CAPZB

Summary

CAPZB (capping actin protein of muscle Z-line subunit beta, HGNC:1491) is a protein-coding gene on chromosome 1p36.13, encoding F-actin-capping protein subunit beta (P47756). F-actin-capping proteins bind in a Ca(2+)-independent manner to the fast growing ends of actin filaments (barbed end) thereby blocking the exchange of subunits at these ends. It is a common-essential gene (DepMap: required in 96.4% of cancer cell lines).

This gene encodes the beta subunit of the barbed-end actin binding protein, which belongs to the F-actin capping protein family. The capping protein is a heterodimeric actin capping protein that blocks actin filament assembly and disassembly at the fast growing (barbed) filament ends and functions in regulating actin filament dynamics as well as in stabilizing actin filament lengths in muscle and nonmuscle cells. A pseudogene of this gene is located on the long arm of chromosome 2. Multiple alternatively spliced transcript variants encoding different isoforms have been found.

Source: NCBI Gene 832 — RefSeq curated summary.

At a glance

• GWAS associations: 37
• Clinical variants (ClinVar): 34 total
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 96.4% of screened cell lines (common-essential)
• MANE Select transcript: NM_004930

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1491
Approved symbol	CAPZB
Name	capping actin protein of muscle Z-line subunit beta
Location	1p36.13
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000077549
Ensembl biotype	protein_coding
OMIM	601572
Entrez	832

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 18 protein_coding, 3 protein_coding_CDS_not_defined, 3 retained_intron, 2 nonsense_mediated_decay

ENST00000264202, ENST00000264203, ENST00000375142, ENST00000375144, ENST00000433834, ENST00000457768, ENST00000459967, ENST00000482808, ENST00000489607, ENST00000674228, ENST00000674278, ENST00000674299, ENST00000674390, ENST00000674432, ENST00000674449, ENST00000898917, ENST00000898918, ENST00000898919, ENST00000898920, ENST00000898921, ENST00000915219, ENST00000915220, ENST00000915221, ENST00000915222, ENST00000943720, ENST00000943721

RefSeq mRNA: 5 — MANE Select: NM_004930 NM_001206540, NM_001206541, NM_001282162, NM_001313932, NM_004930

CCDS: CCDS41277, CCDS55579, CCDS72717, CCDS72718

Canonical transcript exons

ENST00000264202 — 9 exons

Exon	Start	End
ENSE00001546290	19485436	19485539
ENSE00001671615	19344358	19344434
ENSE00001758675	19356635	19356751
ENSE00002251926	19338775	19339617
ENSE00003571541	19385505	19385626
ENSE00003611394	19378540	19378653
ENSE00003629510	19357422	19357563
ENSE00003630963	19419661	19419750
ENSE00003691575	19345187	19345252

Expression profiles

Bgee: expression breadth ubiquitous, 303 present calls, max score 99.08.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 107.9895 / max 493.6261, expressed in 1825 samples.

FANTOM5 promoters (13 alternative TSS)

Promoter ID	TPM avg	Samples expressed
10677	77.0967	1825
10676	26.4530	1811
10658	1.3685	848
10662	0.6922	428
10661	0.6614	392
10666	0.3653	161
10667	0.3481	147
10675	0.3124	138
10674	0.3054	154
10678	0.1175	35

