CAP2

Summary

CAP2 (cyclase associated actin cytoskeleton regulatory protein 2, HGNC:20039) is a protein-coding gene on chromosome 6p22.3, encoding Adenylyl cyclase-associated protein 2 (P40123). Involved in the regulation of actin polymerization.

This gene was identified by its similarity to the gene for human adenylyl cyclase-associated protein. The function of the protein encoded by this gene is unknown. However, the protein appears to be able to interact with adenylyl cyclase-associated protein and actin.

Source: NCBI Gene 10486 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cardiomyopathy, dilated, 2I (Moderate, GenCC) — +1 more curated relationship
• Clinical variants (ClinVar): 88 total — 3 pathogenic, 1 likely-pathogenic
• MANE Select transcript: NM_006366

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20039
Approved symbol	CAP2
Name	cyclase associated actin cytoskeleton regulatory protein 2
Location	6p22.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000112186
Ensembl biotype	protein_coding
OMIM	618385
Entrez	10486

Gene structure

Transcript identifiers

Ensembl transcripts: 28 — 26 protein_coding, 2 nonsense_mediated_decay

ENST00000229922, ENST00000378990, ENST00000465994, ENST00000476263, ENST00000479291, ENST00000489374, ENST00000493172, ENST00000857692, ENST00000857693, ENST00000857694, ENST00000857695, ENST00000857696, ENST00000857697, ENST00000857698, ENST00000857699, ENST00000857700, ENST00000857701, ENST00000857702, ENST00000857703, ENST00000940429, ENST00000940430, ENST00000940431, ENST00000940432, ENST00000950865, ENST00000950866, ENST00000950867, ENST00000950868, ENST00000950869

RefSeq mRNA: 3 — MANE Select: NM_006366 NM_001363533, NM_001363534, NM_006366

CCDS: CCDS4539, CCDS87368, CCDS87369

Canonical transcript exons

ENST00000229922 — 13 exons

Exon	Start	End
ENSE00000686699	17426590	17426690
ENSE00000686701	17462996	17463073
ENSE00000848098	17421555	17421676
ENSE00000848103	17551464	17551604
ENSE00001825170	17556359	17557780
ENSE00003461779	17513849	17513954
ENSE00003481786	17540973	17541148
ENSE00003483910	17543061	17543143
ENSE00003487575	17542837	17542960
ENSE00003533357	17539269	17539458
ENSE00003638289	17507641	17507726
ENSE00003690217	17507169	17507312
ENSE00003746630	17393595	17393746

Expression profiles

Bgee: expression breadth ubiquitous, 280 present calls, max score 99.44.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 15.4061 / max 480.9291, expressed in 1309 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
66145	10.0223	1279
66143	2.3313	784
66144	0.9874	430
66142	0.8509	349
66139	0.5920	275
66141	0.4580	222
66140	0.1644	71

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	99.44	gold quality
biceps brachii	UBERON:0001507	99.43	gold quality
Brodmann (1909) area 23	UBERON:0013554	99.38	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	99.35	gold quality
vastus lateralis	UBERON:0001379	99.32	gold quality
quadriceps femoris	UBERON:0001377	99.27	gold quality
endothelial cell	CL:0000115	99.25	gold quality
skeletal muscle tissue	UBERON:0001134	99.16	gold quality
gluteal muscle	UBERON:0002000	99.15	gold quality
deltoid	UBERON:0001476	99.03	gold quality
hindlimb stylopod muscle	UBERON:0004252	99.02	gold quality
gastrocnemius	UBERON:0001388	98.98	gold quality
frontal pole	UBERON:0002795	98.90	gold quality
tibialis anterior	UBERON:0001385	98.72	gold quality
triceps brachii	UBERON:0001509	98.66	gold quality
muscle organ	UBERON:0001630	98.58	gold quality
skeletal muscle organ	UBERON:0014892	98.58	gold quality
middle temporal gyrus	UBERON:0002771	98.54	gold quality
Brodmann (1909) area 10	UBERON:0013541	98.52	gold quality
diaphragm	UBERON:0001103	98.41	gold quality
primary visual cortex	UBERON:0002436	98.34	gold quality
muscle of leg	UBERON:0001383	98.33	gold quality
orbitofrontal cortex	UBERON:0004167	98.06	gold quality
Brodmann (1909) area 46	UBERON:0006483	98.06	gold quality
muscle tissue	UBERON:0002385	97.80	gold quality
superior frontal gyrus	UBERON:0002661	97.78	gold quality
occipital lobe	UBERON:0002021	97.49	gold quality
heart right ventricle	UBERON:0002080	97.47	gold quality
prefrontal cortex	UBERON:0000451	97.13	gold quality
entorhinal cortex	UBERON:0002728	97.09	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-2	yes	3013.46
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 13)

