ARPC3

Summary

ARPC3 (actin related protein 2/3 complex subunit 3, HGNC:706) is a protein-coding gene on chromosome 12q24.11, encoding Actin-related protein 2/3 complex subunit 3 (O15145). Component of the Arp2/3 complex, a multiprotein complex that mediates actin polymerization upon stimulation by nucleation-promoting factor (NPF). It is a selective cancer dependency (DepMap: 74.6% of cell lines).

This gene encodes one of seven subunits of the human Arp2/3 protein complex. The Arp2/3 protein complex has been conserved through evolution and is implicated in the control of actin polymerization in cells. Alternatively spliced transcript variants have been found for this gene.

Source: NCBI Gene 10094 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Charcot-Marie-Tooth disease (Moderate, GenCC)
• GWAS associations: 3
• Clinical variants (ClinVar): 14 total
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 74.6% of screened cell lines
• MANE Select transcript: NM_001278556

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:706
Approved symbol	ARPC3
Name	actin related protein 2/3 complex subunit 3
Location	12q24.11
Locus type	gene with protein product
Status	Approved
Aliases	p21-Arc, ARC21
Ensembl gene	ENSG00000111229
Ensembl biotype	protein_coding
OMIM	604225
Entrez	10094

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 15 protein_coding, 4 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000228825, ENST00000426440, ENST00000467622, ENST00000471641, ENST00000475777, ENST00000476566, ENST00000547365, ENST00000548878, ENST00000549408, ENST00000888154, ENST00000888155, ENST00000888156, ENST00000888157, ENST00000888158, ENST00000888159, ENST00000888160, ENST00000934421, ENST00000934422, ENST00000934423, ENST00000934424, ENST00000934425

RefSeq mRNA: 2 — MANE Select: NM_001278556 NM_001278556, NM_001287222

CCDS: CCDS9146

Canonical transcript exons

ENST00000228825 — 7 exons

Exon	Start	End
ENSE00000755094	110436110	110436204
ENSE00000755097	110440312	110440388
ENSE00001867869	110450255	110450337
ENSE00001927859	110434823	110435217
ENSE00003490888	110437084	110437152
ENSE00003635812	110436557	110436683
ENSE00003689985	110445452	110445551

Expression profiles

Bgee: expression breadth ubiquitous, 180 present calls, max score 99.67.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 335.7743 / max 2669.2216, expressed in 1828 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
133232	335.1871	1828
133231	0.5872	314

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	99.67	gold quality
leukocyte	CL:0000738	99.66	gold quality
granulocyte	CL:0000094	99.60	gold quality
vermiform appendix	UBERON:0001154	99.45	gold quality
rectum	UBERON:0001052	99.34	gold quality
islet of Langerhans	UBERON:0000006	99.31	gold quality
gall bladder	UBERON:0002110	99.31	gold quality
right lung	UBERON:0002167	99.31	gold quality
lower esophagus mucosa	UBERON:0035834	99.28	gold quality
mucosa of transverse colon	UBERON:0004991	99.27	gold quality
smooth muscle tissue	UBERON:0001135	99.17	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	99.17	gold quality
upper lobe of left lung	UBERON:0008952	99.13	gold quality
metanephros cortex	UBERON:0010533	99.12	gold quality
small intestine Peyer’s patch	UBERON:0003454	99.10	gold quality
bone marrow cell	CL:0002092	99.08	gold quality
body of pancreas	UBERON:0001150	99.08	gold quality
minor salivary gland	UBERON:0001830	99.06	gold quality
transverse colon	UBERON:0001157	99.05	gold quality
left adrenal gland	UBERON:0001234	99.05	gold quality
right adrenal gland	UBERON:0001233	99.03	gold quality
calcaneal tendon	UBERON:0003701	99.03	gold quality
left adrenal gland cortex	UBERON:0035825	99.02	gold quality
adenohypophysis	UBERON:0002196	99.00	gold quality
descending thoracic aorta	UBERON:0002345	98.99	gold quality
body of stomach	UBERON:0001161	98.97	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	98.95	gold quality
right coronary artery	UBERON:0001625	98.94	gold quality
right adrenal gland cortex	UBERON:0035827	98.94	gold quality
left coronary artery	UBERON:0001626	98.91	gold quality

Single-cell (SCXA)

Detected in 22 experiment(s), a significant marker in 20.

