ARC

Summary

ARC (activity regulated cytoskeleton associated protein, HGNC:648) is a protein-coding gene on chromosome 8q24.3, encoding Activity-regulated cytoskeleton-associated protein (Q7LC44). Master regulator of synaptic plasticity that self-assembles into virion-like capsids that encapsulate RNAs and mediate intercellular RNA transfer in the nervous system.

Enables mRNA binding activity and structural molecule activity. Predicted to be involved in several processes, including long-term memory; positive regulation of AMPA receptor activity; and regulation of synaptic plasticity. Predicted to act upstream of or within anterior/posterior pattern specification and endoderm development. Located in cytoplasm and plasma membrane. Is active in virus-like capsid.

Source: NCBI Gene 23237 — automated summary from GO annotations (Alliance of Genome Resources).

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 30 total
• GTEx eGene: eQTL in 19 tissues, sQTL in 0 (q < 0.05)
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.39 (unconstrained)
• MANE Select transcript: NM_015193

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:648
Approved symbol	ARC
Name	activity regulated cytoskeleton associated protein
Location	8q24.3
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0278, Arg3.1
Ensembl gene	ENSG00000198576
Ensembl biotype	protein_coding
OMIM	612461
Entrez	23237

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 1 protein_coding, 1 protein_coding_CDS_not_defined

MANE Select: ENST00000356613

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1, TSL 3: 1

ENST00000356613, ENST00000581404

RefSeq mRNA: 2 — MANE Select: NM_015193 NM_001412852, NM_015193

CCDS: CCDS34950

Canonical transcript exons

ENST00000356613 — 3 exons

Exon	Start	End
ENSE00001418346	142611049	142611857
ENSE00001429918	142612108	142612252
ENSE00001431435	142612484	142614479

Expression profiles

Bgee: expression breadth ubiquitous, 168 present calls, max score 90.87.

FANTOM5 (CAGE): breadth broad, TPM avg 5.6502 / max 1503.9893, expressed in 560 samples.

Highest expression (Bgee): adenohypophysis, pituitary gland, frontal lobe, prefrontal cortex, Brodmann (1909) area 10.

Genetic regulation across tissues (GTEx eQTL / sQTL)

ARC is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 19 tissues and its splicing (sQTL) in 0 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

19 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Muscle Skeletal	eqtl	2.1e-13	-0.35	8:142653806:G:A
Whole Blood	eqtl	2.3e-13	-0.31	8:142613783:G:A
Adipose Subcutaneous	eqtl	3.1e-10	+0.30	8:142610726:A:C
Heart Left Ventricle	eqtl	1.6e-06	-0.32	8:142640550:A:C
Thyroid	eqtl	2.5e-06	-0.26	8:142626169:C:T
Cells Cultured fibroblasts	eqtl	3.4e-06	+0.19	8:142600096:A:G
Artery Tibial	eqtl	9.8e-06	+0.24	8:142613414:G:C
Esophagus Muscularis	eqtl	1.8e-05	-0.28	8:142666333:G:T
Brain Cerebellum	eqtl	1.3e-04	-0.26	8:142628334:T:C
Breast Mammary Tissue	eqtl	1.5e-03	+0.39	8:142319154:T:TCCC
Skin Sun Exposed Lower leg	eqtl	3.6e-03	-0.15	8:142611420:C:T
Artery Aorta	eqtl	7.1e-03	+0.23	8:142608015:C:T
Esophagus Gastroesophageal Junction	eqtl	1.1e-02	+0.27	8:142608053:C:T
Skin Not Sun Exposed Suprapubic	eqtl	1.3e-02	-0.18	8:142610273:A:G
Testis	eqtl	2.7e-02	-0.23	8:142623071:T:C
Spleen	eqtl	3.4e-02	+0.31	8:142612050:C:T
Esophagus Mucosa	eqtl	3.5e-02	-0.16	8:141880140:C:T
Nerve Tibial	eqtl	3.8e-02	-0.15	8:142626169:C:T
Pituitary	eqtl	4.5e-02	-0.26	8:142470862:G:C

FANTOM5 promoters

4 alternative TSS:

Promoter ID	TPM avg	Samples expressed
95412	5.4026	494
95409	0.1097	39
95410	0.0967	44
95411	0.0412	16