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
muscle layer of sigmoid colon	UBERON:0035805	99.08	gold quality
monocyte	CL:0000576	99.07	gold quality
smooth muscle tissue	UBERON:0001135	99.07	gold quality
lower esophagus	UBERON:0013473	99.07	gold quality
lower esophagus muscularis layer	UBERON:0035833	99.07	gold quality
leukocyte	CL:0000738	99.05	gold quality
granulocyte	CL:0000094	99.04	gold quality
mononuclear cell	CL:0000842	99.04	gold quality
left testis	UBERON:0004533	99.01	gold quality
right testis	UBERON:0004534	98.99	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	98.98	gold quality
stromal cell of endometrium	CL:0002255	98.93	gold quality
pylorus	UBERON:0001166	98.93	gold quality
popliteal artery	UBERON:0002250	98.92	gold quality
tibial artery	UBERON:0007610	98.92	gold quality
mucosa of stomach	UBERON:0001199	98.91	gold quality
rectum	UBERON:0001052	98.89	gold quality
endocervix	UBERON:0000458	98.84	gold quality
aorta	UBERON:0000947	98.84	gold quality
ectocervix	UBERON:0012249	98.84	gold quality
esophagus	UBERON:0001043	98.83	gold quality
lymph node	UBERON:0000029	98.82	gold quality
descending thoracic aorta	UBERON:0002345	98.79	gold quality
body of uterus	UBERON:0009853	98.79	gold quality
vermiform appendix	UBERON:0001154	98.78	gold quality
caecum	UBERON:0001153	98.77	gold quality
urethra	UBERON:0000057	98.75	gold quality
colonic epithelium	UBERON:0000397	98.75	gold quality
left uterine tube	UBERON:0001303	98.75	gold quality
transverse colon	UBERON:0001157	98.73	gold quality

Single-cell (SCXA)

Detected in 10 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-MTAB-6701	yes	49.24
E-HCAD-10	yes	39.00
E-CURD-122	yes	20.33
E-CURD-112	yes	14.13
E-ANND-3	yes	9.52
E-MTAB-10042	yes	9.51
E-HCAD-11	yes	6.56
E-MTAB-7606	no	948.29
E-MTAB-6524	no	324.84
E-CURD-120	no	6.22

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

72 targeting CAPZB, 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-3613-3P	100.00	76.36	7965
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-329-3P	99.91	66.56	1234
HSA-MIR-362-3P	99.91	66.38	1267
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-576-5P	99.84	70.46	2582
HSA-MIR-130B-5P	99.83	68.50	1888
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-6515-3P	99.82	68.19	1933
HSA-MIR-2052	99.79	69.37	2031
HSA-MIR-3680-3P	99.75	72.51	3095
HSA-MIR-7856-5P	99.75	69.99	2901
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-5093	99.67	69.26	2291
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-6797-5P	99.61	66.55	2084
HSA-MIR-1249-5P	99.61	66.55	2049

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 96.4% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 9)

• RAGE has a role in endothelial cell membrane repair and regulates F-actin remodeling and membrane resealing (PMID:21844192)
• A subject with micrognathia, cleft palate and hypotonia harbored a de novo, balanced chromosomal translocation that disrupts the CAPZB gene. The function of capzb was analyzed in the zebrafish model. (PMID:26758871)
• CAPZB is involved in tumor progression in cases of epithelioid sarcoma (EpiS), irrespective of the INI1 expression, and may be a potential therapeutic target. The paradoxical relationship between the tumor suppressor INI1 and the oncoprotein CAPZB in the pathogenesis of EpiS remains to be clarified (PMID:26965049)
• At each step during spermatogenesis, the cellular localization of hCPbeta3 changed dynamically. In spermatogonia, hCPbeta3 showed a slight signal in cytoplasm. hCPbeta3 expression was conspicuous mainly from spermatocytes, and hCPbeta3 localization dynamically migrated from cytoplasm to the acrosomal cap and acrosome. In mature spermatozoa, hCPbeta3 accumulated in the postacrosomal region and less so at the midpiece of… (PMID:28104696)
• replication confirmed at genome-wide significance the association of loci at FOXE1 with hypothyroidism, and PDE8B, CAPZB and PDE10A with serum TSH. A total of 12 SNPs seemed to explain nearly 7% of the serum TSH variation (PMID:28727628)
• CAPZB controls spindle orientation independently of its classical role in the actin cytoskeleton by regulating the assembly, stability, and motor activity of the dynein/dynactin complex at the cell cortex, as well as the dynamics of mitotic microtubules. (PMID:28803871)
• A new 1p36.13-1p36.12 microdeletion syndrome characterized by learning disability, behavioral abnormalities, and ptosis. (PMID:32170730)
• Vacuolin-1 inhibits endosomal trafficking and metastasis via CapZbeta. (PMID:33564074)
• Capping protein regulates endosomal trafficking by controlling F-actin density around endocytic vesicles and recruiting RAB5 effectors. (PMID:34796874)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	capzb	ENSDARG00000100252
mus_musculus	Capzb	ENSMUSG00000028745
rattus_norvegicus	Capzb	ENSRNOG00000007330
drosophila_melanogaster	cpb	FBGN0011570
caenorhabditis_elegans		WBGENE00000293

