ACTR2

Summary

ACTR2 (actin related protein 2, HGNC:169) is a protein-coding gene on chromosome 2p14, encoding Actin-related protein 2 (P61160). ATP-binding component of the Arp2/3 complex, a multiprotein complex that mediates actin polymerization upon stimulation by nucleation-promoting factor (NPF). It is a common-essential gene (DepMap: required in 98.3% of cancer cell lines).

The specific function of this gene has not yet been determined; however, the protein it encodes is known to be a major constituent of the ARP2/3 complex. This complex is located at the cell surface and is essential to cell shape and motility through lamellipodial actin assembly and protrusion. Two transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 10097 — RefSeq curated summary.

At a glance

• GWAS associations: 7
• Clinical variants (ClinVar): 36 total — 3 pathogenic, 3 likely-pathogenic
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 98.3% of screened cell lines (common-essential)
• MANE Select transcript: NM_005722

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:169
Approved symbol	ACTR2
Name	actin related protein 2
Location	2p14
Locus type	gene with protein product
Status	Approved
Aliases	ARP2
Ensembl gene	ENSG00000138071
Ensembl biotype	protein_coding
OMIM	604221
Entrez	10097

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 11 protein_coding, 2 nonsense_mediated_decay

ENST00000260641, ENST00000377982, ENST00000471552, ENST00000476840, ENST00000880426, ENST00000880427, ENST00000880428, ENST00000880429, ENST00000880430, ENST00000880431, ENST00000922450, ENST00000922451, ENST00000958822

RefSeq mRNA: 2 — MANE Select: NM_005722 NM_001005386, NM_005722

CCDS: CCDS1881, CCDS46307

Canonical transcript exons

ENST00000260641 — 9 exons

Exon	Start	End
ENSE00000443287	65255545	65255694
ENSE00000758608	65251027	65251099
ENSE00000758609	65253728	65253864
ENSE00000932761	65261247	65261392
ENSE00000932762	65265043	65265175
ENSE00001006428	65227831	65227957
ENSE00001351368	65268564	65271253
ENSE00003471512	65246524	65246739
ENSE00003576050	65239852	65239962

Expression profiles

Bgee: expression breadth ubiquitous, 303 present calls, max score 99.43.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 73.0309 / max 1107.9898, expressed in 1821 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
20621	66.5624	1820
20620	3.2256	1470
20619	3.2203	1416
20622	0.0226	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	99.43	gold quality
mononuclear cell	CL:0000842	99.41	gold quality
leukocyte	CL:0000738	99.35	gold quality
trabecular bone tissue	UBERON:0002483	99.15	gold quality
epithelium of nasopharynx	UBERON:0001951	99.13	gold quality
nasopharynx	UBERON:0001728	99.11	gold quality
vermiform appendix	UBERON:0001154	99.01	gold quality
palpebral conjunctiva	UBERON:0001812	99.01	gold quality
lymph node	UBERON:0000029	98.97	gold quality
caecum	UBERON:0001153	98.97	gold quality
esophagus squamous epithelium	UBERON:0006920	98.93	gold quality
mucosa of sigmoid colon	UBERON:0004993	98.86	gold quality
bone element	UBERON:0001474	98.85	gold quality
bone marrow	UBERON:0002371	98.82	gold quality
visceral pleura	UBERON:0002401	98.81	gold quality
bone marrow cell	CL:0002092	98.78	gold quality
pylorus	UBERON:0001166	98.71	gold quality
cauda epididymis	UBERON:0004360	98.71	gold quality
colonic mucosa	UBERON:0000317	98.70	gold quality
parietal pleura	UBERON:0002400	98.68	gold quality
corpus epididymis	UBERON:0004359	98.62	gold quality
colonic epithelium	UBERON:0000397	98.61	gold quality
oral cavity	UBERON:0000167	98.59	gold quality
caput epididymis	UBERON:0004358	98.58	gold quality
secondary oocyte	CL:0000655	98.54	gold quality
rectum	UBERON:0001052	98.54	gold quality
pericardium	UBERON:0002407	98.54	gold quality
tongue squamous epithelium	UBERON:0006919	98.53	gold quality
pleura	UBERON:0000977	98.47	gold quality
islet of Langerhans	UBERON:0000006	98.44	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-10042	yes	6.93
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F1

miRNA regulators (miRDB)