Top tissues by expression

showing 100 of 280 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
adenohypophysis	UBERON:0002196	90.87	gold quality
pituitary gland	UBERON:0000007	90.16	gold quality
right frontal lobe	UBERON:0002810	86.06	gold quality
prefrontal cortex	UBERON:0000451	85.19	gold quality
Brodmann (1909) area 10	UBERON:0013541	84.08	silver quality
cingulate cortex	UBERON:0003027	83.46	gold quality
anterior cingulate cortex	UBERON:0009835	83.25	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.10	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	82.04	gold quality
ganglionic eminence	UBERON:0004023	81.99	gold quality
frontal cortex	UBERON:0001870	81.85	gold quality
neocortex	UBERON:0001950	81.79	gold quality
ventricular zone	UBERON:0003053	81.72	gold quality
cerebral cortex	UBERON:0000956	80.19	gold quality
Brodmann (1909) area 9	UBERON:0013540	80.18	gold quality
Ammon’s horn	UBERON:0001954	80.11	gold quality
primary visual cortex	UBERON:0002436	79.85	gold quality
amygdala	UBERON:0001876	79.55	gold quality
putamen	UBERON:0001874	78.95	gold quality
forebrain	UBERON:0001890	78.75	gold quality
telencephalon	UBERON:0001893	78.26	gold quality
mucosa of stomach	UBERON:0001199	76.96	gold quality
caudate nucleus	UBERON:0001873	76.45	gold quality
skin of abdomen	UBERON:0001416	76.43	gold quality
occipital lobe	UBERON:0002021	75.88	gold quality
brain	UBERON:0000955	75.56	gold quality
nucleus accumbens	UBERON:0001882	75.55	gold quality
central nervous system	UBERON:0001017	75.35	gold quality
hypothalamus	UBERON:0001898	75.18	gold quality
upper lobe of left lung	UBERON:0008952	75.09	gold quality
Brodmann (1909) area 46	UBERON:0006483	73.82	silver quality
temporal lobe	UBERON:0001871	73.65	gold quality
skin of leg	UBERON:0001511	73.58	gold quality
upper lobe of lung	UBERON:0008948	73.34	gold quality
CA1 field of hippocampus	UBERON:0003881	73.15	silver quality
lower esophagus mucosa	UBERON:0035834	72.91	gold quality
seminal vesicle	UBERON:0000998	70.81	silver quality
omental fat pad	UBERON:0010414	70.77	gold quality
peritoneum	UBERON:0002358	70.72	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	70.71	gold quality
superior frontal gyrus	UBERON:0002661	70.59	gold quality
frontal pole	UBERON:0002795	70.40	gold quality
zone of skin	UBERON:0000014	70.26	gold quality
right lung	UBERON:0002167	69.45	gold quality
adipose tissue of abdominal region	UBERON:0007808	69.20	gold quality
spinal cord	UBERON:0002240	69.09	gold quality
embryo	UBERON:0000922	69.03	gold quality
cartilage tissue	UBERON:0002418	68.84	silver quality
postcentral gyrus	UBERON:0002581	68.07	silver quality
left uterine tube	UBERON:0001303	68.03	gold quality
parietal lobe	UBERON:0001872	67.92	silver quality
gall bladder	UBERON:0002110	67.08	gold quality
substantia nigra	UBERON:0002038	66.61	gold quality
endothelial cell	CL:0000115	66.26	gold quality
cortical plate	UBERON:0005343	66.11	gold quality
triceps brachii	UBERON:0001509	65.21	gold quality
midbrain	UBERON:0001891	65.09	gold quality
lung	UBERON:0002048	65.08	gold quality
gluteal muscle	UBERON:0002000	64.71	gold quality
ectocervix	UBERON:0012249	63.90	gold quality
middle frontal gyrus	UBERON:0002702	63.57	gold quality
vena cava	UBERON:0004087	62.92	gold quality
paraflocculus	UBERON:0005351	62.73	gold quality
tongue squamous epithelium	UBERON:0006919	62.45	gold quality
olfactory bulb	UBERON:0002264	62.44	gold quality
right hemisphere of cerebellum	UBERON:0014890	62.38	gold quality
endometrium epithelium	UBERON:0004811	62.25	gold quality
type B pancreatic cell	CL:0000169	62.23	gold quality
cervix squamous epithelium	UBERON:0006922	62.11	gold quality
cerebellar hemisphere	UBERON:0002245	61.42	gold quality
cerebellar cortex	UBERON:0002129	61.39	gold quality
cervix epithelium	UBERON:0004801	61.34	gold quality
descending thoracic aorta	UBERON:0002345	61.21	gold quality
cortex of kidney	UBERON:0001225	61.18	gold quality
tibial nerve	UBERON:0001323	61.01	gold quality
vagina	UBERON:0000996	60.95	gold quality
left adrenal gland cortex	UBERON:0035825	60.91	gold quality
metanephros cortex	UBERON:0010533	60.68	gold quality
right adrenal gland	UBERON:0001233	60.62	gold quality
cerebellum	UBERON:0002037	60.50	gold quality
buccal mucosa cell	CL:0002336	60.20	gold quality
body of stomach	UBERON:0001161	60.17	gold quality
uterine cervix	UBERON:0000002	59.88	gold quality
adrenal gland	UBERON:0002369	59.75	gold quality
sural nerve	UBERON:0015488	59.71	gold quality
cerebellar vermis	UBERON:0004720	59.58	gold quality
right atrium auricular region	UBERON:0006631	59.47	gold quality
thymus	UBERON:0002370	59.33	silver quality
muscle layer of sigmoid colon	UBERON:0035805	59.28	gold quality
decidua	UBERON:0002450	59.22	silver quality
esophagogastric junction muscularis propria	UBERON:0035841	59.20	gold quality
left adrenal gland	UBERON:0001234	59.08	gold quality
inferior olivary complex	UBERON:0002127	58.97	gold quality
cardiac atrium	UBERON:0002081	58.88	gold quality
adrenal cortex	UBERON:0001235	58.73	gold quality
thoracic aorta	UBERON:0001515	58.42	gold quality
penis	UBERON:0000989	58.39	gold quality
anatomical system	UBERON:0000467	58.34	gold quality
adipose tissue	UBERON:0001013	58.22	gold quality
ascending aorta	UBERON:0001496	58.20	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-CURD-46	yes	202.87
E-ANND-3	yes	4.61