Experiment	Marker?	Max mean expression
E-HCAD-1	yes	83.00
E-HCAD-4	yes	72.85
E-GEOD-135922	yes	55.98
E-HCAD-10	yes	46.50
E-MTAB-6701	yes	46.02
E-MTAB-8410	yes	43.13
E-CURD-46	yes	39.19
E-CURD-122	yes	36.87
E-MTAB-10553	yes	36.67
E-GEOD-134144	yes	30.03
E-MTAB-10287	yes	23.59
E-MTAB-6678	yes	22.88
E-HCAD-9	yes	21.91
E-CURD-88	yes	21.69
E-GEOD-130148	yes	18.45

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CREB1

miRNA regulators (miRDB)

43 targeting ARPC3, 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-6873-3P	100.00	71.42	2626
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-1-3P	99.93	72.35	1914
HSA-MIR-206	99.93	72.50	1893
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-613	99.91	71.50	1710
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-629-3P	99.85	67.99	1875
HSA-MIR-548AZ-3P	99.82	70.56	3549
HSA-MIR-548BC	99.82	70.61	3524
HSA-MIR-548E-3P	99.82	70.59	3514
HSA-MIR-548F-3P	99.82	70.59	3540
HSA-MIR-6817-3P	99.79	68.35	2126
HSA-MIR-548AJ-5P	99.78	71.12	3085
HSA-MIR-548F-5P	99.78	71.02	3093
HSA-MIR-548G-5P	99.78	71.12	3085
HSA-MIR-548X-5P	99.78	71.12	3085
HSA-MIR-26A-5P	99.78	73.52	2303
HSA-MIR-26B-5P	99.78	73.51	2305
HSA-MIR-548A-3P	99.76	70.58	3524
HSA-MIR-4802-3P	99.72	70.13	1273
HSA-MIR-4465	99.71	72.56	2096
HSA-MIR-3177-5P	99.65	70.38	1174
HSA-MIR-3158-5P	99.65	67.51	1763

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 74.6% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 4)

• The actin-related protein 3 structures were more visible with anti-p34Arc monoclonal antibody. (PMID:15793564)
• Endogenous Nogo-B, which may exert its effects through ARPC 2/3 and MYL-9, is necessary for the migration and contraction of airway smooth muscle cells. (PMID:21251247)
• genetic association study in population in Canada: Data suggest that an SNP in the promoter region of ARPC3 (CpG-SNP rs3759384 C>T) is associated with metabolic syndrome complicated by severe abdominal obesity and hypertriglyceridemia in the population studied. (PMID:27055012)
• Cancer cell motility mediated by the actin-related protein 2/3 complex (Arp2/3) is required for vessel co-option in liver metastases in vivo. (PMID:27748747)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	arpc3	ENSDARG00000057882
mus_musculus	Arpc3	ENSMUSG00000029465
rattus_norvegicus	Arpc3	ENSRNOG00000008673
drosophila_melanogaster	Arpc3A	FBGN0038369
drosophila_melanogaster	Arpc3B	FBGN0065032
caenorhabditis_elegans		WBGENE00000203

Protein

Protein identifiers

Actin-related protein 2/3 complex subunit 3 — O15145 (reviewed: O15145)

Alternative names: Arp2/3 complex 21 kDa subunit

All UniProt accessions (3): C9JZD1, O15145, F8VR50

UniProt curated annotations — full annotation on UniProt →

Function. 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. 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.

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

Similarity. Belongs to the ARPC3 family.