154 targeting ACTR2, 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-3163	100.00	77.23	8605
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-590-3P	99.96	74.34	6478

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 98.3% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 40)

• Arp2/3 complex is required for actin polymerization during platelet shape change. (PMID:12036877)
• Platelets activate Arp2/3 complex, assemble actin, and change shape in the absence of WASp, indicating a more specialized role for WASp in these cells. (PMID:12200375)
• Results suggest that recruitment of factors by Wiskott-Aldrich Syndrome protein (WASP) and Scar1 stimulates cellular actin-based motility and actin nucleation with the Arp2/3 complex. (PMID:12429845)
• Arp2/3 complex contribution to actin filament nucleation in platelets and fibroblasts importantly requires free barbed ends generated by severing and uncapping. (PMID:12464680)
• cortactin links receptor endocytosis to actin polymerization by binding both CD2AP and the Arp2/3 complex, which may facilitate the trafficking of internalized growth factor receptors (PMID:12672817)
• ARP2-mediated actin polymerization is regulated by phosphorylation of WASP protein. (PMID:12791263)
• The interaction between cortactin and Arp2/3 complex plays an important role in S1P-mediated remodeling of endothelial cells. (PMID:15242766)
• existence of an Arp2/3 complex-dependent event during the early phase of the life cycles of both primate lentiviruses and intracellular mature vaccinia virus (PMID:15385624)
• signalling pathways leading to Arp2/3-dependent actin nucleation play an important role in Salmonella typhimurium invasion, but are not involved in intracellular Salmonella-induced actin assembly (PMID:15469433)
• T-plastin increases Arp2/3-mediated actin-based movement (PMID:15741236)
• These results indicate that interaction between the Arp2/3 complex and WASP stimulates actin polymerization and integrin beta-1-mediated adhesion during MCP-1-induced chemotaxis of THP-1 cells. (PMID:16004967)
• the binding of the C terminus of SPIN90 with both the Arp2/3 complex (actin-related proteins Arp 2 and Arp 3) and G-actin activates the former, leading to actin polymerization (PMID:16253999)
• in activation of the Arp2/3 complex, the C domain first primes the complex by inducing a necessary conformational change and then initiates nucleus assembly by bringing an actin monomer into proximity of the primed complex (PMID:16403731)
• Coexpression of Arp2 and WAVE2 is correlated with poorer patient outcome. (PMID:16638851)
• signal-induced relief of the autoinhibited fold of IQGAP1 allows activation of N-WASP to stimulate Arp2/3-dependent actin assembly (PMID:17085436)
• High mRNA levels of Arp2 were significantly associated with liver metastasis of colorectal cancer. (PMID:17459058)
• Data show that Chlamydia trachomatis activates Rac and promotes its interaction with WAVE2 and Abi-1 to activate the Arp2/3 complex resulting in the induction of actin cytoskeletal rearrangements that are required for invasion. (PMID:17501982)
• Results suggest that WAVE and the Arp2/3 complex jointly orchestrate different types of actin-based plasma membrane protrusions by promoting ruffling and inhibiting mDia2-induced filopodia. (PMID:18516090)
• Arp2-depleted Jurkat T lymphocytes exhibit defects in spreading on anti-CD3; Arp2-depleted Jurkats exhibit defects in ruffle assembly but not in assembly of mitotic linear protrusions. (PMID:18720401)
• the exchange rate of N-WASP controls the rate of ARP2/3-complex-dependent actin-based motility by regulating the extent of actin polymerization by antagonizing filament capping (PMID:19262673)
