ACTA1

Summary

ACTA1 (actin alpha 1, skeletal muscle, HGNC:129) is a protein-coding gene on chromosome 1q42.13, encoding Actin, alpha skeletal muscle (P68133). Actins are highly conserved proteins that are involved in various types of cell motility and are ubiquitously expressed in all eukaryotic cells.

The product encoded by this gene belongs to the actin family of proteins, which are highly conserved proteins that play a role in cell motility, structure and integrity. Alpha, beta and gamma actin isoforms have been identified, with alpha actins being a major constituent of the contractile apparatus, while beta and gamma actins are involved in the regulation of cell motility. This actin is an alpha actin that is found in skeletal muscle. Mutations in this gene cause a variety of myopathies, including nemaline myopathy, congenital myopathy with excess of thin myofilaments, congenital myopathy with cores, and congenital myopathy with fiber-type disproportion, diseases that lead to muscle fiber defects with manifestations such as hypotonia.

Source: NCBI Gene 58 — RefSeq curated summary.

At a glance

• Gene–disease (curated): alpha-actinopathy (Definitive, ClinGen) — +11 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 624 total — 105 pathogenic, 98 likely-pathogenic
• Phenotypes (HPO): 192
• MANE Select transcript: NM_001100

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:129
Approved symbol	ACTA1
Name	actin alpha 1, skeletal muscle
Location	1q42.13
Locus type	gene with protein product
Status	Approved
Aliases	NEM3
Ensembl gene	ENSG00000143632
Ensembl biotype	protein_coding
OMIM	102610
Entrez	58

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 11 protein_coding

ENST00000366683, ENST00000366684, ENST00000684723, ENST00000871224, ENST00000871225, ENST00000871226, ENST00000871227, ENST00000871228, ENST00000947079, ENST00000947080, ENST00000947081

RefSeq mRNA: 1 — MANE Select: NM_001100 NM_001100

CCDS: CCDS1578

Canonical transcript exons

ENST00000366684 — 7 exons

Exon	Start	End
ENSE00001318140	229431245	229431642
ENSE00001380587	229432987	229433127
ENSE00001433404	229434004	229434094
ENSE00001747528	229431721	229431902
ENSE00001750806	229432556	229432880
ENSE00002352571	229432270	229432431
ENSE00002425382	229431994	229432185

Expression profiles

Bgee: expression breadth ubiquitous, 203 present calls, max score 100.00.

FANTOM5 (CAGE): breadth broad, TPM avg 304.7071 / max 125131.1762, expressed in 334 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
17914	303.7975	325
17913	0.8908	52
17915	0.0188	11

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
gluteal muscle	UBERON:0002000	100.00	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	100.00	gold quality
diaphragm	UBERON:0001103	99.99	gold quality
biceps brachii	UBERON:0001507	99.99	gold quality
triceps brachii	UBERON:0001509	99.99	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	99.99	gold quality
tibialis anterior	UBERON:0001385	99.98	gold quality
hindlimb stylopod muscle	UBERON:0004252	99.98	gold quality
gastrocnemius	UBERON:0001388	99.97	gold quality
body of tongue	UBERON:0011876	99.97	gold quality
skeletal muscle tissue	UBERON:0001134	99.96	gold quality
deltoid	UBERON:0001476	99.94	gold quality
quadriceps femoris	UBERON:0001377	99.93	gold quality
heart right ventricle	UBERON:0002080	99.93	gold quality
vastus lateralis	UBERON:0001379	99.92	gold quality
apex of heart	UBERON:0002098	99.91	gold quality
cardiac ventricle	UBERON:0002082	99.66	gold quality
heart left ventricle	UBERON:0002084	99.65	gold quality
vena cava	UBERON:0004087	99.47	gold quality
left ventricle myocardium	UBERON:0006566	99.31	gold quality
right atrium auricular region	UBERON:0006631	98.86	gold quality
muscle organ	UBERON:0001630	98.72	gold quality
cardiac atrium	UBERON:0002081	98.64	gold quality
myocardium	UBERON:0002349	98.56	gold quality
muscle of leg	UBERON:0001383	98.24	gold quality
heart	UBERON:0000948	97.45	gold quality
pharyngeal mucosa	UBERON:0000355	97.28	gold quality
cardiac muscle of right atrium	UBERON:0003379	97.00	gold quality
muscle tissue	UBERON:0002385	96.97	gold quality
saphenous vein	UBERON:0007318	95.55	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-ANND-5	yes	907.48
E-CURD-112	no	1956.03
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR, EEF1A1, FOS, JUN, NR2F2, REST, ROCK2, SMAD3, SP1, SRF, TBP, TEAD1, TEAD4, TEF, TP53, YY1, ZIC3