RefSeq proteins (2): NP_001265485, NP_001274151 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007204	ARPC3	Family
IPR036753	ARPC3_sf	Homologous_superfamily

Pfam: PF04062

UniProt features (7 total): modified residue 3, initiator methionine 1, chain 1, cross-link 1, sequence conflict 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-O15145-F1	95.28	0.96

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): 47, 56, 61, 14

Function

Pathways and Gene Ontology

Reactome pathways

24 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-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: 231 (showing top): GSE45365_NK_CELL_VS_CD8_TCELL_UP, GSE45365_NK_CELL_VS_CD8A_DC_UP, GOBP_REGULATION_OF_PROTEIN_POLYMERIZATION, REACTOME_INNATE_IMMUNE_SYSTEM, GNF2_BNIP2, MODULE_151, MORF_UBE2I, THEILGAARD_NEUTROPHIL_AT_SKIN_WOUND_DN, GOBP_VESICLE_MEDIATED_TRANSPORT, REACTOME_MEMBRANE_TRAFFICKING, GNF2_LYN, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_SYNAPTIC_VESICLE_RECYCLING, GOBP_REGULATION_OF_VESICLE_MEDIATED_TRANSPORT, GOBP_REGULATION_OF_ACTIN_FILAMENT_BASED_PROCESS

GO Biological Process (5): regulation of actin filament polymerization (GO:0030833), Arp2/3 complex-mediated actin nucleation (GO:0034314), actin polymerization-dependent cell motility (GO:0070358), regulation of synaptic vesicle endocytosis (GO:1900242), cellular response to nerve growth factor stimulus (GO:1990090)

GO Molecular Function (4): actin binding (GO:0003779), structural constituent of cytoskeleton (GO:0005200), protein binding (GO:0005515), actin filament binding (GO:0051015)

GO Cellular Component (15): nucleus (GO:0005634), cytosol (GO:0005829), Arp2/3 protein complex (GO:0005885), focal adhesion (GO:0005925), actin cytoskeleton (GO:0015629), membrane (GO:0016020), lamellipodium (GO:0030027), filamentous actin (GO:0031941), site of double-strand break (GO:0035861), growth cone leading edge (GO:0061850), extracellular exosome (GO:0070062), cytoplasm (GO:0005737), cytoskeleton (GO:0005856), cell leading edge (GO:0031252), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-15 pathways:

Category	Pathways
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
Innate Immune System	1
Axon guidance	1
Nervous system development	1
Disease	1
Parasitic Infection Pathways	1
Leishmania infection	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
cytoskeleton	2
protein-containing complex	2
cell leading edge	2
regulation of actin polymerization or depolymerization	1
actin filament polymerization	1
regulation of protein polymerization	1
actin nucleation	1
cell motility	1
regulation of endocytosis	1
synaptic vesicle endocytosis	1
regulation of synaptic vesicle recycling	1
cellular response to growth factor stimulus	1
response to nerve growth factor	1
cytoskeletal protein binding	1
structural molecule activity	1
cytoskeleton organization	1
binding	1
actin binding	1
protein-containing complex binding	1
intracellular membrane-bounded organelle	1
cytoplasm	1
actin cytoskeleton	1
cell-substrate junction	1
plasma membrane bounded cell projection	1
actin filament	1
site of DNA damage	1
peripheral region of growth cone	1
extracellular vesicle	1
intracellular anatomical structure	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

1618 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ARPC3	ARPC1B	O15143	999
ARPC3	ARPC2	O15144	999
ARPC3	ARPC5	O15511	999
ARPC3	ACTR2	P61160	998
ARPC3	ACTR3	P32391	991
ARPC3	ARPC1A	Q92747	955
ARPC3	WAS	P42768	914
ARPC3	ARPC5L	Q9BPX5	816
ARPC3	ARPC4	P59998	810
ARPC3	WASL	O00401	767
ARPC3	ACTR3B	Q9P1U1	691
ARPC3	ACTR3C	Q9C0K3	686
ARPC3	CTTN	Q14247	672
ARPC3	HCLS1	P14317	658
ARPC3	WASF1	Q92558	635