Protein

Protein identifiers

F-actin-capping protein subunit beta — P47756 (reviewed: P47756)

Alternative names: CapZ beta

All UniProt accessions (8): P47756, A0A384MR50, A0A6I8PIH4, A0A6I8PIN8, A0A6I8PRV6, B1AK85, B1AK87, B1AK88

UniProt curated annotations — full annotation on UniProt →

Function. F-actin-capping proteins bind in a Ca(2+)-independent manner to the fast growing ends of actin filaments (barbed end) thereby blocking the exchange of subunits at these ends. Unlike other capping proteins (such as gelsolin and severin), these proteins do not sever actin filaments. Plays a role in the regulation of cell morphology and cytoskeletal organization. Forms, with CAPZB, the barbed end of the fast growing ends of actin filaments in the dynactin complex and stabilizes dynactin structure. The dynactin multiprotein complex activates the molecular motor dynein for ultra-processive transport along microtubules.

Subunit / interactions. Component of the F-actin capping complex, composed of a heterodimer of an alpha and a beta subunit. Subunit of dynactin, a multiprotein complex part of a tripartite complex with dynein and a adapter, such as BICDL1, BICD2 or HOOK3. The dynactin complex is built around ACTR1A/ACTB filament and consists of an actin-related filament composed of a shoulder domain, a pointed end and a barbed end. Its length is defined by its flexible shoulder domain. The soulder is composed of 2 DCTN1 subunits, 4 DCTN2 and 2 DCTN3. The 4 DCNT2 (via N-terminus) bind the ACTR1A filament and act as molecular rulers to determine the length. The pointed end is important for binding dynein-dynactin cargo adapters. Consists of 4 subunits: ACTR10, DCNT4, DCTN5 and DCTN6. The barbed end is composed of a CAPZA1:CAPZB heterodimers, which binds ACTR1A/ACTB filament and dynactin and stabilizes dynactin. Interacts with ARHGAP17. Interaction with RCSD1/CAPZIP. Component of the WASH complex, composed of F-actin-capping protein subunit alpha (CAPZA1, CAPZA2 or CAPZA3), F-actin-capping protein subunit beta (CAPZB), WASH (WASHC1, WASH2P, WASH3P, WASH4P, WASH5P or WASH6P), WASHC2 (WASHC2A or WASHC2C), WASHC3, WASHC4 and WASHC5. Interacts with ACTG1. Directly interacts with CRACD; this interaction decreases binding to actin.

Subcellular location. Cytoplasm. Cytoskeleton. Myofibril. Sarcomere.

Similarity. Belongs to the F-actin-capping protein beta subunit family.

Isoforms (3)

UniProt ID	Names	Canonical?
P47756-2	1	yes
P47756-1	2
P47756-3	3

RefSeq proteins (5): NP_001193469, NP_001193470, NP_001269091, NP_001300861, NP_004921* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001698	CAPZB	Family
IPR019771	F-actin_capping_bsu_CS	Conserved_site
IPR037282	CapZ_alpha/beta	Homologous_superfamily
IPR042276	CapZ_alpha/beta_2	Homologous_superfamily
IPR043175	CAPZB_N	Homologous_superfamily