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 71 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM
Cerebral cortex	tissue	113.4
Occipital cortex	tissue	113.4
Frontal cortex	tissue	103.9
Somatosensory cortex	tissue	79.7
Pituitary gland	tissue	67.6
Retrosplenial cortex	tissue	66.1
Hippocampal formation	tissue	64.7
Entorhinal cortex	tissue	64.7
Motor cortex	tissue	60.6
Caudate putamen	tissue	58.0
Prefrontal cortex	tissue	57.9
Temporal cortex	tissue	55.9
Retrosplenial and cingulate cortex	tissue	54.8
Insular cortex	tissue	51.5
Olfactory bulb	tissue	35.5
Basal ganglia	tissue	32.0
Putamen	tissue	31.0
Hippocampus	tissue	28.6
Postcentral gyrus	tissue	15.3
Ventral forebrain	tissue	14.8
Adipose tissue	tissue	11.2
Amygdala	tissue	9.9
Adrenal gland	tissue	9.7
Septum	tissue	9.4
Nucleus accumbens	tissue	6.9
Locus coeruleus	tissue	4.5
Vagina	tissue	4.1
Pancreas	tissue	3.8
Seminal vesicle	tissue	3.6
Choroid plexus	tissue	2.9
Corpus callosum	tissue	2.7
Hypothalamus	tissue	2.4
Midbrain	tissue	2.2
Superior colliculi	tissue	2.2
Gallbladder	tissue	1.9
Thalamus	tissue	1.7
Cerebellum	tissue	1.7
Pons	tissue	1.1
Medulla oblongata	tissue	1.1
Periaqueductal gray	tissue	1.1
Spinal cord	tissue	1.0
Placenta	tissue	0.9
Retina	tissue	0.8
Epididymis	tissue	0.8
Substantia nigra	tissue	0.8
Lung	tissue	0.7
Cervix	tissue	0.6
Endometrium 1	tissue	0.6
Thyroid gland	tissue	0.6
Kidney	tissue	0.6
Fallopian tube	tissue	0.5
Tongue	tissue	0.4
Prostate	tissue	0.4
Breast	tissue	0.3
Esophagus	tissue	0.3
Smooth muscle	tissue	0.3
Colon	tissue	0.3
Appendix	tissue	0.3
Spleen	tissue	0.2
Liver	tissue	0.2

Brain sub-regions (HPA Brain Atlas): detected in 289; highest nTPM — Hippocampus, CA1 (70.5), Blood vessel (48.2), Nucleus ambiguus (46.8), Area parastriata, superior (46.0), Dorsal hippocampus (42.6).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): EGR1, EGR3, FOXO3, HIF1A, SRF

Functional genomics

gnomAD constraint: pLI 0.000816, LOEUF 1.39, missense Z 0.324 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000356613 splits into 3 regions with different missense tolerance; 0 are missense-constrained. Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
8:142,613,084–142,613,202	72 / 59.4	1.21	no
8:142,613,203–142,613,652	117 / 194.4	0.60	no
8:142,613,653–142,614,271	265 / 301.7	0.88	no

Literature-anchored findings (GeneRIF, showing 28)