• The Arp2/3 complex, an actin-nucleating factor, is recruited at the ring structure and is important for parasite entry. (PMID:19286135)
• Loss of Arp2/3 function led to defects in cell adhesion and actin assembly at the junction with the target cell (the lytic synapse) (PMID:19913427)
• key residues at this interface were crucial for actin nucleation and Y-branching, high-affinity F-actin binding, and Y-branch stability, demonstrating that the affinity of Arp2/3 complex for F actin independently modulates branch formation and stability. (PMID:20404198)
• the centrosome transiently recruits Arp2/3 to perform processes such as centrosome separation prior to mitotic entry. (PMID:21108927)
• Anthrax edema toxin induced transendothelial cell tunnels are resealed by MIM via Arp2/3-driven actin polymerization. (PMID:22100162)
• Using molecular dynamics simulations and biochemical assays with recombinant Arp2/3 complex, we now show how phosphorylation of Arp2 induces conformational changes permitting activation. (PMID:22125478)
• We demonstrate that WAVE2-Arp2/3 is a major nucleator of actin assembly at the zonula adherens and likely acts in response to junctional Rac signaling (PMID:23051739)
• Neural Wiskott-Aldrich syndrome protein (N-WASP)-mediated p120-catenin interaction with Arp2-Actin complex stabilizes endothelial adherens junctions. (PMID:23212915)
• The Arp2/Arp3 complex has a role in osmotic signaling. (PMID:24344184)
• Cortactin has a role as a scaffold for Arp2/3 and WAVE2 at the epithelial zonula adherens (PMID:24469447)
• study unveils an ARP2/3:VCA-independent function of nuclear-WASp in TH1 gene activation that is uncoupled from its cytoplasmic role in actin polymerization. (PMID:24872192)
• Coronin3 can regulate gastric cancer (GC) invasion and metastasis through Arp2, and the combination of Coronin3 and Arp2 provides a potential marker for predicting GC prognosis. (PMID:24918434)
• The loss of the Arp2/3 complex acts as a stress that initiates cell cycle arrest by triggering p16INK4a/p14Arf transcription. (PMID:25264243)
• Platelet actin nodule formation is dependent on WASp and the ARP2/3 complex. (PMID:26028144)
• Suggest alpha5beta1/Arp2/Arp3/FHOD3 pathway reprograms the actin cytoskeleton to promote invasive migration and local invasion in vivo. (PMID:26370503)
• demonstrate that the Arp2/3 complex in higher eukaryotes is actually a family of complexes with different properties (PMID:26655834)
• RARalpha regulates Arp2/3-mediated actin cytoskeletal dynamics through a non-genomic signaling pathway (PMID:26848712)
• miR-24-1*/let-7a*-ARP2/3 complex-RAC isoforms pathway may represent a novel pathogenic mechanism for Hirschsprung disease. (PMID:26991540)
• Kv3.3 regulates Arp2/3-dependent cortical actin nucleation mediated by Hax-1; resulting cortical actin structures interact with the channel’s gating machinery to slow its inactivation rate during sustained membrane depolarizations; a mutation that leads to late-onset spinocerebellar ataxia type 13. (PMID:26997484)
• These findings indicate that inhibition of the Rac1WAVE2Arp2/3 signaling pathway may promote radiosensitivity, which may partially result from the downregulation of CFL1 in U251 human glioma cells. (PMID:27052944)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	actr2a	ENSDARG00000052438
danio_rerio	actr2b	ENSDARG00000070076
mus_musculus	Actr2	ENSMUSG00000020152
rattus_norvegicus	Actr2	ENSRNOG00000004959
drosophila_melanogaster	Arp2	FBGN0011742
caenorhabditis_elegans		WBGENE00000200