Pfam: PF01115

UniProt features (34 total): strand 11, helix 8, turn 7, modified residue 4, initiator methionine 1, chain 1, splice variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
9YIM	ELECTRON MICROSCOPY	2.62
8F8Q	ELECTRON MICROSCOPY	2.79
9Y9L	ELECTRON MICROSCOPY	3.06
9Y9M	ELECTRON MICROSCOPY	3.06
7T5Q	ELECTRON MICROSCOPY	3.4
9EC0	ELECTRON MICROSCOPY	3.4
9B85	ELECTRON MICROSCOPY	3.47
9B7J	ELECTRON MICROSCOPY	3.49

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P47756-F1	91.18	0.65

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 (4): 2, 2, 263, 235

Function

Pathways and Gene Ontology

Reactome pathways

28 pathways

ID	Pathway
R-HSA-2132295	MHC class II antigen presentation
R-HSA-3371497	HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand
R-HSA-6807878	COPI-mediated anterograde transport
R-HSA-6811436	COPI-independent Golgi-to-ER retrograde traffic
R-HSA-9013405	RHOD GTPase cycle
R-HSA-9035034	RHOF GTPase cycle
R-HSA-9662360	Sensory processing of sound by inner hair cells of the cochlea
R-HSA-983231	Factors involved in megakaryocyte development and platelet production
R-HSA-109582	Hemostasis
R-HSA-1280218	Adaptive Immune System
R-HSA-162582	Signal Transduction
R-HSA-168256	Immune System
R-HSA-194315	Signaling by Rho GTPases
R-HSA-199977	ER to Golgi Anterograde Transport
R-HSA-199991	Membrane Trafficking
R-HSA-2262752	Cellular responses to stress
R-HSA-392499	Metabolism of proteins
R-HSA-446203	Asparagine N-linked glycosylation
R-HSA-5653656	Vesicle-mediated transport
R-HSA-597592	Post-translational protein modification
R-HSA-6811442	Intra-Golgi and retrograde Golgi-to-ER traffic
R-HSA-8856688	Golgi-to-ER retrograde transport
R-HSA-8953897	Cellular responses to stimuli
R-HSA-9012999	RHO GTPase cycle
R-HSA-948021	Transport to the Golgi and subsequent modification
R-HSA-9659379	Sensory processing of sound
R-HSA-9709957	Sensory Perception
R-HSA-9716542	Signaling by Rho GTPases, Miro GTPases and RHOBTB3

MSigDB gene sets: 268 (showing top): GOBP_NEGATIVE_REGULATION_OF_PROTEIN_CONTAINING_COMPLEX_ASSEMBLY, GOBP_REGULATION_OF_PROTEIN_POLYMERIZATION, GOBP_REGULATION_OF_CELL_MORPHOGENESIS, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_POLYMERIZATION, GOBP_BARBED_END_ACTIN_FILAMENT_CAPPING, THEILGAARD_NEUTROPHIL_AT_SKIN_WOUND_DN, GOBP_NEGATIVE_REGULATION_OF_ACTIN_FILAMENT_DEPOLYMERIZATION, RIZKI_TUMOR_INVASIVENESS_3D_DN, REACTOME_MEMBRANE_TRAFFICKING, SARRIO_EPITHELIAL_MESENCHYMAL_TRANSITION_DN, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_COMPONENT_ORGANIZATION, GOBP_REGULATION_OF_ACTIN_FILAMENT_BASED_PROCESS, MARTINEZ_RB1_TARGETS_UP

GO Biological Process (8): cytoskeleton organization (GO:0007010), actin polymerization or depolymerization (GO:0008154), regulation of cell morphogenesis (GO:0022604), lamellipodium assembly (GO:0030032), barbed-end actin filament capping (GO:0051016), cell projection organization (GO:0030030), actin cytoskeleton organization (GO:0030036), actin filament capping (GO:0051693)

GO Molecular Function (3): actin binding (GO:0003779), cadherin binding (GO:0045296), protein binding (GO:0005515)