IntAct

207 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
ARPC1B	ARPC3	psi-mi:“MI:2364”(proximity)	0.880
ARPC3	ARPC1B	psi-mi:“MI:0914”(association)	0.880
ARPC5L	ARPC1B	psi-mi:“MI:0914”(association)	0.830
ARPC3	ARPC4	psi-mi:“MI:0915”(physical association)	0.800
ARPC5	ARPC3	psi-mi:“MI:0914”(association)	0.730

BioGRID (372): ARPC3 (Two-hybrid), ARPC3 (Two-hybrid), ARPC3 (Two-hybrid), ARPC3 (Two-hybrid), ARPC3 (Affinity Capture-MS), ARPC3 (Affinity Capture-MS), ARPC3 (Affinity Capture-MS), ARPC2 (Affinity Capture-MS), ARPC1A (Affinity Capture-MS), ARPC5L (Affinity Capture-MS), ARPC5 (Affinity Capture-MS), CLUH (Affinity Capture-MS), ACTR2 (Affinity Capture-MS), DOCK7 (Affinity Capture-MS), DOCK8 (Affinity Capture-MS)

ESM2 similar proteins: A1AVW3, A1BDQ9, A1DPK7, A8G2V3, A8MGN0, A9A5W9, B3DQN7, B3EFT2, B3EM52, B3QLJ0, B4S4Y9, B4SCX8, B8CNS1, B8DHM6, C0SPB1, C4QGM3, O15145, O32042, O48397, P06942, P06944, P09877, P0C141, P0C571, P0CA85, P0CA86, P13844, P18611, P21000, P30909, P35976, P38475, P81375, Q01639, Q0A442, Q1WTX9, Q3AT43, Q3T035, Q4ZZG6, Q54EY1

Diamond homologs: A1DPK7, O15145, O15604, O96624, Q05933, Q1ECJ7, Q3T035, Q7T0U5, Q9JM76, Q9XWV3, Q9Y7J4

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
ARPC3	“form complex”	ARP2/3	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 126 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
RHO GTPases Activate WASPs and WAVEs	12	48.8×	9e-16
Parasite infection	11	48.8×	1e-14
Leishmania phagocytosis	11	48.8×	1e-14
RHO GTPases activate PAKs	6	41.8×	1e-07
Fcgamma receptor (FCGR) dependent phagocytosis	11	39.3×	2e-13
EPHB-mediated forward signaling	10	34.0×	1e-11
FCGR3A-mediated phagocytosis	14	33.6×	9e-16
Regulation of actin dynamics for phagocytic cup formation	14	33.1×	9e-16

GO biological processes:

GO term	Partners	Fold	FDR
Arp2/3 complex-mediated actin nucleation	8	82.6×	2e-11
actin polymerization or depolymerization	6	45.1×	1e-06
actin filament polymerization	5	23.6×	4e-04
platelet aggregation	5	16.5×	1e-03
cellular response to type II interferon	7	14.3×	2e-04
actin filament organization	7	8.1×	2e-03
actin cytoskeleton organization	9	7.0×	8e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	0
Likely benign	0
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

953 predictions. Top by Δscore:

Variant	Effect	Δscore
12:110435215:CCA:C	acceptor_gain	1.0000
12:110435216:CA:C	acceptor_gain	1.0000
12:110435216:CAC:C	acceptor_gain	1.0000
12:110435218:C:CC	acceptor_gain	1.0000
12:110436200:CACTT:C	acceptor_gain	1.0000
12:110436202:CTT:C	acceptor_gain	1.0000
12:110436203:TT:T	acceptor_gain	1.0000
12:110436204:TCTAA:T	acceptor_loss	1.0000
12:110436205:C:CC	acceptor_gain	1.0000
12:110436205:C:T	acceptor_loss	1.0000
12:110436206:T:C	acceptor_loss	1.0000
12:110436679:TTGCA:T	acceptor_gain	1.0000
12:110436680:TGCA:T	acceptor_gain	1.0000
12:110436682:CA:C	acceptor_gain	1.0000
12:110436684:C:CC	acceptor_gain	1.0000
12:110437079:ATTAC:A	donor_loss	1.0000
12:110437080:TTAC:T	donor_loss	1.0000
12:110437081:TACC:T	donor_loss	1.0000
12:110437082:A:AT	donor_loss	1.0000
12:110437083:C:T	donor_loss	1.0000
12:110437148:TCATT:T	acceptor_gain	1.0000
12:110437149:CATT:C	acceptor_gain	1.0000
12:110437149:CATTC:C	acceptor_gain	1.0000
12:110437151:TT:T	acceptor_gain	1.0000
12:110437153:C:CC	acceptor_gain	1.0000
12:110437153:CTACA:C	acceptor_loss	1.0000
12:110437154:T:C	acceptor_loss	1.0000
12:110440307:TTTA:T	donor_loss	1.0000
12:110440308:TTACC:T	donor_loss	1.0000
12:110440309:TACCT:T	donor_loss	1.0000

AlphaMissense

1186 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:110435188:G:C	F168L	1.000
12:110435188:G:T	F168L	1.000
12:110435189:A:G	F168S	1.000
12:110435190:A:G	F168L	1.000
12:110435194:T:A	R166S	1.000
12:110435194:T:G	R166S	1.000
12:110435203:A:C	F163L	1.000
12:110435203:A:T	F163L	1.000
12:110435205:A:G	F163L	1.000
12:110435212:C:A	W160C	1.000
12:110435212:C:G	W160C	1.000
12:110435214:A:G	W160R	1.000
12:110435214:A:T	W160R	1.000
12:110435215:C:A	W159C	1.000
12:110435215:C:G	W159C	1.000
12:110435217:A:G	W159R	1.000
12:110435217:A:T	W159R	1.000
12:110436110:C:A	K158N	1.000
12:110436110:C:G	K158N	1.000
12:110436156:C:G	R143T	1.000
12:110436162:C:T	G141E	1.000
12:110436163:C:G	G141R	1.000
12:110436163:C:T	G141R	1.000
12:110436173:C:A	R137S	1.000
12:110436173:C:G	R137S	1.000
12:110436174:C:A	R137M	1.000
12:110436174:C:G	R137T	1.000
12:110436177:A:G	L136P	1.000
12:110436598:A:G	L113P	1.000
12:110436603:A:C	F111L	1.000

dbSNP variants (sampled 300 via entrez): RS1000120781 (12:110442375 A>C,T), RS1000137416 (12:110447591 G>C), RS1000210057 (12:110447448 G>T), RS1000485991 (12:110441065 G>C), RS1000535968 (12:110445676 G>A), RS1000689008 (12:110451722 C>T), RS1001236656 (12:110441996 A>C), RS1001255886 (12:110448075 T>G), RS1001418222 (12:110446967 G>A,C,T), RS1001481533 (12:110441138 C>T), RS1001864825 (12:110451358 T>C), RS1002090863 (12:110452332 A>C,G), RS1002339827 (12:110451042 G>A,C), RS1002626220 (12:110434477 A>G), RS1002835716 (12:110437570 G>A,C)

Disease associations

OMIM: gene MIM:604225 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
Charcot-Marie-Tooth disease	Moderate	Autosomal dominant

Mondo (1): Charcot-Marie-Tooth disease (MONDO:0015626)

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST006445_6	Femoral neck bone mineral density	6.000000e-06
GCST007329_25	Automobile speeding propensity	2.000000e-08
GCST008103_92	Bipolar disorder	1.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0007785	femoral neck bone mineral density
EFO:0008579	risk-taking behaviour

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D002607	Charcot-Marie-Tooth Disease	C10.500.300.200; C10.574.500.495.200; C10.668.829.800.300.200; C16.131.666.300.200; C16.320.400.375.200

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067049 (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
7.18	Kd	66.59	nM	CHEMBL5653589
7.18	ED50	66.59	nM	CHEMBL5653589
5.46	Kd	3469	nM	CHEMBL3752910
5.46	ED50	3469	nM	CHEMBL3752910