Paralogs (26): ACTR6 (ENSG00000075089), ACTB (ENSG00000075624), ACTL6B (ENSG00000077080), ACTR5 (ENSG00000101442), ACTR3C (ENSG00000106526), ACTA2 (ENSG00000107796), ACTR8 (ENSG00000113812), ACTR1B (ENSG00000115073), ACTR3 (ENSG00000115091), ACTL8 (ENSG00000117148), ACTRT1 (ENSG00000123165), ACTR10 (ENSG00000131966), ACTR3B (ENSG00000133627), ACTL6A (ENSG00000136518), ACTR1A (ENSG00000138107), ACTA1 (ENSG00000143632), ACTL7B (ENSG00000148156), ACTC1 (ENSG00000159251), ACTG2 (ENSG00000163017), ACTBL2 (ENSG00000169067), ACTRT2 (ENSG00000169717), ACTL9 (ENSG00000181786), ACTG1 (ENSG00000184009), ACTRT3 (ENSG00000184378), ACTL7A (ENSG00000187003), ACTL10 (ENSG00000288649)

Protein

Protein identifiers

Actin-related protein 2 — P61160 (reviewed: P61160)

Alternative names: Actin-like protein 2

All UniProt accessions (3): P61160, A0A1B0GWD0, A0A1B0GWH0

UniProt curated annotations — full annotation on UniProt →

Function. ATP-binding component of the Arp2/3 complex, a multiprotein complex that mediates actin polymerization upon stimulation by nucleation-promoting factor (NPF). The Arp2/3 complex mediates the formation of branched actin networks in the cytoplasm, providing the force for cell motility. Seems to contact the pointed end of the daughter actin filament. In podocytes, required for the formation of lamellipodia downstream of AVIL and PLCE1 regulation. In addition to its role in the cytoplasmic cytoskeleton, the Arp2/3 complex also promotes actin polymerization in the nucleus, thereby regulating gene transcription and repair of damaged DNA. The Arp2/3 complex promotes homologous recombination (HR) repair in response to DNA damage by promoting nuclear actin polymerization, leading to drive motility of double-strand breaks (DSBs).

Subunit / interactions. Component of the Arp2/3 complex composed of ACTR2/ARP2, ACTR3/ARP3, ARPC1B/p41-ARC, ARPC2/p34-ARC, ARPC3/p21-ARC, ARPC4/p20-ARC and ARPC5/p16-ARC. Interacts with AVIL.

Subcellular location. Cytoplasm. Cytoskeleton. Cell projection. Nucleus.

Similarity. Belongs to the actin family. ARP2 subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
P61160-1	1	yes
P61160-2	2

RefSeq proteins (2): NP_001005386, NP_005713* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004000	Actin	Family
IPR020902	Actin/actin-like_CS	Conserved_site
IPR043129	ATPase_NBD	Homologous_superfamily

Pfam: PF00022

UniProt features (10 total): binding site 3, modified residue 3, sequence conflict 2, chain 1, splice variant 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
9I2B	ELECTRON MICROSCOPY	3
8P94	ELECTRON MICROSCOPY	3.3
6UHC	ELECTRON MICROSCOPY	3.9
6YW6	ELECTRON MICROSCOPY	4.2
6YW7	ELECTRON MICROSCOPY	4.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P61160-F1	93.96	0.88

Functional residue map

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

Ligand- & substrate-binding residues (3): 160–162; 214–218; 305–310

Post-translational modifications (3): 1, 299, 322

Function

Pathways and Gene Ontology

Reactome pathways

25 pathways

ID	Pathway
R-HSA-2029482	Regulation of actin dynamics for phagocytic cup formation
R-HSA-3928662	EPHB-mediated forward signaling
R-HSA-5663213	RHO GTPases Activate WASPs and WAVEs
R-HSA-6798695	Neutrophil degranulation
R-HSA-8856828	Clathrin-mediated endocytosis
R-HSA-9664422	FCGR3A-mediated phagocytosis
R-HSA-1266738	Developmental Biology
R-HSA-162582	Signal Transduction
R-HSA-1643685	Disease
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System
R-HSA-194315	Signaling by Rho GTPases
R-HSA-195258	RHO GTPase Effectors
R-HSA-199991	Membrane Trafficking
R-HSA-2029480	Fcgamma receptor (FCGR) dependent phagocytosis
R-HSA-2682334	EPH-Ephrin signaling
R-HSA-422475	Axon guidance
R-HSA-5653656	Vesicle-mediated transport
R-HSA-5663205	Infectious disease
R-HSA-9658195	Leishmania infection
R-HSA-9664407	Parasite infection
R-HSA-9664417	Leishmania phagocytosis
R-HSA-9675108	Nervous system development
R-HSA-9716542	Signaling by Rho GTPases, Miro GTPases and RHOBTB3
R-HSA-9824443	Parasitic Infection Pathways