GO Cellular Component (17): cytosol (GO:0005829), cytoskeleton (GO:0005856), brush border (GO:0005903), F-actin capping protein complex (GO:0008290), postsynaptic density (GO:0014069), actin cytoskeleton (GO:0015629), membrane (GO:0016020), sarcomere (GO:0030017), lamellipodium (GO:0030027), cortical cytoskeleton (GO:0030863), extracellular exosome (GO:0070062), WASH complex (GO:0071203), Schaffer collateral - CA1 synapse (GO:0098685), hippocampal mossy fiber to CA3 synapse (GO:0098686), sperm head-tail coupling apparatus (GO:0120212), cytoplasm (GO:0005737), asymmetric synapse (GO:0032279)

Reactome top-level categories

Rollup of top-15 pathways:

Category	Pathways
RHO GTPase cycle	2
Adaptive Immune System	1
Cellular responses to stress	1
ER to Golgi Anterograde Transport	1
Golgi-to-ER retrograde transport	1
Sensory processing of sound	1
Hemostasis	1
Immune System	1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1
Membrane Trafficking	1
Transport to the Golgi and subsequent modification	1
Vesicle-mediated transport	1
Cellular responses to stimuli	1
Post-translational protein modification	1
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
cytoplasm	2
protein-containing complex	2
cytoskeleton	2
neuron to neuron synapse	2
organelle organization	1
actin filament organization	1
cell morphogenesis	1
regulation of anatomical structure morphogenesis	1
lamellipodium organization	1
plasma membrane bounded cell projection assembly	1
actin filament capping	1
cellular component organization	1
cytoskeleton organization	1
actin filament-based process	1
negative regulation of actin filament depolymerization	1
negative regulation of actin filament polymerization	1
cytoskeletal protein binding	1
cell adhesion molecule binding	1
binding	1
intracellular membraneless organelle	1
microvillus	1
apical part of cell	1
cluster of actin-based cell projections	1
actin cytoskeleton	1
asymmetric synapse	1
postsynaptic specialization	1
myofibril	1
cell leading edge	1
plasma membrane bounded cell projection	1
cell cortex	1
extracellular vesicle	1
synapse	1
thorny excrescence	1
hippocampal mossy fiber expansion	1
intracellular anatomical structure	1
postsynaptic density	1

Protein interactions and networks

STRING

3658 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CAPZB	CAPZA2	P47755	991
CAPZB	CAPZA1	P52907	985
CAPZB	PDE8B	O95263	852
CAPZB	WDR1	O75083	658
CAPZB	ARPC3	O15145	630
CAPZB	TMOD4	Q9NZQ9	605
CAPZB	DCTN2	Q13561	584
CAPZB	WNT2	P09544	565
CAPZB	TWF2	Q6IBS0	557
CAPZB	CAPZA3	Q96KX2	552
CAPZB	ACTR3C	Q9C0K3	547
CAPZB	DCTN4	Q9UJW0	544
CAPZB	ACTN1	P12814	543
CAPZB	TFAP2A	P05549	543
CAPZB	ACTR3B	Q9P1U1	540

IntAct

210 interactions, top by confidence:

A	B	Type	Score
DCTN1	DCTN6	psi-mi:“MI:0914”(association)	0.780
VPS29	VPS26C	psi-mi:“MI:0914”(association)	0.760
CAPZA1	CAPZB	psi-mi:“MI:0915”(physical association)	0.740
CNOT3	CNOT1	psi-mi:“MI:0914”(association)	0.740
DCTN2	DCTN6	psi-mi:“MI:0914”(association)	0.730
DCTN2	DCTN3	psi-mi:“MI:0914”(association)	0.730
CFTR	CAPZB	psi-mi:“MI:0915”(physical association)	0.720
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
SH3KBP1	USP27X	psi-mi:“MI:0914”(association)	0.640
CAPZB	CNOT1	psi-mi:“MI:0914”(association)	0.640
DCTN5	DCTN6	psi-mi:“MI:0914”(association)	0.640
CAPZA2	CNOT1	psi-mi:“MI:0914”(association)	0.640
CNOT7	CAPZA2	psi-mi:“MI:0914”(association)	0.640
PLEKHO2	CAPZB	psi-mi:“MI:0914”(association)	0.640