miRNA regulators (miRDB)

38 targeting ACTA1, 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-4500	99.99	72.72	2367
HSA-MIR-223-3P	99.99	70.14	1140
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-202-3P	99.84	71.41	1290
HSA-MIR-6875-3P	99.82	70.26	2983
HSA-MIR-12129	99.72	67.45	1311
HSA-MIR-1200	99.71	70.42	1838
HSA-MIR-587	99.64	70.86	2611
HSA-MIR-567	99.63	68.57	1219
HSA-MIR-1252-3P	99.55	67.71	2862
HSA-MIR-297	99.40	69.58	1418
HSA-MIR-4251	99.40	69.19	3363
HSA-MIR-103A-1-5P	99.39	67.78	1545

Literature-anchored findings (GeneRIF, showing 40)

• IGF-I-induced activation of the skeletal alpha-actin promoter is regulated by the L-type VGCC and calcineurin but independent of nuclear factor of activated T-cell transcriptional activity as C2C12 myoblasts differentiate into myotubes. (PMID:14684598)
• Actin-related myopathy may occur without any missense mutation in the ACTA1 gene (PMID:15072110)
• Results describe clinical and pathological features associated with 29 alpha-actin (ACTA1) mutations found in 38 individuals with nemaline myopathy from 28 families. (PMID:15236405)
• two csae of nemaline myopathy showed novel mutations in the skeletal muscle aphaa-actin gene, one had g268d mutation and other had mutation, K373E. (PMID:15336687)
• Three heterozygous missense mutations of the skeletal muscle alpha actin gene (ACTA1) in three unrelated cases of congenital fiber type disproportion (CFTD) from Japan and Australia. (PMID:15468086)
• Missense mutations of ACTA1 cause an autosomal dominant congenital myopathy with cores. (PMID:15520409)
• Enhanced expression of alpha skeletal muscle actin is associated with liver metastases from gastrointestinal tumours (PMID:15679046)
• A heterozygous GTG-ATG mutation (Val163Met) was found in exon 4 of ACTA1 in affected individuals with nemaline myopathy with intranuclear rods. (PMID:16427282)
• Here we report for the first time three patients with severe nemaline myopathy and mutations of the ACTA1 stop codon: TAG>TAT (tyrosine), TAG>CAG (glutamine) and TAG>TGG (tryptophan). (PMID:16945536)
• These data suggest that ACTA1 congenital fiber type disproportion (CFTD) mutations cause weakness by disrupting sarcomere function rather than structure. (PMID:17387733)
• Regulation of skeletal alpha-actin by androgens/SARMs may represent an important model system for understanding androgen anabolic action in the muscle. (PMID:18063690)
• Nemaline myopathy with exclusively intranuclear rods and a novel mutation in ACTA1 (Q139H). (PMID:18461503)
• congenital myopathy-causing ACTA1 mutations (Review) (PMID:18976909)
• circulating actin are associated with early sepsis (PMID:19002257)
• progressive immobilization of Fc epsilon RI during aggregation was sensitive to syk or actin polymerization inhibition. Therefore, desensitization is also not dependent on receptor immobilization. (PMID:19150851)
• This study shows that the disappearance of CD34-positive stromal cells and appearance of alpha-SMA-positive stromal myofibroblasts may be associated with transformation of cervical cervical intraepithelial neoplasias to squamous cell carcinomas. (PMID:19383239)
• Low plasma gelsolin and detectable circulating actin identify chronic hemodialysis patients at highest risk for 1-year mortality. (PMID:19389844)
• description of 177 different disease-causing ACTA1 mutations, including 85 that have not been described before (PMID:19562689)
• In summary, these results suggest that actin, likely modulated by the GTPases RhoA and Cdc42 and by bacterial proteins, is involved in the formation of the typical parasitophorous vacuole. (PMID:19635823)