MSigDB gene sets: 368 (showing top): GOBP_MEIOTIC_CHROMOSOME_SEGREGATION, GOBP_REGULATION_OF_DOUBLE_STRAND_BREAK_REPAIR, GOBP_REGULATION_OF_DNA_RECOMBINATION, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_CELL_POLARITY, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GNF2_BNIP2, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_RESPONSE_TO_PEPTIDE, GOCC_SECRETORY_GRANULE, MODULE_151, chr2p14, GOBP_SPINDLE_LOCALIZATION, GOBP_CHROMOSOME_LOCALIZATION

GO Biological Process (14): establishment or maintenance of cell polarity (GO:0007163), asymmetric cell division (GO:0008356), positive regulation of lamellipodium assembly (GO:0010592), meiotic chromosome movement towards spindle pole (GO:0016344), cytosolic transport (GO:0016482), meiotic cytokinesis (GO:0033206), Arp2/3 complex-mediated actin nucleation (GO:0034314), positive regulation of transcription by RNA polymerase II (GO:0045944), spindle localization (GO:0051653), cilium assembly (GO:0060271), cellular response to type II interferon (GO:0071346), positive regulation of double-strand break repair via homologous recombination (GO:1905168), actin cytoskeleton organization (GO:0030036), meiotic cell cycle (GO:0051321)

GO Molecular Function (6): actin binding (GO:0003779), structural constituent of cytoskeleton (GO:0005200), ATP binding (GO:0005524), nucleotide binding (GO:0000166), protein binding (GO:0005515), actin filament binding (GO:0051015)

GO Cellular Component (16): extracellular region (GO:0005576), nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829), Arp2/3 protein complex (GO:0005885), focal adhesion (GO:0005925), cell cortex (GO:0005938), actin cytoskeleton (GO:0015629), membrane (GO:0016020), actin cap (GO:0030478), azurophil granule lumen (GO:0035578), site of double-strand break (GO:0035861), cell projection (GO:0042995), extracellular exosome (GO:0070062), ficolin-1-rich granule lumen (GO:1904813), cytoskeleton (GO:0005856)

Reactome top-level categories

Rollup of top-14 pathways:

Category	Pathways
Innate Immune System	2
Fcgamma receptor (FCGR) dependent phagocytosis	1
EPH-Ephrin signaling	1
RHO GTPase Effectors	1
Membrane Trafficking	1
Leishmania phagocytosis	1
Immune System	1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1
Signaling by Rho GTPases	1
Vesicle-mediated transport	1
Axon guidance	1
Nervous system development	1
Disease	1
Parasitic Infection Pathways	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
meiotic cell cycle	2
meiotic cell cycle process	2
cytoskeleton organization	2
cytoskeleton	2
cytoplasm	2
cellular process	1
cell division	1
regulation of lamellipodium assembly	1
lamellipodium assembly	1
positive regulation of plasma membrane bounded cell projection assembly	1
positive regulation of lamellipodium organization	1
meiotic chromosome segregation	1
chromosome movement towards spindle pole	1
cytosol	1
intracellular transport	1
cytoskeleton-dependent cytokinesis	1
actin nucleation	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
cell cycle process	1
organelle localization	1
axoneme assembly	1
intraciliary transport involved in cilium assembly	1
cilium organization	1
protein localization to cilium	1
organelle assembly	1
trans-Golgi to periciliary membrane compartment transport	1
plasma membrane bounded cell projection assembly	1
ciliary transition zone assembly	1
response to type II interferon	1
cellular response to cytokine stimulus	1
double-strand break repair via homologous recombination	1
regulation of double-strand break repair via homologous recombination	1
positive regulation of DNA recombination	1
positive regulation of double-strand break repair	1
actin filament-based process	1
cell cycle	1
sexual reproduction	1

