CCM2L

Summary

CCM2L (CCM2 like scaffold protein, HGNC:16153) is a protein-coding gene on chromosome 20q11.21, encoding Cerebral cavernous malformations 2 protein-like (Q9NUG4).

Predicted to act upstream of or within several processes, including heart development; negative regulation of homotypic cell-cell adhesion; and positive regulation of fibroblast growth factor production.

Source: NCBI Gene 140706 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 72 total
• MANE Select transcript: NM_001365692

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16153
Approved symbol	CCM2L
Name	CCM2 like scaffold protein
Location	20q11.21
Locus type	gene with protein product
Status	Approved
Aliases	dJ310O13.5
Ensembl gene	ENSG00000101331
Ensembl biotype	protein_coding
Entrez	140706

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 6 protein_coding

ENST00000262659, ENST00000452892, ENST00000953124, ENST00000953125, ENST00000953126, ENST00000953127

RefSeq mRNA: 2 — MANE Select: NM_001365692 NM_001365692, NM_080625

CCDS: CCDS13195, CCDS93028

Canonical transcript exons

ENST00000452892 — 10 exons

Exon	Start	End
ENSE00000661143	32014904	32015071
ENSE00000661144	32017800	32017883
ENSE00000661145	32017979	32018162
ENSE00000661146	32022660	32022795
ENSE00000898445	32025856	32025919
ENSE00001382880	32018943	32019409
ENSE00003499347	32031001	32032180
ENSE00003574168	32029700	32029838
ENSE00003689818	32028995	32029124
ENSE00003888949	32010438	32010484

Expression profiles

Bgee: expression breadth ubiquitous, 207 present calls, max score 95.57.

FANTOM5 (CAGE): breadth broad, TPM avg 1.9493 / max 451.1032, expressed in 599 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
184008	1.4162	454
184007	0.4129	210
184006	0.1202	80

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
spleen	UBERON:0002106	95.57	gold quality
apex of heart	UBERON:0002098	90.57	gold quality
oocyte	CL:0000023	85.06	gold quality
secondary oocyte	CL:0000655	85.00	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.24	gold quality
left ventricle myocardium	UBERON:0006566	82.04	gold quality
endothelial cell	CL:0000115	81.65	silver quality
heart left ventricle	UBERON:0002084	81.63	gold quality
cardiac ventricle	UBERON:0002082	81.46	gold quality
subcutaneous adipose tissue	UBERON:0002190	80.14	gold quality
adipose tissue of abdominal region	UBERON:0007808	79.79	gold quality
omental fat pad	UBERON:0010414	79.68	gold quality
peritoneum	UBERON:0002358	79.61	gold quality
right lung	UBERON:0002167	79.46	gold quality
adipose tissue	UBERON:0001013	79.36	gold quality
metanephros	UBERON:0000081	77.89	gold quality
heart	UBERON:0000948	77.78	gold quality
upper lobe of left lung	UBERON:0008952	77.29	gold quality
upper lobe of lung	UBERON:0008948	77.09	gold quality
cardiac muscle of right atrium	UBERON:0003379	76.87	gold quality
right lobe of thyroid gland	UBERON:0001119	76.84	gold quality
body of uterus	UBERON:0009853	76.19	gold quality
right atrium auricular region	UBERON:0006631	76.12	gold quality
cardiac atrium	UBERON:0002081	76.07	gold quality
left uterine tube	UBERON:0001303	75.61	gold quality
heart right ventricle	UBERON:0002080	75.40	gold quality
lung	UBERON:0002048	75.24	gold quality
adrenal tissue	UBERON:0018303	75.18	gold quality
metanephros cortex	UBERON:0010533	74.62	gold quality
placenta	UBERON:0001987	74.37	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.83
E-MTAB-6678	no	2.43

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NR1I2

miRNA regulators (miRDB)

33 targeting CCM2L, 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-196A-5P	100.00	68.16	684
HSA-MIR-196B-5P	100.00	68.16	681
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-1299	99.77	71.24	2389
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-6745	99.74	65.33	1321
HSA-MIR-4428	99.73	66.41	1733
HSA-MIR-4530	99.69	66.47	1509
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-875-3P	99.63	69.47	2548
HSA-MIR-6740-3P	99.48	68.49	1392
HSA-MIR-766-5P	99.47	67.91	2225
HSA-MIR-4254	99.11	65.15	1315
HSA-MIR-6814-5P	99.03	66.68	1273
HSA-MIR-4297	98.77	66.95	2013
HSA-MIR-12114	98.70	63.45	730
HSA-MIR-4725-5P	98.67	65.42	628
HSA-MIR-504-5P	98.67	65.40	631
HSA-MIR-5572	98.55	65.84	970
HSA-MIR-6881-5P	98.16	67.38	665
HSA-MIR-12120	98.05	68.44	1768
HSA-MIR-3670	97.88	64.39	763
HSA-MIR-3928-3P	97.61	66.53	1096
HSA-MIR-5196-3P	97.57	65.98	979
HSA-MIR-874-5P	96.93	63.92	1014
HSA-MIR-6729-3P	96.91	66.79	703
HSA-MIR-6802-5P	94.94	65.95	366
HSA-MIR-7108-3P	94.37	64.79	183
HSA-MIR-10396A-3P	93.99	62.06	94