• CAP2 is up-regulated in human cancers and that is possibly related to multistage hepatocarcinogenesis. (PMID:17000669)
• An important conserved function of CAP2 in higher vertebrates may be associated with the process of skeletal muscle development. (PMID:23022774)
• CAP2 overexpression is a novel prognostic marker in malignant melanoma. CAP2 expression seems to increase stepwise during tumor progression, suggesting the involvement of CAP2 in the aggressive behavior of malignant melanoma. (PMID:26374196)
• CAP2 is upregulated in breast cancer and is associated with the expression of progesterone receptor and patient survival (PMID:27573674)
• CAP2 is a Valuable Biomarker for Diagnosis and Prognostic in Patients with Gastric Cancer. (PMID:30047046)
• CAP2 joins other regulators of actin dynamics demonstrated to cause human genetic diseases. Our study is the first to demonstrate a mutation in CAP2 in human and a direct role for mutated CAP2 and perturbation of actin dynamics in the pathogenesis of DCM and possibly also conduction abnormalities in humans. (PMID:30518548)
• CAP2 is highly expressed in gastric cancer tissues in close relation with the tumor progression. CAP2 is an independent risk factor for 5-year survival rate after radical gastrectomy for gastric cancer. (PMID:31640951)
• Study used lysine-to-glutamine mutations to map the relevant lysines on actin for INF2 regulation. K50Q- and K61Q-actin, when bound to CAP2, inhibit full-length INF2 but not INF2 lacking inhibitory domain (DID). CAP WH2 domain binds INF2-DID with submicromolar affinity but has weak affinity for actin monomers, while INF2-C-terminal diaphanous autoregulatory domain binds CAP/K50Q-actin 5-fold better than CAP/WT-actin. (PMID:31871199)
• CAP2 expression in ovarian cancer is an independent prognostic factor for recurrence-free survival. (PMID:32211793)
• Endoplasmic Reticulum Stress Induces CAP2 Expression Promoting Epithelial-Mesenchymal Transition in Liver Cancer Cells. (PMID:34294609)
• Analysis of mRNA and Protein Levels of CAP2, DLG1 and ADAM10 Genes in Post-Mortem Brain of Schizophrenia, Parkinson’s and Alzheimer’s Disease Patients. (PMID:35163460)
• An association study of cyclase-associated protein 2 and frailty. (PMID:37537790)
• CAP2 contributes to Parkinson’s disease diagnosed by neutrophil extracellular trap-related immune activity. (PMID:38846945)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	cap2	ENSDARG00000104478
mus_musculus	Cap2	ENSMUSG00000021373
rattus_norvegicus	Cap2	ENSRNOG00000043350
drosophila_melanogaster	capt	FBGN0261458
caenorhabditis_elegans		WBGENE00000294
caenorhabditis_elegans	cas-2	WBGENE00015975

Paralogs (1): CAP1 (ENSG00000131236)

Protein

Protein identifiers

Adenylyl cyclase-associated protein 2 — P40123 (reviewed: P40123)

All UniProt accessions (5): B7Z385, E9PDI2, P40123, F8WDB9, F8WEW0

UniProt curated annotations — full annotation on UniProt →

Function. Involved in the regulation of actin polymerization.

Subcellular location. Cell membrane.

Disease relevance. Cardiomyopathy, dilated, 2I (CMD2I) [MIM:620462] A form of dilated cardiomyopathy, a disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death. CMD2I is an autosomal recessive, severe form characterized by onset in infancy or childhood. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the CAP family.

