4, A2AFR3, A4IJ06, B9EJ86, E1C3P4, F1LXF1, G9CGD6, O08874, O14795, P49797, Q05AA6, Q0P4Q4, Q0VGY8, Q13474, Q14CM0, Q16513, Q3B7D5, Q566C5, Q5F3L9, Q5R803, Q62769, Q641K1, Q69ZK0, Q6DRP4, Q6NTL4, Q6PAJ1, Q6ZM86, Q7Z628, Q80TI0, Q8BHD4, Q8BMS9, Q8C0V9, Q8CB96, Q8IZC4, Q8K2Y9, Q8TCU6, Q923Q2, Q92625, Q96NE9, Q9BSQ5

Diamond homologs: Q6DRP4, Q8K2Y9, Q8VCC6, Q9BSQ5, Q9NUG4

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
STK25	up-regulates	CCM2	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

521 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	93
Likely pathogenic	26
Uncertain significance	200
Likely benign	98
Benign	37

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1030944	NM_031443.4(CCM2):c.643C>T (p.Gln215Ter)	Pathogenic
1070815	NM_031443.4(CCM2):c.228dup (p.Pro77fs)	Pathogenic
1076028	NM_031443.4(CCM2):c.151G>T (p.Glu51Ter)	Pathogenic
1076241	NC_000007.13:g.(?45067284)(45115676_?)del	Pathogenic
1172564	GRCh37/hg19 7p13(chr7:45058501-45136990)x1	Pathogenic
1173046	NM_031443.4(CCM2):c.586_589del (p.Val196fs)	Pathogenic
1256400	NC_000007.13:g.(?45039923)(45115656_?)del	Pathogenic
1328001	NM_031443.4(CCM2):c.236_237del (p.Tyr79fs)	Pathogenic
1330532	NM_031443.4(CCM2):c.305dup (p.His104fs)	Pathogenic
1344507	NM_031443.4(CCM2):c.147del (p.Leu49fs)	Pathogenic
1355285	NC_000007.13:g.(?45109405)(45109580_?)del	Pathogenic
1366649	NM_031443.4(CCM2):c.298C>T (p.Gln100Ter)	Pathogenic
1383573	NM_031443.4(CCM2):c.93del (p.Ala32fs)	Pathogenic
1400162	NM_031443.4(CCM2):c.473-2A>G	Pathogenic
1415667	NM_031443.4(CCM2):c.528_532del (p.Leu177fs)	Pathogenic
1427461	NC_000007.13:g.(?45039933)(45039982_?)del	Pathogenic
1456955	NM_031443.4(CCM2):c.1071_1074dup (p.Glu359delinsProTer)	Pathogenic
1458144	NM_031443.4(CCM2):c.83_87del (p.Arg28fs)	Pathogenic
1693392	NM_031443.4(CCM2):c.569dup (p.Glu191fs)	Pathogenic
1978046	NM_031443.4(CCM2):c.43delinsATTTAAACGAGTATTTAAA (p.Ser15delinsIleTer)	Pathogenic
1998853	NM_031443.4(CCM2):c.199dup (p.Val67fs)	Pathogenic
2014757	NM_031443.4(CCM2):c.369dup (p.Trp124fs)	Pathogenic
2021487	NM_031443.4(CCM2):c.50_54del (p.Phe17fs)	Pathogenic
2109629	NM_031443.4(CCM2):c.663del (p.Val220_Tyr221insTer)	Pathogenic
2136535	NM_031443.4(CCM2):c.652del (p.Gln218fs)	Pathogenic
2426972	NC_000007.13:g.(?45039933)(45115674_?)del	Pathogenic
2426973	NC_000007.13:g.(?45103497)(45109580_?)del	Pathogenic
2426974	NC_000007.13:g.(?45077832)(45115674_?)del	Pathogenic
253618	GRCh37/hg19 7p13(chr7:45065944-45115876)x1	Pathogenic
2574653	NM_031443.4(CCM2):c.338T>C (p.Leu113Pro)	Pathogenic