• Data identify a novel signaling pathway in the endocrine L cell, whereby Cdc42 regulates actin remodeling, activation of the cannonical 1/2-ERK1/2 pathway and PAK1, and GLP-1 secretion in response to insulin. (PMID:19819966)
• Asef2 activates Rac1 to modulate adhesion and actin dynamics and thereby regulate cell migration (PMID:19934221)
• First insights of S100A10 function as a regulator of the filamentous actin network. (PMID:20100475)
• Data demonstrate for the first time that L-plastin contributes to the fine-tuning of actin turn-over, an activity which is regulated by Ser5 phosphorylation promoting its high affinity binding to the cytoskeleton. (PMID:20169155)
• ACTA1 mutations are involved in fiber size disproportion in congenital myotonic dystrophy (PMID:20179953)
• these data identify NHS as a new regulator of actin remodelling. (PMID:20332100)
• We conclude that the Drosophila indirect flight muscles provide a good model system for studying ACTA1 mutations (PMID:20452215)
• Podocyte BK(Ca) channels are regulated by synaptopodin, Rho, and actin microfilaments. (PMID:20630939)
• Simultaneous tracking of both TCR clusters and GFP-actin speckles reveals their dynamic association and individual flow patterns. Actin retrograde flow directs the inward transport of TCR clusters (PMID:20686692)
• BCL2 interaction with actin in vitro may inhibit cell motility by enhancing actin polymerization (PMID:20716950)
• Results confirm that DNaseI-binding loop (D-loop) is involved in stabilization of skeletal muscle actin structure, both as monomers and filaments; actin is stabilized by ligands (by phalloidin, aluminum fluoride, & ATP [and to lesser extent by ADP]). (PMID:20718862)
• These findings demonstrated that PI3K-mediated actin rearrangements are required for Cronobacter sakazakii invasion of human brain microvascular endothelial cells. (PMID:20809254)
• Results suggest that actin polymerization and bundling by VASP are critical for spine formation, expansion, and modulating synaptic strength. (PMID:20826790)
• Data show that concurrent phosphorylation of cortactin by ERK1/2 and tyrosine kinases enables cells with the ability to regulate actin dynamics. (PMID:21079800)
• Centrosomal actin was detected with the anti-actin antibody 1C7 that recognizes antiparallel (“lower dimer”) actin dimers. (PMID:21108927)
• Actin-EGFP and ezrin-EGFP accumulated below pilus-coated beads when force was applied. (PMID:21340023)
• a link between extramuscular expression of alpha-skeletal muscle actin and clinical symptoms in non-skeletal muscle tissues of patients with ACTA1 mutations, and probably a functional role of alpha-skeletal muscle actin during fetal development (PMID:21514153)
• Over-expression of Nkx2.5 and/or cardiac alpha-actin inhibit the contraction ability of adipose tissue-derived stromal cells-derived cardiomyocytes. (PMID:21691712)
• Data show that the urinary messenger RNA (mRNA) levels of alpha-smooth muscle actin (alpha-SMA), fibronectin, and matrix metalloproteinase-9 (MMP-9) were significantly higher in the diabetic nephropathy (DN) group, and mRNA levels increased with DN progression. (PMID:21824169)
• High alpha-actin is associated with colorectal carcinogenesis. (PMID:21912905)
• Actin accumulates throughout the activated immunological synapse. (PMID:21931536)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	acta1a	ENSDARG00000036371
danio_rerio	actc1a	ENSDARG00000042535
danio_rerio	acta1b	ENSDARG00000055618
danio_rerio	actc1c	ENSDARG00000076126
mus_musculus	Acta1	ENSMUSG00000031972
rattus_norvegicus	Acta1	ENSRNOG00000017786