• Arc/MS2 mRNA assembles into particles that move independently, bidirectionally, and intermittently. These observations identify several phases of Arc mRNA movement that serve as potential points for regulating Arc mRNA localization. (PMID:17120280)
• Arc Expression Is Increased in medial frontal cortex of patients with Alzheimer’s Disease. (PMID:22036569)
• Strong fibrinogen and Abeta deposition is demonstrated in small- and medium-sized vessels, but not in large cerebral arteries, of 24-month-old transgenic arcAbeta mice. (PMID:22302811)
• analysis of dynamic, multifaceted control of Arc synthesis during mAchR signaling (PMID:22584581)
• we report a novel ARC single nucleotide polymorphism associated with a reduced risk of developing Alzheimer disease. (PMID:22622366)
• Degradation of Arc by clathrin-localized Triad3A regulates the availability of synaptic AMPA receptors. (PMID:24945773)
• Arc is a flexible multi-domain protein that exists in monomeric and oligomeric forms, compatible with a diverse, hub-like role in plasticity-related processes. (PMID:25748042)
• mRNA levels of ARC and SGK1 did not differ significantly between the schizophrenia or control samples. (PMID:26038830)
• we propose that the peculiar characteristics of Arc protein, such as its optimal expression after ongoing experience or familiar behavior could explain how familiarization and recognition memories are stored and preserved in the mammalian brain–{REVIEW} (PMID:26380114)
• this is the first report associating an ARC SNP with schizophrenia and supports recent large-scale GWAS findings implicating the ARC complex in schizophrenia risk (PMID:26474411)
• We tested whether ARC variants are associated with six measures of cognitive functioning in 670 healthy subjects in the Norwegian Cognitive NeuroGenetics (NCNG) by extracting data from its Genome-Wide Association Study (GWAS). (PMID:26516611)
• ARC confers resistance to sunitinib in renal cell carcinoma through alternate angiogenesis pathways (PMID:26995091)
• Study identified several rare mutations that reduced ARC expression in schizophrenia patients. Furthermore, DNA methylation of ARC in schizophrenia patients may be associated with a downregulation of ARC mRNA expression. These findings suggest that multiple rare ARC variants and DNA methylation of ARC might contribute to the pathogenesis of schizophrenia. (PMID:27464451)
• missense mutations in TRIAD3 abolished the interaction of TRIAD3A with Arc, disrupting Arc ubiquitination, and consequently Arc degradation. (PMID:27995769)
• Our results indicated that the Arc gene would confer susceptibility to Alzheimer disease in Han Chinese, probably through changing the protein structure or affecting the Arc expression in brain tissues, which would finally contribute to the pathogenesis and development of AD. (PMID:28108859)
• The ARC complex revealed association with verbal and total IQ in child. (PMID:28671113)
• The findings have important implications for the structural organization of ARC with respect to distinct functions, such as postsynaptic signal transduction and virus-like capsid formation (PMID:30028513)
• Our data highlighted that PCAT6 acts as a key activator of ARC expression by forming a complex with EZH2, inhibiting cell apoptosis and contributing to colon cancer progression. These findings elucidated that PCAT6 may be a novel prognostic predictor and therapeutic target of colon cancer (PMID:30569799)
• Activity-Regulated Cytoskeleton-Associated Protein (Arc/Arg3.1) is Transiently Expressed after Heat Shock Stress and Suppresses Heat Shock Factor 1. (PMID:30796345)
• Multiscale Imaging Reveals Aberrant Functional Connectome Organization and Elevated Dorsal Striatal Arc Expression in Advanced Age. (PMID:31826916)
• Structure of Drosophila melanogaster ARC1 reveals a repurposed molecule with characteristics of retroviral Gag. (PMID:31911950)
• Activity-regulated cytoskeleton-associated protein predicts symptom response to cognitive behavioral therapy among individuals with first-episode psychosis. (PMID:32145691)
• Arc self-association and formation of virus-like capsids are mediated by an N-terminal helical coil motif. (PMID:33175445)
• Arc and Homer1 are involved in comorbid epilepsy and depression: A microarray data analysis. (PMID:35665606)
• NMDA Receptor-Arc Signaling Is Required for Memory Updating and Is Disrupted in Alzheimer’s Disease. (PMID:36796600)
• Gut-derived 4-hydroxyphenylacetic acid attenuates sepsis-induced acute kidney injury by upregulating ARC to inhibit necroptosis. (PMID:37714058)
• Arc regulates brain damage and neuroinflammation via Sirt1 signaling following subarachnoid hemorrhage. (PMID:37820952)
• Tau regulates Arc stability in neuronal dendrites via a proteasome-sensitive but ubiquitin-independent pathway. (PMID:38552740)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Arc	ENSMUSG00000022602
rattus_norvegicus	Arc	ENSRNOG00000043465