SpliceAI

2937 predictions. Top by Δscore:

Variant	Effect	Δscore
22:30264460:CGTAT:C	acceptor_gain	1.0000
22:30264996:GCTTA:G	donor_loss	1.0000
22:30264997:CTTAC:C	donor_loss	1.0000
22:30264998:TTA:T	donor_loss	1.0000
22:30264999:TA:T	donor_loss	1.0000
22:30265000:A:AC	donor_gain	1.0000
22:30265001:C:A	donor_loss	1.0000
22:30265001:C:CC	donor_gain	1.0000
22:30266764:A:AC	donor_gain	1.0000
22:30266765:C:CC	donor_gain	1.0000
22:30266765:CTGAG:C	donor_gain	1.0000
7:45000360:GAAG:G	donor_gain	1.0000
7:45000364:G:T	donor_loss	1.0000
7:45000365:T:G	donor_loss	1.0000
7:45064450:T:TA	acceptor_gain	1.0000
7:45064451:G:A	acceptor_gain	1.0000
7:45064462:GAGA:G	acceptor_gain	1.0000
7:45064633:G:GA	donor_gain	1.0000
7:45064642:GACAG:G	donor_gain	1.0000
7:45064643:ACAG:A	donor_loss	1.0000
7:45064644:CAGGT:C	donor_loss	1.0000
7:45064645:AG:A	donor_loss	1.0000
7:45064646:GG:G	donor_loss	1.0000
7:45064647:G:T	donor_loss	1.0000
7:45064648:T:G	donor_loss	1.0000
7:45064653:G:GT	donor_gain	1.0000
7:45069959:GCG:G	donor_gain	1.0000
7:45069962:G:GG	donor_gain	1.0000
7:45069967:T:G	donor_gain	1.0000
7:45072780:CTTT:C	donor_gain	1.0000

AlphaMissense

2912 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:45074271:T:C	L306P	1.000
7:45074283:T:A	L310Q	1.000
7:45074283:T:C	L310P	1.000
7:45074306:T:C	F318L	1.000
7:45074307:T:C	F318S	1.000
7:45074308:T:A	F318L	1.000
7:45074308:T:G	F318L	1.000
7:45074319:T:C	L322P	1.000
7:45074355:T:C	F334S	1.000
7:45074367:T:C	L338P	1.000
7:45074376:T:C	L341P	1.000
7:45074396:T:C	F348L	1.000
7:45074398:C:A	F348L	1.000
7:45074398:C:G	F348L	1.000
7:45074400:T:C	L349P	1.000
7:45075780:T:C	L353P	1.000
7:45075788:T:C	F356L	1.000
7:45075789:T:C	F356S	1.000
7:45075790:C:A	F356L	1.000
7:45075790:C:G	F356L	1.000
7:45075816:T:C	F365S	1.000
7:45075824:T:C	F368L	1.000
7:45075826:C:A	F368L	1.000
7:45075826:C:G	F368L	1.000
7:45075828:T:C	L369P	1.000
7:45038272:T:C	F17S	0.999
7:45038276:A:C	K18N	0.999
7:45038276:A:T	K18N	0.999
7:45063979:T:C	L89P	0.999
7:45064518:T:C	L115P	0.999

dbSNP variants (sampled 300 via entrez): RS1000043915 (7:45047481 G>A,T), RS1000051254 (7:45041001 CAA>C), RS1000065517 (7:45035577 T>A), RS1000104849 (7:45040820 CTA>C), RS1000120007 (7:45075818 G>A,C), RS1000121403 (7:45019953 A>G), RS1000182916 (7:45051804 G>A), RS1000201929 (7:45018615 C>T), RS1000215339 (7:45059756 A>G), RS1000253050 (7:45057142 T>G), RS1000316192 (7:45054257 G>A), RS1000326712 (7:45014151 T>C), RS1000357321 (7:45052085 C>G,T), RS1000400722 (7:45035301 A>G), RS1000418413 (7:45035859 G>A)