Protein interactions and networks

STRING

4010 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ACTR2	ARPC3	O15145	998
ACTR2	ARPC5	O15511	998
ACTR2	WAS	P42768	998
ACTR2	ARPC2	O15144	997
ACTR2	WASL	O00401	994
ACTR2	ARPC1B	O15143	991
ACTR2	ACTR3	P32391	985
ACTR2	ACTR3C	Q9C0K3	976
ACTR2	ACTR3B	Q9P1U1	976
ACTR2	ARPC1A	Q92747	950
ACTR2	CFL1	P23528	920
ACTR2	CFL2	Q9Y281	917
ACTR2	HCLS1	P14317	890
ACTR2	CTTN	Q14247	890
ACTR2	WASF2	Q9Y6W5	888

IntAct

196 interactions, top by confidence:

A	B	Type	Score
ARPC1B	ARPC2	psi-mi:“MI:0915”(physical association)	0.920
ARPC1B	ARPC2	psi-mi:“MI:0914”(association)	0.920
ARPC4	ARPC1B	psi-mi:“MI:0914”(association)	0.910
ARPC1A	ARPC2	psi-mi:“MI:0914”(association)	0.900
ARPC1A	ARPC2	psi-mi:“MI:0915”(physical association)	0.900
ARPC5	ARPC1B	psi-mi:“MI:0914”(association)	0.890
ACTR3	ARPC1B	psi-mi:“MI:0914”(association)	0.890

BioGRID (527): ACTR2 (Affinity Capture-MS), ACTR2 (Affinity Capture-MS), ACTR2 (Affinity Capture-MS), ACTR2 (Affinity Capture-MS), ACTR2 (Affinity Capture-MS), ACTR2 (Affinity Capture-MS), ACTR2 (Affinity Capture-RNA), ACTR2 (Co-fractionation), ACTR2 (Co-fractionation), ACTR2 (Co-fractionation), ACTR2 (Co-fractionation), ACTR2 (Co-fractionation), ACTR2 (Co-fractionation), ACTR2 (Co-fractionation), ACTR2 (Co-fractionation)

ESM2 similar proteins: A2YUL5, A4IFE3, A7MB62, O94241, O94630, O96621, P02583, P20360, P32381, P38673, P38696, P42023, P42025, P45888, P45889, P53487, P53488, P53489, P53503, P61160, P61161, P61162, P61163, P61164, P85515, Q2TA43, Q4R6J9, Q4R821, Q54HE7, Q54HE9, Q54I79, Q56A35, Q5BL41, Q5M7U6, Q5R4K0, Q5XIK1, Q61JZ2, Q641W9, Q6Z256, Q7SXW6

Diamond homologs: A2YUL5, A3C6D7, A7MB62, O13419, O18840, O65315, O96621, P02578, P04751, P07837, P0C539, P10365, P10984, P10986, P10990, P10995, P11426, P15475, P20359, P20399, P26197, P30162, P30163, P32381, P43239, P45888, P48465, P48975, P49055, P53455, P53458, P53459, P53460, P53470, P53479, P53480, P53482, P53485, P53487, P53488

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
BMP7	up-regulates	ACTR2	binding
GDF11	up-regulates	ACTR2	binding
ACTR2	“form complex”	ARP2/3	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 177 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
Parasite infection	11	32.5×	3e-12
Leishmania phagocytosis	11	32.5×	3e-12
RHO GTPases Activate WASPs and WAVEs	11	29.8×	6e-12
RHO GTPases activate PAKs	6	27.9×	3e-06
Fcgamma receptor (FCGR) dependent phagocytosis	11	26.2×	3e-11
EPHB-mediated forward signaling	10	22.7×	1e-09
FCGR3A-mediated phagocytosis	14	22.4×	7e-13
Regulation of actin dynamics for phagocytic cup formation	13	20.5×	6e-12

GO biological processes:

GO term	Partners	Fold	FDR
Arp2/3 complex-mediated actin nucleation	8	57.7×	4e-10
actin polymerization or depolymerization	5	26.2×	2e-04
actin filament polymerization	6	19.8×	1e-04
cellular response to type II interferon	6	8.6×	8e-03
actin cytoskeleton organization	12	6.5×	1e-04
cilium assembly	10	5.0×	5e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	3
Uncertain significance	17
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (6)