BioGRID (1341): CAPZB (Affinity Capture-MS), CAPZB (Affinity Capture-MS), CAPZB (Affinity Capture-MS), CAPZB (Affinity Capture-MS), CAPZB (Affinity Capture-MS), CAPZB (Affinity Capture-MS), CAPZB (Affinity Capture-MS), CAPZB (Affinity Capture-MS), CAPZB (Affinity Capture-MS), CAPZB (Affinity Capture-MS), CAPZB (Affinity Capture-MS), CAPZB (Affinity Capture-MS), CAPZB (Affinity Capture-Western), ARPC2 (Co-fractionation), ARPC3 (Co-fractionation)

ESM2 similar proteins: A0M8R8, A0M8S9, A0M8V0, A0PFK5, A1X151, A4D7Q3, A4D7S9, A4FUA8, B2GUZ5, P13127, P25229, P28497, P47753, P47754, P47755, P47756, P47757, P52907, Q00PJ7, Q07DV7, Q07DY0, Q07DZ0, Q07E00, Q07E23, Q07E36, Q07E47, Q09YH6, Q09YJ9, Q09YL0, Q09YN4, Q108U5, Q29221, Q2IBA7, Q2IBB9, Q2IBE7, Q2QL78, Q2QL88, Q2QL99, Q2QLA8, Q2QLB9

Diamond homologs: A0PFK7, P13021, P13517, P14315, P34686, P47756, P47757, P48603, P79136, P86209, Q2URJ3, Q4INI2, Q4WKB4, Q5BGP0, Q5R507, Q5XI32, Q6BXG6, Q6CBA2, Q6CPK5, Q6FQL7, Q7SCP4, Q9HGP5, Q9M9G7

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 197 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
Downstream signal transduction	6	16.4×	4e-04
RHO GTPases activate IQGAPs	6	14.9×	6e-04
Parasite infection	5	12.4×	2e-03
Leishmania phagocytosis	5	12.4×	2e-03
RHO GTPases Activate WASPs and WAVEs	5	11.4×	2e-03
Signaling by high-kinase activity BRAF mutants	5	11.4×	2e-03
Sensory processing of sound	5	11.1×	2e-03
COPI-independent Golgi-to-ER retrograde traffic	7	10.5×	7e-04

GO biological processes:

GO term	Partners	Fold	FDR
barbed-end actin filament capping	6	27.2×	9e-05
positive regulation of microtubule polymerization	5	19.0×	4e-03
positive regulation of axon extension	5	14.4×	5e-03
regulation of apoptotic process	11	5.2×	5e-03
actin cytoskeleton organization	11	4.9×	5e-03
protein phosphorylation	12	4.6×	5e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	13
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2896 predictions. Top by Δscore:

Variant	Effect	Δscore
1:19339618:C:CA	acceptor_loss	1.0000
1:19345182:CTCA:C	donor_loss	1.0000
1:19345183:TCA:T	donor_loss	1.0000
1:19345185:A:AG	donor_loss	1.0000
1:19345186:C:CA	donor_loss	1.0000
1:19345248:TCCAT:T	acceptor_gain	1.0000
1:19345249:CCAT:C	acceptor_gain	1.0000
1:19345249:CCATC:C	acceptor_gain	1.0000
1:19345250:CAT:C	acceptor_gain	1.0000
1:19345250:CATC:C	acceptor_gain	1.0000
1:19345251:AT:A	acceptor_gain	1.0000
1:19345251:ATCTG:A	acceptor_loss	1.0000
1:19345252:TCTG:T	acceptor_loss	1.0000
1:19345253:C:CC	acceptor_gain	1.0000
1:19345253:CT:C	acceptor_loss	1.0000
1:19345256:C:CT	acceptor_gain	1.0000
1:19345257:A:T	acceptor_gain	1.0000
1:19356749:CTC:C	acceptor_gain	1.0000
1:19356751:CCTGG:C	acceptor_loss	1.0000
1:19356752:C:CC	acceptor_gain	1.0000
1:19357419:TA:T	donor_loss	1.0000
1:19357421:C:CA	donor_loss	1.0000
1:19357428:TTC:T	donor_gain	1.0000
1:19357429:TCT:T	donor_gain	1.0000
1:19378538:A:AC	donor_gain	1.0000
1:19378539:C:CC	donor_gain	1.0000
1:19378539:CA:C	donor_gain	1.0000
1:19378539:CAG:C	donor_gain	1.0000
1:19378539:CAGG:C	donor_gain	1.0000
1:19378539:CAGGT:C	donor_gain	1.0000

AlphaMissense

1792 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:19344406:A:G	L228P	1.000
1:19344414:T:A	R225S	1.000
1:19344414:T:G	R225S	1.000
1:19344415:C:G	R225T	1.000
1:19344427:T:A	E221V	1.000
1:19344428:C:T	E221K	1.000
1:19345187:C:A	E218D	1.000
1:19345187:C:G	E218D	1.000
1:19345200:C:A	G214V	1.000
1:19345200:C:T	G214E	1.000
1:19345201:C:A	G214W	1.000
1:19345201:C:G	G214R	1.000
1:19345201:C:T	G214R	1.000
1:19356645:A:G	L193P	1.000
1:19356647:G:C	S192R	1.000
1:19356647:G:T	S192R	1.000
1:19356649:T:G	S192R	1.000
1:19356651:C:T	G191D	1.000
1:19356652:C:G	G191R	1.000
1:19356654:C:T	G190E	1.000
1:19356655:C:G	G190R	1.000
1:19356655:C:T	G190R	1.000
1:19356657:A:G	L189P	1.000
1:19356693:A:G	L177P	1.000
1:19356697:A:G	W176R	1.000
1:19356697:A:T	W176R	1.000
1:19356699:A:G	L175P	1.000
1:19356699:A:T	L175Q	1.000
1:19356702:A:C	M174R	1.000
1:19356711:G:A	S171F	1.000

dbSNP variants (sampled 300 via entrez): RS1000011476 (1:19459010 T>A), RS1000027674 (1:19434292 G>A), RS1000037330 (1:19361796 C>T), RS1000041746 (1:19422550 C>T), RS1000066236 (1:19396985 C>T), RS1000077111 (1:19392106 C>G), RS1000082716 (1:19360024 G>A), RS1000134514 (1:19354084 T>G), RS1000142764 (1:19379254 A>G), RS1000176058 (1:19349497 G>A), RS1000194079 (1:19480844 G>A,T), RS1000205885 (1:19465900 G>A), RS1000210150 (1:19474998 C>T), RS1000227591 (1:19400582 G>C), RS1000228273 (1:19364222 T>C)

Disease associations

OMIM: gene MIM:601572 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

37 associations (top):