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:88067) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 28 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal cued conditioning behavior	1
abnormal spatial learning	1
abnormal contextual conditioning behavior	1
reduced long-term potentiation	1
abnormal embryo development	1
absent mesoderm	1
failure to gastrulate	1
abnormal proximal-distal axis patterning	1
embryonic growth arrest	1
abnormal nervous system electrophysiology	1
disorganized extraembryonic tissue	1
abnormal conditioned taste aversion behavior	1
abnormal AMPA-mediated synaptic currents	1
enhanced long-term potentiation	1
decreased fear-related response	1
abnormal nervous system physiology	1
abnormal embryonic-extraembryonic boundary morphology	1
embryonic growth retardation	1
disorganized embryonic tissue	1
abnormal extraembryonic tissue physiology	1
abnormal miniature excitatory postsynaptic currents	1
abnormal spatial reference memory	1
impaired contextual conditioning behavior	1
impaired cued conditioning behavior	1
abnormal extraembryonic ectoderm morphology	1

+3 more (showing top 25).

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Gallus gallus	Q8AWC3	71.4%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
TSNARE1	protein-coding	203062
ADGRB1	protein-coding	575
PSCA	protein-coding	8000
JRK	protein-coding	8629
LINC00051	ncRNA	619434

Protein

Protein identifiers

Activity-regulated cytoskeleton-associated protein — Q7LC44 (reviewed: Q7LC44)

Alternative names: Activity-regulated gene 3.1 protein homolog

All UniProt accessions (1): Q7LC44

UniProt curated annotations — full annotation on UniProt →

Function. Master regulator of synaptic plasticity that self-assembles into virion-like capsids that encapsulate RNAs and mediate intercellular RNA transfer in the nervous system. ARC protein is released from neurons in extracellular vesicles that mediate the transfer of ARC mRNA into new target cells, where ARC mRNA can undergo activity-dependent translation. ARC capsids are endocytosed and are able to transfer ARC mRNA into the cytoplasm of neurons. Acts as a key regulator of synaptic plasticity: required for protein synthesis-dependent forms of long-term potentiation (LTP) and depression (LTD) and for the formation of long-term memory. Regulates synaptic plasticity by promoting endocytosis of AMPA receptors (AMPARs) in response to synaptic activity: this endocytic pathway maintains levels of surface AMPARs in response to chronic changes in neuronal activity through synaptic scaling, thereby contributing to neuronal homeostasis. Acts as a postsynaptic mediator of activity-dependent synapse elimination in the developing cerebellum by mediating elimination of surplus climbing fiber synapses. Accumulates at weaker synapses, probably to prevent their undesired enhancement. This suggests that ARC-containing virion-like capsids may be required to eliminate synaptic material. Required to transduce experience into long-lasting changes in visual cortex plasticity and for long-term memory. Involved in postsynaptic trafficking and processing of amyloid-beta A4 (APP) via interaction with PSEN1. In addition to its role in synapses, also involved in the regulation of the immune system: specifically expressed in skin-migratory dendritic cells and regulates fast dendritic cell migration, thereby regulating T-cell activation.

Subunit / interactions. Homooligomer; homooligomerizes into virion-like capsids. Interacts with SH3GL1/endophilin-2, SH3GL3/endophilin-3 and DNM2/DYN2. Interacts with CAMK2B (in the kinase inactive state); leading to target ARC to inactive synapses. Interacts with PSEN1.

Subcellular location. Extracellular vesicle membrane. Postsynaptic cell membrane. Synapse. Postsynaptic density. Early endosome membrane. Cell projection. Dendrite. Cytoplasm. Cytoskeleton. Cell cortex. Dendritic spine. Cytoplasmic vesicle. Secretory vesicle. Acrosome. Clathrin-coated vesicle membrane.

Post-translational modifications. Palmitoylation anchors the protein into the membrane by allowing direct insertion into the hydrophobic core of the lipid bilayer. Ubiquitinated by UBE3A, leading to its degradation by the proteasome, thereby promoting AMPA receptors (AMPARs) expression at synapses. Ubiquitinated by RNF216 at Lys-268 and Lys-269 limiting ARC protein levels induced by synaptic activity and thus regulating ARC-dependent forms of synaptic plasticity. Phosphorylation at Ser-260 by CaMK2 prevents homooligomerization into virion-like capsids by disrupting an interaction surface essential for high-order oligomerization. Phosphorylation by CaMK2 inhibits synaptic activity.

Domain organisation. The protein is evolutionarily related to retrotransposon Gag proteins: it contains large N- and C-terminal domains that form a bi-lobar architecture similar to the capsid domain of human immunodeficiency virus (HIV) gag protein. It contains structural elements found within viral Gag polyproteins originated from the Ty3/gypsy retrotransposon family and retains the ability to form virion-like capsid structures that can mediate mRNA transfer between cells. Tetrapod and fly Arc protein-coding genes originated independently from distinct lineages of Ty3/gypsy retrotransposons.