Variant ID	HGVS	Classification
1327542	NC_000002.11:g.65335411_65479694del	Pathogenic
443261	GRCh37/hg19 2p15-14(chr2:63234780-67908846)x1	Pathogenic
687379	GRCh37/hg19 2p15-14(chr2:63536353-65793944)x1	Pathogenic
3897632	NM_005722.4(ACTR2):c.752_753del (p.Ile251fs)	Likely pathogenic
443366	GRCh37/hg19 2p15-14(chr2:61701437-65731084)x1	Likely pathogenic
4682541	GRCh37/hg19 2p16.1-14(chr2:56466440-65809354)x3	Likely pathogenic

SpliceAI

1550 predictions. Top by Δscore:

Variant	Effect	Δscore
2:65227927:G:GT	donor_gain	1.0000
2:65227928:A:T	donor_gain	1.0000
2:65239837:A:AG	acceptor_gain	1.0000
2:65239837:ACT:A	acceptor_gain	1.0000
2:65239839:T:TA	acceptor_gain	1.0000
2:65239845:A:AG	acceptor_gain	1.0000
2:65239846:T:G	acceptor_gain	1.0000
2:65239850:A:AG	acceptor_gain	1.0000
2:65239850:AGTTT:A	acceptor_gain	1.0000
2:65239851:G:GT	acceptor_gain	1.0000
2:65239851:GT:G	acceptor_gain	1.0000
2:65239851:GTT:G	acceptor_gain	1.0000
2:65239851:GTTT:G	acceptor_gain	1.0000
2:65239851:GTTTG:G	acceptor_gain	1.0000
2:65239960:AAGG:A	donor_loss	1.0000
2:65239961:AGG:A	donor_loss	1.0000
2:65239963:G:GG	donor_gain	1.0000
2:65239963:GT:G	donor_loss	1.0000
2:65239964:T:G	donor_loss	1.0000
2:65246738:AGGT:A	donor_loss	1.0000
2:65246741:T:G	donor_loss	1.0000
2:65251021:TTACA:T	acceptor_loss	1.0000
2:65251022:TACAG:T	acceptor_loss	1.0000
2:65251024:CAG:C	acceptor_loss	1.0000
2:65251025:A:C	acceptor_loss	1.0000
2:65251026:G:A	acceptor_loss	1.0000
2:65255543:A:AG	acceptor_gain	1.0000
2:65255544:G:GG	acceptor_gain	1.0000
2:65255676:ATT:A	donor_gain	1.0000
2:65255691:TACAG:T	donor_loss	1.0000

AlphaMissense

2568 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:65227943:G:C	D12H	1.000
2:65227944:A:C	D12A	1.000
2:65227944:A:T	D12V	1.000
2:65227949:G:C	G14R	1.000
2:65227949:G:T	G14C	1.000
2:65227950:G:A	G14D	1.000
2:65227950:G:T	G14V	1.000
2:65227953:C:T	T15I	1.000
2:65227955:G:T	G16W	1.000
2:65227956:G:A	G16E	1.000
2:65239860:G:C	K19N	1.000
2:65239860:G:T	K19N	1.000
2:65239865:G:A	G21E	1.000
2:65239913:G:A	G37E	1.000
2:65246593:G:C	G77R	1.000
2:65246594:G:A	G77D	1.000
2:65246594:G:T	G77V	1.000
2:65246629:T:A	W89R	1.000
2:65246629:T:C	W89R	1.000
2:65246693:C:T	T110I	1.000
2:65251074:G:C	Q141H	1.000
2:65251074:G:T	Q141H	1.000
2:65251082:T:C	L144P	1.000
2:65251088:T:G	L146W	1.000
2:65251099:G:C	G150R	1.000
2:65253739:G:C	G154R	1.000
2:65253740:G:A	G154D	1.000
2:65253740:G:T	G154V	1.000
2:65253751:G:C	D158H	1.000
2:65253752:A:C	D158A	1.000

dbSNP variants (sampled 300 via entrez): RS1000149032 (2:65251793 A>G), RS1000197628 (2:65249204 T>C), RS1000205038 (2:65263713 C>T), RS1000223679 (2:65266992 C>G,T), RS1000314381 (2:65246067 A>G), RS1000349797 (2:65268902 A>G), RS1000367944 (2:65245484 C>A,G,T), RS1000377398 (2:65271748 C>T), RS1000383291 (2:65228865 G>A), RS1000466409 (2:65257417 C>T), RS1000503818 (2:65261853 A>G), RS1000689455 (2:65227866 G>A), RS1000744440 (2:65234237 A>T), RS1000795725 (2:65245766 T>C), RS1001004203 (2:65245612 A>G)