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), ACTR2 (ENSG00000138071), ACTR1A (ENSG00000138107), ACTL7B (ENSG00000148156), ACTC1 (ENSG00000159251), ACTG2 (ENSG00000163017), ACTBL2 (ENSG00000169067), ACTRT2 (ENSG00000169717), ACTL9 (ENSG00000181786), ACTG1 (ENSG00000184009), ACTRT3 (ENSG00000184378), ACTL7A (ENSG00000187003), ACTL10 (ENSG00000288649)

Protein

Protein identifiers

Actin, alpha skeletal muscle — P68133 (reviewed: P68133)

Alternative names: Alpha-actin-1

All UniProt accessions (3): P68133, A0A804HKV3, A6NL76

UniProt curated annotations — full annotation on UniProt →

Function. Actins are highly conserved proteins that are involved in various types of cell motility and are ubiquitously expressed in all eukaryotic cells.

Subunit / interactions. Polymerization of globular actin (G-actin) leads to a structural filament (F-actin) in the form of a two-stranded helix. Each actin can bind to 4 others. Interacts with alpha-actinin. Identified in a complex composed of ACTA1, COBL, GSN AND TMSB4X. Interacts with TTID. Interacts (via its C-terminus) with USP25; the interaction occurs for all USP25 isoforms but is strongest for isoform USP25m in muscle differentiating cells.

Subcellular location. Cytoplasm. Cytoskeleton.

Post-translational modifications. Oxidation of Met-46 and Met-49 by MICALs (MICAL1, MICAL2 or MICAL3) to form methionine sulfoxide promotes actin filament depolymerization. MICAL1 and MICAL2 produce the (R)-S-oxide form. The (R)-S-oxide form is reverted by MSRB1 and MSRB2, which promotes actin repolymerization. Monomethylation at Lys-86 (K84me1) regulates actin-myosin interaction and actomyosin-dependent processes. Demethylation by ALKBH4 is required for maintaining actomyosin dynamics supporting normal cleavage furrow ingression during cytokinesis and cell migration. N-terminal cleavage of acetylated cysteine of intermediate muscle actin by ACTMAP. Methylated at His-75 by SETD3. (Microbial infection) Monomeric actin is cross-linked by V.cholerae toxins RtxA and VgrG1 in case of infection: bacterial toxins mediate the cross-link between Lys-52 of one monomer and Glu-272 of another actin monomer, resulting in formation of highly toxic actin oligomers that cause cell rounding. The toxin can be highly efficient at very low concentrations by acting on formin homology family proteins: toxic actin oligomers bind with high affinity to formins and adversely affect both nucleation and elongation abilities of formins, causing their potent inhibition in both profilin-dependent and independent manners.

Disease relevance. Congenital myopathy 2A, typical, autosomal dominant (CMYO2A) [MIM:161800] A muscular disorder characterized by generalized muscle weakness, delayed motor milestones, hypotonia, and muscle fiber abnormalities on histologic examination. Histologic findings include abnormal thread- or rod-like structures (nemaline rods), intranuclear rods, clumped filaments, cores, or fiber-type disproportion. The spectrum of clinical phenotypes ranges from severe neonatal presentations to onset of a milder disorder in childhood. The disease is caused by variants affecting the gene represented in this entry. Congenital myopathy 2B, severe infantile, autosomal recessive (CMYO2B) [MIM:620265] An autosomal recessive skeletal muscle disorder characterized by severe hypotonia with lack of spontaneous movements and respiratory insufficiency, usually leading to death in infancy or early childhood. Longer survival has been reported. The disease is caused by variants affecting the gene represented in this entry. Congenital myopathy 2C, severe infantile, autosomal dominant (CMYO2C) [MIM:620278] An autosomal dominant skeletal muscle disorder characterized by severe congenital weakness usually resulting in death from respiratory failure in the first year or so of life. Patients present at birth with hypotonia, lack of antigravity movements, poor head control, and difficulties feeding or breathing, often requiring tube-feeding and mechanical ventilation. Decreased fetal movements may be observed in some cases. The disease is caused by variants affecting the gene represented in this entry. Myopathy, scapulohumeroperoneal (SHPM) [MIM:616852] An autosomal dominant muscular disorder characterized by progressive muscle weakness with initial scapulo-humeral-peroneal and distal distribution. Over time, muscle weakness progresses to proximal muscle groups. Clinical characteristics include scapular winging, mild lower facial weakness, foot drop due to foot eversion and dorsiflexion weakness, and selective muscle atrophy. Age at onset and disease progression are variable. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. In vertebrates 3 main groups of actin isoforms, alpha, beta and gamma have been identified. The alpha actins are found in muscle tissues and are a major constituent of the contractile apparatus. The beta and gamma actins coexist in most cell types as components of the cytoskeleton and as mediators of internal cell motility.