Similarity. Belongs to the ARC/ARG3.1 family.

RefSeq proteins (2): NP_001399781, NP_056008* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR023263	Arc	Family
IPR040814	Arc_C-lobe	Domain
IPR045557	Arc_N	Domain
IPR048965	Arc_N-lobe	Domain

Pfam: PF18162, PF19284, PF21395

UniProt features (27 total): helix 12, region of interest 3, mutagenesis site 2, turn 2, modified residue 2, cross-link 2, chain 1, strand 1, coiled-coil region 1, compositionally biased region 1

Structure

Experimental structures (PDB)

11 structures by resolution:

PDB	Title	Method	Resolution (Å)
6YTU	Atomic-resolution structure of the coiled-coil dimerisation domain of human Arc	X-RAY DIFFRACTION	0.95
8QF4	Complex between N-lobe of Arc and nanobody H11	X-RAY DIFFRACTION	1.02
6TNQ	Crystal structure of the human Arc N-lobe bound to repeat 4 from GKAP	X-RAY DIFFRACTION	1.3
8QF5	Complex between N-lobe of Arc and nanobody E5	X-RAY DIFFRACTION	1.5
26AP	Complex between N-lobe Arc mutant F267/F5Phe and nanobody H11	X-RAY DIFFRACTION	1.5
9PZZ	Genetically encoded fluorescent nanobody H11 with …	X-RAY DIFFRACTION	1.56
6TN7	Crystal structure of the human Arc C-lobe	X-RAY DIFFRACTION	1.67
7R1Z	C-terminal domain of hArc in complex with nanobodies H11 and C11, collapsed crystal form	X-RAY DIFFRACTION	1.94
6TQ0	Crystal structure of the human Arc N-lobe bound to repeat peptide 5 from GKAP	X-RAY DIFFRACTION	1.95
7R23	Crystal structure of human Arc CTD in complex with two anti-Arc nanobodies	X-RAY DIFFRACTION	2.77
9Q00	Genetically encoded fluorescent nanobody H11 with …	X-RAY DIFFRACTION	2.84

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q7LC44-F1	66.72	0.10

Antibody-complex structures (SAbDab)

4 antibodies co-crystallized with this protein: 7R1Z, 7R23, 8QF4, 8QF5

Human Protein Atlas

Protein class: Predicted intracellular proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): microtubules; vesicles

Antibody reliability (HPA): IF approved

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)

Type	Positions
Phosphoserine	260
Phosphothreonine	278
Glycyl lysine isopeptide (lys-gly) (interchain with g-cter in ubiquitin)	268, 269

Mutagenesis-validated functional residues (2)

Position	Phenotype
268	complete loss of rnf216-mediated ubiquitination; when associated by a-269.
269	complete loss of rnf216-mediated ubiquitination; when associated by a-268.

Function

Pathways and Gene Ontology

Reactome pathways

0 curated (TAS) of 6; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

6 pathways:

ID	Pathway	Evidence
R-HSA-9031628	NGF-stimulated transcription	electronic
R-HSA-198725	Nuclear Events (kinase and transcription factor activation)	—
R-HSA-162582	Signal Transduction	—
R-HSA-187037	Signaling by NTRK1 (TRKA)	—
R-HSA-166520	Signaling by NTRKs	—
R-HSA-9006934	Signaling by Receptor Tyrosine Kinases	—

MSigDB gene sets: 250 (showing top): GSE45365_NK_CELL_VS_BCELL_UP, MORF_RAGE, GOBP_DENDRITE_DEVELOPMENT, GOBP_MEMORY, GOBP_COGNITION, GOBP_BEHAVIOR, GOBP_REGULATION_OF_CELL_MORPHOGENESIS, GOCC_SECRETORY_GRANULE, GOBP_REGULATION_OF_NEURONAL_SYNAPTIC_PLASTICITY, MODULE_45, GOBP_DENDRITIC_SPINE_DEVELOPMENT, GOBP_NEUROGENESIS, GOBP_VESICLE_MEDIATED_TRANSPORT, MODULE_16, NAGASHIMA_NRG1_SIGNALING_UP

GO Biological Process (14): endocytosis (GO:0006897), long-term memory (GO:0007616), regulation of neuronal synaptic plasticity (GO:0048168), modulation of chemical synaptic transmission (GO:0050804), mRNA transport (GO:0051028), protein homooligomerization (GO:0051260), long-term synaptic potentiation (GO:0060291), dendritic spine morphogenesis (GO:0060997), regulation of dendritic spine morphogenesis (GO:0061001), regulation of postsynaptic neurotransmitter receptor internalization (GO:0099149), vesicle-mediated intercellular transport (GO:0110077), regulation of long-term synaptic potentiation (GO:1900271), regulation of long-term synaptic depression (GO:1900452), positive regulation of AMPA receptor activity (GO:2000969)