Isoforms (3)

UniProt ID	Names	Canonical?
P40123-1	1	yes
P40123-2	2
P40123-3	3

RefSeq proteins (3): NP_001350462, NP_001350463, NP_006357* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001837	Adenylate_cyclase-assoc_CAP	Family
IPR006599	CARP_motif	Domain
IPR013912	Adenylate_cyclase-assoc_CAP_C	Domain
IPR013992	Adenylate_cyclase-assoc_CAP_N	Conserved_site
IPR016098	CAP/MinC_C	Homologous_superfamily
IPR017901	C-CAP_CF_C-like	Domain
IPR018106	CAP_CS_N	Conserved_site
IPR028417	CAP_CS_C	Conserved_site
IPR036222	CAP_N_sf	Homologous_superfamily
IPR036223	CAP_C_sf	Homologous_superfamily
IPR053950	CAP_N	Domain

Pfam: PF01213, PF08603, PF21938

UniProt features (15 total): sequence variant 3, modified residue 3, splice variant 2, region of interest 2, compositionally biased region 2, initiator methionine 1, chain 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P40123-F1	83.78	0.66

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 (3): 2, 301, 309

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-428890	Role of ABL in ROBO-SLIT signaling
R-HSA-1266738	Developmental Biology
R-HSA-376176	Signaling by ROBO receptors
R-HSA-422475	Axon guidance
R-HSA-9675108	Nervous system development

MSigDB gene sets: 225 (showing top): WAMUNYOKOLI_OVARIAN_CANCER_LMP_DN, MODULE_52, YAGI_AML_WITH_INV_16_TRANSLOCATION, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_CELL_POLARITY, GOZGIT_ESR1_TARGETS_DN, ASTON_MAJOR_DEPRESSIVE_DISORDER_DN, GOBP_POSITIVE_REGULATION_OF_LYASE_ACTIVITY, FRASOR_RESPONSE_TO_SERM_OR_FULVESTRANT_DN, PATIL_LIVER_CANCER, SENESE_HDAC1_AND_HDAC2_TARGETS_DN, GOBP_POSITIVE_REGULATION_OF_CATALYTIC_ACTIVITY, GOBP_REGULATION_OF_ADENYLATE_CYCLASE_ACTIVITY, GOBP_CELL_JUNCTION_ORGANIZATION, GOBP_POSITIVE_REGULATION_OF_MOLECULAR_FUNCTION, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_1

GO Biological Process (8): cell morphogenesis (GO:0000902), actin filament organization (GO:0007015), establishment or maintenance of cell polarity (GO:0007163), signal transduction (GO:0007165), activation of adenylate cyclase activity (GO:0007190), obsolete cAMP-mediated signaling (GO:0019933), presynaptic actin cytoskeleton organization (GO:0099140), cytoskeleton organization (GO:0007010)

GO Molecular Function (4): actin binding (GO:0003779), adenylate cyclase binding (GO:0008179), identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (4): cytoplasm (GO:0005737), plasma membrane (GO:0005886), postsynaptic density (GO:0014069), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Signaling by ROBO receptors	1
Axon guidance	1
Nervous system development	1
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
actin cytoskeleton organization	2
cellular process	2
cellular anatomical structure	2
anatomical structure morphogenesis	1
supramolecular fiber organization	1
cell communication	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
positive regulation of adenylate cyclase activity	1
presynaptic cytoskeleton organization	1
organelle organization	1
cytoskeletal protein binding	1
enzyme binding	1
protein binding	1
binding	1
intracellular anatomical structure	1
membrane	1
cell periphery	1
asymmetric synapse	1
postsynaptic specialization	1

Protein interactions and networks

STRING

974 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CAP2	WDR1	O75083	456
CAP2	PFN4	Q8NHR9	443
CAP2	DBN1	Q16643	373
CAP2	CAPZB	P47756	360
CAP2	TWF2	Q6IBS0	355
CAP2	CNTRL	Q7Z7A1	353
CAP2	SUN2	Q9UH99	353
CAP2	GPR4	P46093	348
CAP2	ACY1	Q03154	339
CAP2	TWF1	Q12792	326
CAP2	CFL1	P23528	322
CAP2	CGA	P01215	318
CAP2	PFN1	P07737	311
CAP2	CFL2	Q9Y281	309
CAP2	TDRP	Q86YL5	307