Disease associations

OMIM: gene MIM:607929 | disease phenotypes: MIM:603284, MIM:616268

GenCC curated gene-disease

Disease	Classification	Inheritance
cerebral cavernous malformation 2	Definitive	Autosomal dominant
famililal cerebral cavernous malformations	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
cerebral cavernous malformation 2	Definitive	AD

Mondo (7): cerebral cavernous malformation 2 (MONDO:0011304), cerebral cavernous malformation (MONDO:0000820), cavernous hemangioma (MONDO:0003155), autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome (MONDO:0014558), vasculitis (MONDO:0018882), vascular dementia (MONDO:0004648), famililal cerebral cavernous malformations (MONDO:0031037)

Orphanet (4): Familial cerebral cavernous malformation (Orphanet:221061), KAT6-related intellectual disability-craniofacial anomalies-cardiac defects syndrome (Orphanet:457193), Vasculitis (Orphanet:52759), NON RARE IN EUROPE: Cerebral cavernous malformations (Orphanet:164)

HPO phenotypes

35 total (30 of 35 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000951	Abnormality of the skin
HP:0001009	Telangiectasia
HP:0001028	Hemangioma
HP:0001048	Cavernous hemangioma
HP:0001250	Seizure
HP:0001297	Stroke
HP:0001324	Muscle weakness
HP:0001342	Cerebral hemorrhage
HP:0002170	Intracranial hemorrhage
HP:0002315	Headache
HP:0002514	Cerebral calcification
HP:0002516	Increased intracranial pressure
HP:0002572	Episodic vomiting
HP:0002650	Scoliosis
HP:0002858	Meningioma
HP:0003011	Abnormality of the musculature
HP:0003401	Paresthesia
HP:0003829	Typified by incomplete penetrance
HP:0006576	Hepatic vascular malformations
HP:0007797	Developmental retinal vascular malformation
HP:0007872	Choroidal hemangioma
HP:0009588	Vestibular schwannoma
HP:0009592	Astrocytoma
HP:0010512	Adrenal calcification
HP:0011276	Vascular skin abnormality
HP:0011513	Retinal cavernous hemangioma
HP:0012721	Venous malformation
HP:0012748	Focal T2 hyperintense brainstem lesion
HP:0012749	Focal T2 hypointense brainstem lesion

GWAS associations

20 associations (top):

Study	Trait	p-value
GCST001009_3	Nephropathy	2.000000e-09
GCST001725_109	Inflammatory bowel disease	3.000000e-14
GCST003974_1	Tonsillectomy	1.000000e-09
GCST005194_253	Coronary artery disease	1.000000e-07
GCST005194_258	Coronary artery disease	2.000000e-07
GCST005195_83	Coronary artery disease	4.000000e-08
GCST005196_254	Coronary artery disease	9.000000e-08
GCST005851_15	Delirium	1.000000e-06
GCST006429_24	Suicidal ideation	4.000000e-06
GCST006627_70	Diastolic blood pressure	2.000000e-09
GCST006979_198	Heel bone mineral density	5.000000e-10
GCST007856_14	Colorectal cancer or advanced adenoma	6.000000e-06
GCST010866_174	Coronary artery disease	4.000000e-10
GCST011365_115	Myocardial infarction	8.000000e-07
GCST011365_135	Myocardial infarction	2.000000e-06
GCST90002381_229	Eosinophil count	8.000000e-15
GCST90002382_369	Eosinophil percentage of white cells	4.000000e-12
GCST90002385_578	High light scatter reticulocyte count	9.000000e-13
GCST90002386_491	High light scatter reticulocyte percentage of red cells	6.000000e-12
GCST90002387_178	Immature fraction of reticulocytes	2.000000e-10