GO Molecular Function (4): mRNA binding (GO:0003729), structural molecule activity (GO:0005198), RNA binding (GO:0003723), protein binding (GO:0005515)

GO Cellular Component (20): acrosomal vesicle (GO:0001669), cytoplasm (GO:0005737), cytosol (GO:0005829), cytoskeleton (GO:0005856), plasma membrane (GO:0005886), cell cortex (GO:0005938), postsynaptic density (GO:0014069), clathrin-coated vesicle membrane (GO:0030665), early endosome membrane (GO:0031901), neuronal cell body (GO:0043025), dendritic spine (GO:0043197), membrane raft (GO:0045121), postsynaptic membrane (GO:0045211), neuronal ribonucleoprotein granule (GO:0071598), glutamatergic synapse (GO:0098978), virus-like capsid (GO:0170047), extracellular vesicle (GO:1903561), dendrite (GO:0030425), cytoplasmic vesicle (GO:0031410), synapse (GO:0045202)

Reactome top-level categories

5 top-level categories:

Category	Pathways
Nuclear Events (kinase and transcription factor activation)	1
Signaling by Receptor Tyrosine Kinases	1
Signaling by NTRKs	1
Signaling by NTRK1 (TRKA)	1
Signal Transduction	1

GO top-level categories

showing 60 of 63 GO namespaces:

Category	Terms
regulation of synaptic plasticity	4
cellular anatomical structure	3
cytoplasm	3
cell periphery	2
postsynapse	2
vesicle budding from membrane	1
membrane invagination	1
import into cell	1
memory	1
chemical synaptic transmission	1
regulation of trans-synaptic signaling	1
RNA transport	1
protein complex oligomerization	1
positive regulation of synaptic transmission	1
neuron projection development	1
neuron projection morphogenesis	1
dendrite morphogenesis	1
dendritic spine development	1
dendritic spine organization	1
regulation of neuron projection development	1
regulation of anatomical structure morphogenesis	1
dendritic spine morphogenesis	1
regulation of postsynapse organization	1
regulation of receptor internalization	1
regulation of biological quality	1
postsynaptic neurotransmitter receptor internalization	1
intercellular transport	1
vesicle-mediated transport	1
long-term synaptic potentiation	1
long-term synaptic depression	1
AMPA glutamate receptor activity	1
positive regulation of ion transmembrane transporter activity	1
regulation of AMPA receptor activity	1
RNA binding	1
molecular_function	1
nucleic acid binding	1
binding	1
secretory granule	1
intracellular anatomical structure	1
intracellular membraneless organelle	1
membrane	1
asymmetric synapse	1
postsynaptic specialization	1
clathrin-coated vesicle	1
coated vesicle membrane	1
early endosome	1
endosome membrane	1
somatodendritic compartment	1
cell body	1
dendrite	1
neuron spine	1
membrane microdomain	1
synaptic membrane	1
cytoplasmic ribonucleoprotein granule	1
neuron projection cytoplasm	1
synapse	1
extracellular region	1
vesicle	1
extracellular membrane-bounded organelle	1
neuron projection	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 5 of 38 annotations. The rest are phylogenetic / computational / electronic (IEA).

5 experimentally-supported GO terms:

GO term	NS	Evidence
cytoplasm	CC	direct assay
plasma membrane	CC	direct assay
virus-like capsid	CC	direct assay
mRNA binding	MF	direct assay
structural molecule activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 742 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ARC	GRIA1	P42261	800
ARC	BDNF	P23560	674
ARC	UBE3A	P78355	613
ARC	DLG4	P78352	612
ARC	EGR1	P18146	608
ARC	FOS	P01100	607
ARC	NPAS4	Q8IUM7	570
ARC	HOMER1	Q86YM7	570
ARC	FMR1	Q06787	564
ARC	CREB1	P16220	563
ARC	GRIN2B	Q13224	508
ARC	CAMK2A	Q9UQM7	498
ARC	GRIA2	P42262	481
ARC	FXR2	P51116	450
ARC	GRIN2A	Q12879	444

IntAct

Human interaction partners of ARC in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

7 partners by confidence:

Partner	Interaction type	MIscore	Records
CSRP2	physical association	0.560	3
S100P	physical association	0.560	3
SH2D4A	physical association	0.560	3
TBX18	physical association	0.560	3
FER	association	0.530	2
DLG4	physical association	0.400	1
KRT15	physical association	0.370	1