IntAct

92 interactions, top by confidence:

A	B	Type	Score
MED4	MED19	psi-mi:“MI:0914”(association)	0.900
PIK3CA	PIK3R2	psi-mi:“MI:0914”(association)	0.900
CAP2	ACTG1	psi-mi:“MI:0915”(physical association)	0.860
ACTG1	CAP2	psi-mi:“MI:0915”(physical association)	0.860
ACTB	CAP2	psi-mi:“MI:0915”(physical association)	0.820
CAP2	CAP2	psi-mi:“MI:0915”(physical association)	0.670
CFL1	CAP2	psi-mi:“MI:0914”(association)	0.640
TWF2	CAP2	psi-mi:“MI:0914”(association)	0.640
BCL7A	ARID1A	psi-mi:“MI:0914”(association)	0.640
BCL7C	ARID1A	psi-mi:“MI:0914”(association)	0.640
	CAP2	psi-mi:“MI:0915”(physical association)	0.560
CAP2	PS1TP5BP1	psi-mi:“MI:0915”(physical association)	0.560
CAP2	CFL2	psi-mi:“MI:0915”(physical association)	0.560
CAP2		psi-mi:“MI:0915”(physical association)	0.560

BioGRID (104): CAP2 (Two-hybrid), CAP2 (Two-hybrid), CAP2 (Two-hybrid), CAP2 (Two-hybrid), MT1P3 (Two-hybrid), CAP2 (Affinity Capture-MS), CAP2 (Affinity Capture-MS), CAP2 (Affinity Capture-MS), CAP2 (Affinity Capture-MS), CAP2 (Affinity Capture-MS), CAP2 (Two-hybrid), CAP2 (Two-hybrid), CAP2 (Affinity Capture-MS), POTEI (Affinity Capture-MS), CAP2 (Affinity Capture-MS)

ESM2 similar proteins: A2YPT7, A3KPF2, A3KPP3, A7SKJ3, A7TTC4, O01757, O75002, O95163, P40123, P47123, P47758, P52481, P53738, Q09454, Q14AI0, Q2TAQ1, Q32PE2, Q3SYG4, Q4FZX7, Q501D5, Q54ML6, Q5JS54, Q5R5X8, Q5YLB4, Q66I84, Q6AX60, Q6C619, Q6GL75, Q6GMB0, Q6PD82, Q74ZJ1, Q7TT37, Q7XI75, Q811G0, Q84W92, Q8LPK4, Q8LPL6, Q8VHU4, Q8WND5, Q8X0S4

Diamond homologs: O65902, P36621, P40122, P40123, P40124, P40125, P52481, P54654, Q01518, Q08163, Q3SYV4, Q4R4I6, Q5R5X8, Q5R8B4, Q9CYT6, P17555

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 53 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Formation of the canonical BAF (cBAF) complex	5	83.5×	3e-07
Formation of neuronal progenitor and neuronal BAF (npBAF and nBAF)	5	60.1×	1e-06
Sensory processing of sound by outer hair cells of the cochlea	7	37.6×	2e-07
Regulation of MITF-M-dependent genes involved in pigmentation	5	34.9×	2e-05
Sensory processing of sound by inner hair cells of the cochlea	7	30.1×	3e-07
Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs)	5	15.5×	4e-04
MITF-M-regulated melanocyte development	5	15.0×	5e-04
Epigenetic regulation of gene expression	6	11.3×	4e-04

GO biological processes:

GO term	Partners	Fold	FDR
regulation of G0 to G1 transition	5	70.2×	2e-06
regulation of nucleotide-excision repair	5	62.7×	3e-06
regulation of mitotic metaphase/anaphase transition	5	51.6×	5e-06
positive regulation of double-strand break repair	5	35.8×	3e-05
regulation of G1/S transition of mitotic cell cycle	5	31.9×	4e-05
axonogenesis	5	16.7×	5e-04
chromatin remodeling	7	10.6×	2e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	1
Uncertain significance	71
Likely benign	3
Benign	1