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0007924	tonsillectomy risk measurement
EFO:0004320	suicidal ideation
EFO:0006336	diastolic blood pressure
EFO:0009270	heel bone mineral density
EFO:0004842	eosinophil count
EFO:0007991	eosinophil percentage of leukocytes
EFO:0007986	reticulocyte count

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D015140	Dementia, Vascular	C10.228.140.300.400; C10.228.140.300.510.800.500; C10.228.140.380.230; C10.228.140.695.500; C14.907.137.126.372.500; C14.907.253.560.350.500; F03.615.400.350
D006392	Hemangioma, Cavernous	C04.557.645.375.385; C10.228.140.232.625; C14.907.454.385; C15.378.463.515.385
D014657	Vasculitis	C14.907.940
C566394	Cerebral Cavernous Malformations 2 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

25 total (human), top 25 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases abundance, increases expression	3
Benzo(a)pyrene	affects methylation, increases expression	2
Tretinoin	increases expression, decreases expression	2
aristolochic acid I	increases expression	1
FR900359	affects phosphorylation	1
triphenyl phosphate	affects expression	1
di-n-butylphosphoric acid	affects expression	1
2-palmitoylglycerol	increases expression	1
abrine	decreases expression	1
Sunitinib	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Air Pollutants, Occupational	decreases expression	1
Arsenic	decreases expression, increases abundance	1
Cadmium	increases expression, increases abundance	1
Caffeine	decreases phosphorylation	1
Doxorubicin	decreases expression	1
Hydralazine	affects cotreatment, increases expression	1
Nickel	decreases expression	1
Thiram	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Valproic Acid	affects cotreatment, increases expression	1
Aflatoxin B1	increases methylation	1
Cadmium Chloride	increases expression, increases abundance	1
Copper Sulfate	decreases expression	1
Particulate Matter	increases abundance, decreases expression	1

Clinical trials (associated diseases)