Study	Trait	p-value
GCST001069_1	Thyroid volume	3.000000e-18
GCST001069_4	Thyroid volume	3.000000e-14
GCST001069_5	Thyroid volume	2.000000e-11
GCST001069_8	Thyroid volume	1.000000e-14
GCST001473_3	Crohn’s disease and psoriasis	8.000000e-06
GCST001487_1	Thyroid function	2.000000e-08
GCST001856_30	Thyroid hormone levels	4.000000e-21
GCST001856_50	Thyroid hormone levels	3.000000e-14
GCST001856_51	Thyroid hormone levels	1.000000e-08
GCST002458_2	Serum thyroid-stimulating hormone levels	3.000000e-07
GCST002831_2	Lead levels in blood	3.000000e-06
GCST003988_22	Hypothyroidism	8.000000e-09
GCST004607_6	Plateletcrit	4.000000e-11
GCST006897_7	Hyperthyroidism	6.000000e-10
GCST006898_2	Hypothyroidism	9.000000e-11
GCST006979_856	Heel bone mineral density	2.000000e-28
GCST006979_857	Heel bone mineral density	1.000000e-17
GCST007001_1	Cerebrospinal AB1-42 levels in normal cognition	5.000000e-07
GCST008163_286	Height	1.000000e-06
GCST008165_1	Thyroid stimulating hormone levels	9.000000e-09
GCST010653_57	Thyroid stimulating hormone levels	4.000000e-39
GCST010653_58	Thyroid stimulating hormone levels	2.000000e-72
GCST010696_18	Cortical thickness (min-P)	1.000000e-10
GCST010697_49	Cortical surface area (min-P)	9.000000e-13
GCST010698_58	Subcortical volume (min-P)	9.000000e-10
GCST010699_28	Brain morphology (min-P)	3.000000e-09
GCST010700_3	Cortical thickness (MOSTest)	2.000000e-20
GCST010701_23	Cortical surface area (MOSTest)	2.000000e-44
GCST010702_68	Subcortical volume (MOSTest)	2.000000e-11
GCST010703_80	Brain morphology (MOSTest)	3.000000e-16

EFO canonical traits (11, from GWAS)

EFO ID	Trait name
EFO:0004296	thyroid function
EFO:0004730	hormone measurement
EFO:0007985	platelet crit
EFO:0009270	heel bone mineral density
EFO:0004670	beta-amyloid 1-42 measurement
EFO:0004346	neuroimaging measurement
EFO:0004840	cortical thickness
EFO:0000714	survival time
EFO:0008039	BMI-adjusted hip circumference
EFO:0004980	appendicular lean mass
EFO:0004309	platelet count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295764 (SINGLE PROTEIN)

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

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.41	Kd	393.4	nM	CHEMBL5653589
6.41	ED50	393.4	nM	CHEMBL5653589
5.05	Kd	8898	nM	CHEMBL3752910
5.05	ED50	8898	nM	CHEMBL3752910

PubChem BioAssay actives

2 with measured affinity, of 12 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147997: Binding affinity to human CAPZB incubated for 45 mins by Kinobead based pull down assay	kd	0.3934	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147997: Binding affinity to human CAPZB incubated for 45 mins by Kinobead based pull down assay	kd	8.8979	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases methylation, affects methylation, decreases expression	3
Tobacco Smoke Pollution	affects expression, decreases methylation, increases expression	3
bisphenol A	increases expression, decreases expression	2
triphenyl phosphate	affects expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, decreases expression	1
sodium arsenite	increases expression	1
ochratoxin A	increases acetylation, increases expression	1
benzo(e)pyrene	increases methylation	1
4-hydroxy-2-nonenal	affects binding	1
aflatoxin B2	increases methylation	1
cupric oxide	increases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
ICG 001	decreases expression	1
bisphenol B	increases expression	1
quinocetone	decreases expression	1
bisphenol S	affects cotreatment, decreases methylation	1
jinfukang	decreases expression, affects cotreatment	1
LDN 193189	increases expression, affects cotreatment	1
Temozolomide	decreases expression	1
Arsenic Trioxide	increases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Air Pollutants	increases abundance, decreases expression	1
Ethanol	increases expression	1
Cisplatin	affects cotreatment, decreases expression	1
Cocaine	decreases expression	1
Doxorubicin	increases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Formaldehyde	decreases expression	1
Furaldehyde	affects cotreatment, increases expression	1

ChEMBL screening assays

9 unique, capped per target: 9 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4118730	Binding	Binding affinity to CAPZB in human NCI-H23 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — Bioorg Med Chem

Clinical trials (associated diseases)

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