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
2574649	NM_006366.3(CAP2):c.636+1G>A	Pathogenic
2574650	NM_006366.3(CAP2):c.948T>G (p.Tyr316Ter)	Pathogenic
2574651	NM_006366.3(CAP2):c.1288del (p.Cys430fs)	Pathogenic
4845338	NM_006366.3(CAP2):c.870del (p.Ser291fs)	Likely pathogenic

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

3147 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:17507283:A:C	S139R	1.000
6:17507285:C:A	S139R	1.000
6:17507285:C:G	S139R	1.000
6:17507301:T:A	W145R	1.000
6:17507301:T:C	W145R	1.000
6:17507663:T:A	V156D	1.000
6:17507689:T:C	F165L	1.000
6:17507691:T:A	F165L	1.000
6:17507691:T:G	F165L	1.000
6:17507703:G:C	R169S	1.000
6:17507703:G:T	R169S	1.000
6:17507705:T:A	V170D	1.000
6:17507271:G:C	A135P	0.999
6:17507272:C:A	A135D	0.999
6:17507293:C:A	A142D	0.999
6:17507303:G:C	W145C	0.999
6:17507303:G:T	W145C	0.999
6:17507683:G:C	A163P	0.999
6:17507684:C:A	A163D	0.999
6:17507690:T:C	F165S	0.999
6:17507690:T:G	F165C	0.999
6:17507692:T:G	Y166D	0.999
6:17507702:G:C	R169T	0.999
6:17507702:G:T	R169M	0.999
6:17513868:T:A	W184R	0.999
6:17513868:T:C	W184R	0.999
6:17507231:A:C	R121S	0.998
6:17507231:A:T	R121S	0.998
6:17507266:T:C	L133P	0.998
6:17507268:T:C	S134P	0.998

dbSNP variants (sampled 300 via entrez): RS1000003228 (6:17468525 C>G,T), RS1000043829 (6:17526149 G>A,T), RS1000047896 (6:17537974 G>A), RS1000057237 (6:17444589 C>T), RS1000068368 (6:17478282 G>T), RS1000085541 (6:17450940 G>A), RS1000099910 (6:17538220 C>T), RS1000102682 (6:17478046 G>A), RS1000106355 (6:17419877 A>C), RS1000111421 (6:17438277 A>G), RS1000141463 (6:17461267 T>C), RS1000155093 (6:17394133 G>A,T), RS1000155976 (6:17403052 A>G), RS1000177166 (6:17444115 G>A,T), RS1000183544 (6:17525094 G>T)

Disease associations

OMIM: gene MIM:618385 | disease phenotypes: MIM:620462

GenCC curated gene-disease

Disease	Classification	Inheritance
cardiomyopathy, dilated, 2I	Moderate	Autosomal recessive
familial isolated dilated cardiomyopathy	Supportive	Autosomal dominant

Mondo (2): cardiomyopathy, dilated, 2I (MONDO:0957545), (MONDO:0015470)

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression	8
Acetaminophen	decreases expression	3
Cadmium Chloride	decreases expression, increases abundance, increases expression	3
bisphenol A	decreases expression, increases expression	2
entinostat	decreases expression, affects cotreatment	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression, decreases expression	2
Benzo(a)pyrene	increases expression, increases methylation	2
Nickel	decreases expression	2
Dronabinol	increases expression	2
Particulate Matter	decreases expression, increases abundance, increases expression	2
FR900359	affects phosphorylation	1
decabromobiphenyl ether	decreases expression	1
trimellitic anhydride	decreases expression	1
afimoxifene	decreases reaction, increases expression	1
sodium arsenite	increases expression	1
tetrabromobisphenol A	decreases expression	1
coumarin	decreases phosphorylation	1
beta-methylcholine	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
chloropicrin	increases expression	1
AM 251	decreases expression	1
corosolic acid	increases expression	1
K 7174	increases expression	1
nutlin 3	affects cotreatment, increases secretion	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
jinfukang	decreases expression, affects cotreatment	1
incobotulinumtoxinA	decreases expression	1

Clinical trials (associated diseases)

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