BioGRID (36 interactions; top human partners by supporting records): RNF216 (Affinity Capture-Western; 3 records), FAM83B (Affinity Capture-MS; 2 records), FER (Affinity Capture-MS; 2 records), KRAS (Proximity Label-MS; 2 records), NDE1 (Affinity Capture-MS; 2 records), SSFA2 (Affinity Capture-MS; 2 records), STUB1 (Affinity Capture-Western; 2 records), TMEM55A (Affinity Capture-MS; 2 records), C15orf59 (Affinity Capture-MS), CSRP2 (Two-hybrid), DDX39A (Affinity Capture-RNA), EGFR (Proximity Label-MS), FGFR1 (Proximity Label-MS), GSK3B (Affinity Capture-Western), KRT15 (Two-hybrid)

Disease & clinical

Genetic variants

Variant evidence for ARC: 30 ClinVar records (0 pathogenic / likely pathogenic); 2 GWAS associations.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	22
Likely benign	2
Benign	2

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 29 predictions of 92):

Position(s)	Effect	Δscore	Sites
8:142612253–142612254	acceptor_loss	1.0000	6
8:142612120	donor_gain	0.9900
8:142612106–142612107	donor_loss	0.9800	6
8:142612108	donor_loss	0.9700
8:142612482–142612483	donor_loss	0.9700	5
8:142612108	donor_loss	0.9600
8:142611858–142611859	acceptor_loss	0.9500	6
8:142612108	donor_loss	0.9100
8:142612255	acceptor_gain	0.9000
8:142612408	donor_gain	0.8700

AlphaMissense

1,015 missense substitutions predicted likely pathogenic (of 2,570 scored), across 242 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M38	9	0.941	0.992
F267	8	0.986	1.000
H245	8	0.984	0.998
F271	8	0.978	1.000
F220	8	0.977	1.000
F301	8	0.951	0.999
F120	8	0.949	0.993
F214	8	0.904	0.984
D216	8	0.890	0.971
H46	8	0.882	0.987
N244	8	0.801	0.968
W253	7	0.996	1.000
W254	7	0.995	0.999
W264	7	0.995	0.999
W87	7	0.992	0.999
W108	7	0.985	0.996
W116	7	0.985	0.999
E112	7	0.979	0.995
W238	7	0.977	0.993
C98	7	0.965	0.998

HPA cancer prognostics

RNA cancer specificity: Cancer enriched (Glioblastoma Multiforme)

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

6 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	2.44e-06
Glioblastoma Multiforme (TCGA)	unfavorable	8.58e-05
Pancreatic Adenocarcinoma (validation)	unfavorable	0.000387
Liver Hepatocellular Carcinoma (TCGA)	unfavorable	0.0005
Glioblastoma Multiforme (validation)	unfavorable	0.000509
Breast Invasive Carcinoma (TCGA)	unfavorable	0.000943

Disease associations

OMIM: gene MIM:612461 | disease phenotypes:

GWAS associations

2 associations:

Study	Trait	p-value
GCST007329_15	Automobile speeding propensity	7e-10
GCST009440_6	Age-related cognitive decline (attention/processing speed) (slope of z-scores)	2e-6

EFO canonical traits (from GWAS)

2 canonical traits:

EFO ID	Trait name
EFO:0008579	risk-taking behaviour
EFO:0007710	cognitive decline measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Cadmium Chloride	decreases expression, increases expression	3
sodium arsenite	affects methylation, increases expression	2
Cisplatin	decreases expression, affects cotreatment, increases expression	2
Copper	affects binding, decreases expression, increases expression	2
Tobacco Smoke Pollution	increases expression	2
Aflatoxin B1	decreases methylation, increases expression	2
aristolochic acid I	increases expression	1
OTX015	increases expression	1
TAK-243	increases sumoylation	1
methylmercuric chloride	increases expression	1
propionaldehyde	increases expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
beta-lapachone	increases expression	1
butyraldehyde	increases expression	1
benzo(e)pyrene	increases methylation	1
ferrous chloride	increases expression	1
aflatoxin B2	decreases methylation	1
cupric oxide	increases expression	1
gallium arsenide	increases expression	1
pentanal	increases expression	1
15-acetyldeoxynivalenol	increases expression	1
aluminum maltolate	increases expression, decreases reaction	1
2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one	decreases reaction, increases expression	1
nutlin 3	affects cotreatment, increases expression	1
abrine	increases expression	1
(4-amino-1,4-dihydro-3-(2-pyridyl)-5-thioxo-1,2,4-triazole)copper(II)	increases expression	1
licochalcone B	increases expression	1
jinfukang	affects cotreatment, increases expression, decreases expression	1
NSC 689534	affects binding, increases expression	1
(+)-JQ1 compound	increases expression	1

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.