PubChem BioAssay actives

2 with measured affinity, of 4 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	2147891: Binding affinity to human ARPC3 incubated for 45 mins by Kinobead based pull down assay	kd	0.0666	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147891: Binding affinity to human ARPC3 incubated for 45 mins by Kinobead based pull down assay	kd	3.4685	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Tobacco Smoke Pollution	affects expression, increases expression	3
bisphenol A	increases expression	2
sodium arsenite	decreases expression, increases expression	2
Arsenic Trioxide	affects binding, decreases reaction, increases expression	2
Tretinoin	increases expression	2
bisphenol F	decreases expression, affects cotreatment	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
pyrogallol 1,3-dimethyl ether	affects localization, decreases expression, affects cotreatment	1
tetrahydropalmatine	decreases expression	1
arsenite	increases reaction, affects binding	1
manganese chloride	decreases expression, increases abundance	1
4-aminophenylarsenoxide	affects binding, decreases reaction	1
CD 437	decreases expression	1
3-(4’-hydroxy-3’-adamantylbiphenyl-4-yl)acrylic acid	decreases expression	1
bisphenol B	increases expression	1
bisphenol AF	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
Sunitinib	increases expression	1
Vorinostat	increases expression	1
Benzo(a)pyrene	decreases methylation	1
Caffeine	decreases phosphorylation	1
Dexamethasone	affects cotreatment, decreases expression	1
Dinitrochlorobenzene	affects binding	1
Diuron	decreases expression	1
Doxorubicin	decreases expression	1
Fluorouracil	decreases expression	1
Furaldehyde	affects cotreatment, affects localization, increases expression	1
Hydrogen Peroxide	affects expression	1
Indomethacin	affects cotreatment, decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5650933	Binding	Binding affinity to human ARPC3 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04762758	PHASE3	UNKNOWN	Phase III Trial Assessing the Efficacy and Safety of PXT3003 in CMT1A Patients
NCT00271635	PHASE2	COMPLETED	Ascorbic Acid Treatment in CMT1A Trial (AATIC)
NCT01401257	PHASE2	COMPLETED	Phase II, Randomized, Placebo-controlled Trial in Patients With Charcot-marie-tooth Disease Type 1A
NCT02561702	PHASE2	COMPLETED	Mexiletine for Muscle Cramps in Charcot Marie Tooth Disease
NCT02967679	PHASE2	COMPLETED	SERENDEM : MD1003 in Patients Suffering From Demyelinating Neuropathies, an Open Label Pilot Study
NCT03124459	PHASE2	TERMINATED	Study of ACE-083 in Patients With Charcot-Marie-Tooth Disease
NCT03254199	PHASE2	TERMINATED	A Study to Assess the Safety and Effectiveness of FLX-787 in Subjects With Charcot-Marie-Tooth Disease Experiencing Muscle Cramps.
NCT03943290	PHASE2	TERMINATED	Extension Study to Evaluate the Long-Term Effects of ACE-083 in Patients With Facioscapulohumeral Muscular Dystrophy (FSHD) and Charcot-Marie Tooth (CMT) Disease Types 1 and X (CMT1 and CMTX)
NCT05777226	PHASE2	UNKNOWN	Research of SORD-CMT Natural History and Epalrestat Treatment
NCT06482437	PHASE2	COMPLETED	Safety and Efficacy of NMD670 in Adult Patients With Type 1 and Type 2 Charcot-Marie-Tooth Disease
NCT01289704	PHASE2/PHASE3	UNKNOWN	Treadmill, Stretching and Proprioceptive Exercise (TreSPE) Rehabilitation Program for Charcot-Marie-Tooth Neuropathy Type 1A (CMT1A)