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	ccm2l	ENSDARG00000063089
mus_musculus	Ccm2l	ENSMUSG00000027474
rattus_norvegicus	Ccm2l	ENSRNOG00000009191

Paralogs (1): CCM2 (ENSG00000136280)

Protein

Protein identifiers

Cerebral cavernous malformations 2 protein-like — Q9NUG4 (reviewed: Q9NUG4)

All UniProt accessions (1): Q9NUG4

UniProt curated annotations — full annotation on UniProt →

Similarity. Belongs to the CCM2 family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9NUG4-1	1	yes
Q9NUG4-2	2
Q9NUG4-3	3

RefSeq proteins (2): NP_001352621, NP_542192 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR026159	Malcavernin	Family
IPR032375	CCM2_C	Domain

Pfam: PF16545

UniProt features (13 total): compositionally biased region 6, region of interest 3, splice variant 3, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NUG4-F1	59.84	0.16

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 48 (showing top): CREL_01, ACTACCT_MIR196A_MIR196B, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, SOX9_B1, GOBP_HEART_MORPHOGENESIS, LEF1_Q6, GATA4_Q3, chr20q11, AGCGCAG_MIR191, IVANOVA_HEMATOPOIESIS_STEM_CELL_LONG_TERM, GOBP_CIRCULATORY_SYSTEM_DEVELOPMENT, PR_Q2, MIKKELSEN_MEF_LCP_WITH_H3K27ME3, MIKKELSEN_NPC_WITH_LCP_H3K27ME3, MARTENS_TRETINOIN_RESPONSE_UP

GO Biological Process (1): biological_process (GO:0008150)

GO Molecular Function (2): molecular_function (GO:0003674), protein binding (GO:0005515)

GO Cellular Component (1): cellular_component (GO:0005575)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	1

Protein interactions and networks

STRING

966 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CCM2L	PDCD10	Q9BUL8	714
CCM2L	MAP3K3	Q99759	696
CCM2L	KRIT1	O00522	666
CCM2L	XKR7	Q5GH72	589
CCM2L	HEG1	Q9ULI3	584
CCM2L	RASIP1	Q5U651	507
CCM2L	ITGB1BP1	O14713	477
CCM2L	SNX17	Q15036	459
CCM2L	BPIFB6	Q8NFQ5	407
CCM2L	FOXS1	O43638	398
CCM2L	E9PNW1	E9PNW1	380
CCM2L	ZCCHC14	Q8WYQ9	369
CCM2L	TTLL9	Q3SXZ7	364
CCM2L	POFUT1	Q9H488	358
CCM2L	DUSP15	Q9H1R2	348

IntAct

18 interactions, top by confidence:

A	B	Type	Score
PSMB1	CCM2L	psi-mi:“MI:0915”(physical association)	0.560
CAMK2B	CCM2L	psi-mi:“MI:0915”(physical association)	0.560
PBX4	CCM2L	psi-mi:“MI:0915”(physical association)	0.560
CCM2L	USE1	psi-mi:“MI:0915”(physical association)	0.560
GRB2	MYO1C	psi-mi:“MI:0914”(association)	0.350
MYC		psi-mi:“MI:0914”(association)	0.350
CCM2L	CAMK2B	psi-mi:“MI:0915”(physical association)	0.000
CCM2L	PBX4	psi-mi:“MI:0915”(physical association)	0.000
USE1	CCM2L	psi-mi:“MI:0915”(physical association)	0.000
CCM2L	cdiA	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (7): CCM2L (Two-hybrid), CCM2L (Two-hybrid), CCM2L (Two-hybrid), CCM2L (Two-hybrid), PBX4 (Two-hybrid), CCM2L (Affinity Capture-MS), CCM2L (Cross-Linking-MS (XL-MS))

ESM2 similar proteins: A0A8I3NFE2, A0FI79, A1A5B6, A4D2P6, D7PF45, F1LXF1, O15357, O60346, O75808, P11274, P49796, P52734, P53349, P59672, P70268, P78524, P98174, Q0QWG9, Q13233, Q13905, Q16825, Q3MII6, Q50H33, Q5RDA9, Q62925, Q63433, Q6NS60, Q6P549, Q6PDJ6, Q6WVG3, Q7Z5H3, Q8BL80, Q8BUP8, Q8N2R8, Q8TF61, Q8VHK2, Q8WXD9, Q924W7, Q92625, Q96CX2

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

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	64
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2035 predictions. Top by Δscore:

Variant	Effect	Δscore
20:32014901:CAGG:C	acceptor_loss	1.0000
20:32014902:A:AG	acceptor_gain	1.0000
20:32014902:A:C	acceptor_loss	1.0000
20:32014902:AG:A	acceptor_gain	1.0000
20:32014903:G:GG	acceptor_gain	1.0000
20:32014903:GG:G	acceptor_gain	1.0000
20:32014903:GGGC:G	acceptor_gain	1.0000
20:32014903:GGGCT:G	acceptor_gain	1.0000
20:32015067:TCAAG:T	donor_loss	1.0000
20:32015070:AGGT:A	donor_loss	1.0000
20:32018129:G:GT	donor_gain	1.0000
20:32018158:GACCG:G	donor_gain	1.0000
20:32022652:T:TA	acceptor_gain	1.0000
20:32022653:G:A	acceptor_gain	1.0000
20:32022793:GCA:G	donor_gain	1.0000
20:32022796:G:GG	donor_gain	1.0000
20:32025847:T:A	acceptor_gain	1.0000
20:32025920:G:GG	donor_gain	1.0000
20:32028993:A:AG	acceptor_gain	1.0000
20:32028994:G:GG	acceptor_gain	1.0000
20:32029696:A:AG	acceptor_gain	1.0000
20:32029697:T:G	acceptor_gain	1.0000
20:32029698:A:AG	acceptor_gain	1.0000
20:32029699:G:GA	acceptor_gain	1.0000
20:32029699:GT:G	acceptor_gain	1.0000
20:32029699:GTT:G	acceptor_gain	1.0000
20:32029699:GTTGC:G	acceptor_gain	1.0000
20:32030997:GCA:G	acceptor_loss	1.0000
20:32031000:G:T	acceptor_loss	1.0000
20:32010478:G:T	donor_gain	0.9900

AlphaMissense

3705 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:32018055:T:C	L120P	1.000
20:32018145:T:C	L150P	1.000
20:32019384:T:C	L303P	1.000
20:32017801:T:C	F67S	0.999
20:32017813:T:C	L71P	0.999
20:32017861:T:C	L87P	0.999
20:32017867:T:C	L89P	0.999
20:32017870:T:C	L90P	0.999
20:32017879:C:A	A93D	0.999
20:32018028:T:C	L111P	0.999
20:32018049:T:C	L118P	0.999
20:32018052:T:C	L119P	0.999
20:32018055:T:A	L120H	0.999
20:32018064:G:C	R123P	0.999
20:32018085:T:C	L130P	0.999
20:32018115:C:A	A140D	0.999
20:32018148:T:C	L151P	0.999
20:32018154:T:A	L153H	0.999
20:32018154:T:C	L153P	0.999
20:32019393:T:C	L306P	0.999
20:32022685:T:C	L320P	0.999
20:32029749:T:C	L438P	0.999
20:32031082:T:C	I495T	0.999
20:32031091:A:T	D498V	0.999
20:32031093:A:C	S499R	0.999
20:32031095:C:A	S499R	0.999
20:32031095:C:G	S499R	0.999
20:32031096:T:C	F500L	0.999
20:32031098:C:A	F500L	0.999
20:32031098:C:G	F500L	0.999

dbSNP variants (sampled 300 via entrez): RS1000153060 (20:32032587 A>G), RS1000276220 (20:32018841 G>A), RS1000352604 (20:32028739 G>A,T), RS1000543428 (20:32031097 T>C,G), RS1000609883 (20:32032272 C>G), RS1000989558 (20:32030672 T>TA), RS1001086478 (20:32030404 A>C), RS1001117127 (20:32013196 G>A), RS1001189159 (20:32025268 C>A,T), RS1001264161 (20:32025088 TTTC>T), RS1001427565 (20:32018737 A>T), RS1001500426 (20:32012525 C>T), RS1001512342 (20:32017053 C>T), RS1001554160 (20:32012147 T>C), RS1001598668 (20:32009699 C>T)

Disease associations

OMIM: gene `` | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST003720_4	Migraine	1.000000e-08
GCST009440_13	Age-related cognitive decline (attention/processing speed) (slope of z-scores)	6.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007710	cognitive decline measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

31 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	5
trichostatin A	affects cotreatment, increases expression	2
entinostat	increases expression, affects cotreatment	2
Vorinostat	affects cotreatment, increases expression	2
Benzo(a)pyrene	increases expression, increases methylation	2
Estradiol	decreases reaction, increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
sotorasib	affects cotreatment, increases expression	1
propionaldehyde	increases expression	1
bisphenol A	increases expression	1
sodium arsenite	increases expression	1
butyraldehyde	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment	1
pentanal	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, affects cotreatment, increases expression	1
ICG 001	increases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, increases expression, decreases expression	1
licochalcone B	increases expression	1
trametinib	affects cotreatment, increases expression	1
NVP-BKM120	affects cotreatment, increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Aldehydes	increases expression	1
Carbamazepine	affects expression	1
Diethylhexyl Phthalate	decreases expression	1
Lipopolysaccharides	increases expression, affects response to substance, affects cotreatment	1
Malathion	increases expression	1
Nickel	decreases expression	1
Thimerosal	decreases expression	1
Antirheumatic Agents	increases expression	1

Clinical trials (associated diseases)

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