206 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00128895	PHASE4	TERMINATED	Prevention of Relapses in Proteinase 3 (PR3)-Anti-neutrophil Cytoplasmic Antibodies (ANCA)-Associated Vasculitis
NCT00307671	PHASE4	COMPLETED	Treatment of Necrotizing Vasculitides for Patients Older Than 65 Years
NCT01151644	PHASE4	UNKNOWN	Safety and Efficacy of Anti-Pandemic H1N1 Vaccination in Rheumatic Diseases
NCT01405807	PHASE4	UNKNOWN	Alemtuzumab for ANCA Associated Refractory Vasculitis
NCT03762824	PHASE4	COMPLETED	Combined Pneumococcal Conjugate and Polysaccharide Vaccination in Inflammatory Rheumatic Disease
NCT06763783	PHASE4	ENROLLING_BY_INVITATION	Vaccination Against Herpes Zoster in Patients With Inflammatory Rheumatic Diseases
NCT00165763	PHASE4	COMPLETED	Efficacy and Safety of Donepezil Hydrochloride (Aricept) in Vascular Dementia
NCT00847860	PHASE4	COMPLETED	Cilostazol Verse Asprin for Vascular Dementia in Poststroke Patients With White Matter Lesions
NCT00947531	PHASE4	COMPLETED	A Clinical Trial to Evaluate the Safety and Efficacy of 20 ml Cerebrolysin in Patients With Vascular Dementia
NCT00950430	PHASE4	ENROLLING_BY_INVITATION	Imaging of Brain Amyloid Plaques in the Aging Population
NCT00103792	PHASE3	COMPLETED	Mycophenolate Mofetil for Treatment of Relapses of Wegener’s Disease or Microscopic Polyangiitis (MPA)
NCT01257802	PHASE3	TERMINATED	GnRH-a for Ovarian Protection During CYC Therapy for Rheumatic Diseases
NCT01663623	PHASE3	COMPLETED	Belimumab in Remission of VASculitis
NCT01933724	PHASE3	ACTIVE_NOT_RECRUITING	The Assessment of Prednisone In Remission Trial (TAPIR) - Patient Centric Approach
NCT03371095	PHASE3	COMPLETED	Induction Therapy With Anti-TNFα vs Cyclophosphamide in Severe Behçet Disease
NCT03692416	PHASE3	UNKNOWN	The Effect of Some Drugs Used in Treatment of Vasculitis on the Complement System in Children
NCT06321601	PHASE3	RECRUITING	Study to Evaluate Avacopan in Combination With a Rituximab or Cyclophosphamide-containing Regimen, in Children From 6 Years to < 18 Years of Age With AAV.
NCT00099216	PHASE3	COMPLETED	Efficacy and Safety of Rivastigmine Capsules in Patients With Probable Vascular Dementia
NCT00130338	PHASE3	COMPLETED	Rivastigmine Capsules in Patients With Probable Vascular Dementia
NCT00209456	PHASE3	COMPLETED	Dopamine Transporter Scintigraphy Imaging (DAT-Imaging) in Patients With Lewy Body Dementia
NCT00249158	PHASE3	COMPLETED	A Study of the Effectiveness and Safety of Risperidone in the Treatment of Behavioral Disturbances in Patients With Dementia
NCT00261573	PHASE3	COMPLETED	A Study of the Safety and Effectiveness of Galantamine Versus Placebo in the Treatment of Patients With Vascular Dementia or Mixed Dementia
NCT00621647	PHASE3	COMPLETED	Seroquel- Agitation Associated With Dementia
NCT02453932	PHASE3	COMPLETED	Efficacy and Safety of Tianzhi Granule in Mild to Moderate Vascular Dementia
NCT03682185	PHASE3	COMPLETED	The Healthy Patterns Sleep Study
NCT03789760	PHASE3	COMPLETED	The Clinical Trial of Chinese Herbal Medicine (SaiLuoTong) Capsule
NCT03804229	PHASE3	ACTIVE_NOT_RECRUITING	Efficacy and Safety of Butylphthalide Soft Capsule for the Treatment of Vascular Dementia
NCT03986424	PHASE3	COMPLETED	Local Study of Akatinol Memantine in VaD in Russia
NCT04552041	PHASE3	COMPLETED	Prospekta in the Treatment of Cognitive, Behavioral and Psychiatric Disorders in Patients With Vascular Dementia.
NCT03474614	PHASE2	TERMINATED	Effect of Oral Propranolol on mRNA Expresssion in Symptomatic Cavernous Malformation
NCT03589014	PHASE2	COMPLETED	Treat_CCM: Propranolol in Familial Cerebral Cavernous Malformation
NCT05085561	PHASE2	COMPLETED	The Symptomatic Cerebral Cavernous Malformation Trial of REC-994
NCT00001155	PHASE2	COMPLETED	Treatment of Wegener’s Granulomatosis With Cyclophosphamide
NCT00001256	PHASE2	COMPLETED	Steroids and Methotrexate to Treat Systemic Vasculitis
NCT00001901	PHASE2	COMPLETED	Etanercept to Treat Wegener’s Granulomatosis
NCT00004357	PHASE2	COMPLETED	Absorption of Corticosteroids in Children With Juvenile Dermatomyositis
NCT00004567	PHASE2	COMPLETED	Comparison of Treatments to Maintain Disease Remission in Patients With Wegener’s Granulomatosis and Related Vasculitis Syndromes
NCT00005928	PHASE2	COMPLETED	Effects of Angiotensin-Converting Enzyme Inhibitor (Ramipril) Therapy on Blood Vessel Inflammation
NCT00029107	PHASE2	COMPLETED	Rituximab to Treat Hepatitis C-Associated Cryoglobulinemic Vasculitis
NCT01170936	PHASE2	COMPLETED	Ilaris® in Urticarial Vasculitis - Investigation of Treatment Responses