Disease associations

OMIM: gene MIM:604221 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): intellectual disability (MONDO:0001071)

Orphanet (1): NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

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

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST004744_46	Lung adenocarcinoma	3.000000e-06
GCST004748_81	Lung cancer	2.000000e-06
GCST005194_80	Coronary artery disease	8.000000e-07
GCST006979_7	Heel bone mineral density	8.000000e-12
GCST009391_1542	Metabolite levels	7.000000e-06
GCST009870_8	Calcific aortic valve stenosis	1.000000e-06
GCST010866_35	Coronary artery disease	6.000000e-09

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0009270	heel bone mineral density
EFO:0010510	NG-monomethyl-arginine measurement
EFO:0000266	aortic stenosis

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6090 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 903 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL514201	TALMAPIMOD	2	903

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

ChEMBL bioactivities

3 potent at pChembl≥5 of 5 total, top 3 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.40	Kd	4	nM	TALMAPIMOD
6.76	Kd	174.4	nM	CHEMBL3752910
6.76	ED50	174.4	nM	CHEMBL3752910

PubChem BioAssay actives

2 with measured affinity, of 254 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
2-[6-chloro-5-[(2R,5S)-4-[(4-fluorophenyl)methyl]-2,5-dimethylpiperazine-1-carbonyl]-1-methylindol-3-yl]-N,N-dimethyl-2-oxoacetamide	1424898: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.0040	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147798: Binding affinity to human ACTR2 incubated for 45 mins by Kinobead based pull down assay	kd	0.1744	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol F	increases expression, affects cotreatment	2
bisphenol A	decreases expression, increases expression	2
Nickel	increases expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
TAK-243	increases sumoylation	1
geldanamycin	increases expression	1
uranyl acetate	affects expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, decreases expression	1
trichostatin A	increases expression	1
cobaltous chloride	decreases expression	1
beta-methylcholine	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
chloropicrin	increases expression	1
nickel acetate	affects expression	1
nutlin 3	affects cotreatment, increases secretion	1
bisphenol B	increases expression	1
bisphenol S	increases expression	1
jinfukang	decreases expression	1
bisphenol AF	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Air Pollutants	increases abundance, affects expression	1
Cadmium	decreases expression	1
Dactinomycin	affects cotreatment, increases secretion	1
Dexamethasone	affects cotreatment, increases expression	1
Furaldehyde	affects cotreatment, affects localization, increases expression	1
Indomethacin	affects cotreatment, increases expression	1
Ivermectin	decreases expression	1
Methotrexate	decreases expression	1
Ozone	affects expression, increases abundance	1
Plant Extracts	affects cotreatment, increases expression	1

ChEMBL screening assays

23 unique, capped per target: 23 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1035863	Binding	Binding affinity to human ACTR2 at 10 uM relative to control	Assessment of chemical coverage of kinome space and its implications for kinase drug discovery. — J Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD
NCT02591446	Not specified	COMPLETED	Transcranial Magnetic Stimulation Studies in Autism Spectrum Disorders
NCT02714868	Not specified	COMPLETED	Evaluation of Project TEAM (Teens Making Environmental and Activity Modifications)
NCT02721394	Not specified	UNKNOWN	FCT With Young Children With ID in the UK: A Feasibility Project V.1
NCT02746614	Not specified	COMPLETED	Psychomotor Therapy Effects in Adaptive Behavior and Motor Proficiency in Intellectual Disability
NCT02836405	Not specified	COMPLETED	TMS for the Investigation of Brain Plasticity in Autism Spectrum Disorders