NCT00541164	PHASE1/PHASE2	COMPLETED	Effects of Coenzyme Q10 on Charcot-Marie-Tooth Disease
NCT05361031	PHASE1/PHASE2	COMPLETED	The Safety and Tolerability of Engensis (VM202) in Patients With Charcot-Marie-Tooth Disease Subtype 1A (CMT1A)
NCT07223632	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Treatment of Charcot-Marie-Tooth Disease, Axonal, Type 2S (CMT2S) in an Individual Patient
NCT00149045	Not specified	COMPLETED	Follow up and Observation of Charcot Marie Tooth Disease in Families
NCT01193075	Not specified	RECRUITING	Natural History Evaluation of Charcot Marie Tooth Disease (CMT) Types CMT1B, CMT2A, CMT4A, CMT4C, and Others
NCT01203085	Not specified	COMPLETED	Development of Charcot Marie Tooth Disease (CMT) Pediatric Scale for Children With CMT
NCT01455623	Not specified	COMPLETED	Development and Validation of a Disability Severity Index for CMT
NCT01918826	Not specified	UNKNOWN	Evaluation of the Analgesic Efficiency of the Transcutaneous Neurostimulation in the Charcot Syndrome Marie Tooth on the Pains of Lower Limbs
NCT02001038	Not specified	COMPLETED	Survey of Current Management of Orthopaedic Complications in CMT Patients
NCT02011204	Not specified	COMPLETED	Study of Electrical Impedance Myography (EIM) in ALS
NCT02194010	Not specified	COMPLETED	Disability Severity Scale (DSI) and Hereditary Motor and Sensory Neuropathy Overall Disability Scale (HMSN-R-ODS)
NCT02429947	Not specified	COMPLETED	An Analysis of the Symptomatic Domains Most Relevant to Charcot Marie Tooth Neuropathy (CMT) Patients
NCT02532244	Not specified	COMPLETED	Genetics of Pediatric-Onset Motor Neuron and Neuromuscular Diseases
NCT02699190	Not specified	COMPLETED	LeukoSEQ: Whole Genome Sequencing as a First-Line Diagnostic Tool for Leukodystrophies
NCT02788734	Not specified	COMPLETED	Patient Reported Outcomes Measures (PROM) in Carpal Tunnel Therapies in Patients With Inherited Neuropathies
NCT02979145	Not specified	UNKNOWN	Charcot-Marie-Tooth Disease (CMT) Infant Scale (INC-6611)
NCT03047369	Not specified	RECRUITING	The Myelin Disorders Biorepository Project
NCT03460951	Not specified	COMPLETED	Diffusion Tensor Imaging in Chronic Inflammatory Demyelinating Polyneuropathy (PIDC)
NCT03715283	Not specified	COMPLETED	Change in MUNIX in Patients With CMT1A Undergoing a Home Ankle Strengthening Program Versus Standard of Care
NCT03782883	Not specified	COMPLETED	The Impact of Charcot-Marie-Tooth Disease in the Real World
NCT03810508	Not specified	TERMINATED	A Natural History Study of Charcot-Marie-Tooth 4J (CMT4J)
NCT03966287	Not specified	COMPLETED	Analysis of Pain and Quality of Life in Patients With Charcot-Marie-Tooth Neuropathy (CMT)
NCT04010188	Not specified	RECRUITING	A Registered Cohort Study on Charcot-Marie-Tooth Disease
NCT04283175	Not specified	COMPLETED	Validation Study of Posturology Platforms for Evaluating Postural Control of Hemiparetic and Neuro-muscular Patients
NCT04461613	Not specified	UNKNOWN	Physical Activity in Persons With Charcot-Marie-Tooth: Developing a Measurement Instrument
NCT04786522	Not specified	COMPLETED	Irisin Levels in Patients With Charcot-Marie-Tooth (CMT) Disease
NCT04967716	Not specified	UNKNOWN	Genetics of Charcot-Marie-Tooth Dystrophy and Related Diseases
NCT04980807	Not specified	COMPLETED	Observational Study of Neuromuscular Function in CMT Type 1&2 and Healthy Controls
NCT05011006	Not specified	NOT_YET_RECRUITING	NT-3 Levels and Function in Individuals With CMT