Similarity. Belongs to the actin family.

RefSeq proteins (1): NP_001091* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004000	Actin	Family
IPR004001	Actin_CS	Conserved_site
IPR020902	Actin/actin-like_CS	Conserved_site
IPR043129	ATPase_NBD	Homologous_superfamily

Pfam: PF00022

Catalyzed reactions (Rhea), 1 shown:

• ATP + H2O = ADP + phosphate + H(+) (RHEA:13065)

UniProt features (137 total): sequence variant 84, helix 19, strand 17, modified residue 6, turn 4, chain 2, cross-link 2, region of interest 2, initiator methionine 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
7RNS	X-RAY DIFFRACTION	1.14
7RNU	X-RAY DIFFRACTION	1.45
7RNV	X-RAY DIFFRACTION	2.15
9DUV	ELECTRON MICROSCOPY	3.3
9DUU	ELECTRON MICROSCOPY	3.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P68133-F1	95.21	0.92

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 (8): 86, 52, 272, 2, 46, 49, 63, 75

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-390522	Striated Muscle Contraction
R-HSA-9764561	Regulation of CDH1 Function
R-HSA-9913351	Formation of the dystrophin-glycoprotein complex (DGC)
R-HSA-9958825	Activation of STAT3 by cadherin engagement
R-HSA-1474244	Extracellular matrix organization
R-HSA-3000171	Non-integrin membrane-ECM interactions
R-HSA-397014	Muscle contraction

MSigDB gene sets: 566 (showing top): GOBP_MUSCLE_TISSUE_DEVELOPMENT, BIOCARTA_MAL_PATHWAY, GCANCTGNY_MYOD_Q6, BECKER_TAMOXIFEN_RESISTANCE_UP, AREB6_03, GOBP_STRIATED_MUSCLE_CELL_DIFFERENTIATION, AREB6_01, DARWICHE_SKIN_TUMOR_PROMOTER_DN, DARWICHE_PAPILLOMA_RISK_LOW_DN, DARWICHE_PAPILLOMA_RISK_HIGH_DN, DARWICHE_SQUAMOUS_CELL_CARCINOMA_DN, MODULE_329, SARRIO_EPITHELIAL_MESENCHYMAL_TRANSITION_DN, CAGCTG_AP4_Q5, MODULE_503

GO Biological Process (5): muscle contraction (GO:0006936), positive regulation of gene expression (GO:0010628), skeletal muscle thin filament assembly (GO:0030240), skeletal muscle fiber development (GO:0048741), mesenchyme migration (GO:0090131)

GO Molecular Function (7): structural constituent of cytoskeleton (GO:0005200), ATP binding (GO:0005524), hydrolase activity (GO:0016787), myosin binding (GO:0017022), ADP binding (GO:0043531), nucleotide binding (GO:0000166), protein binding (GO:0005515)

GO Cellular Component (14): stress fiber (GO:0001725), obsolete extracellular space (GO:0005615), cytosol (GO:0005829), striated muscle thin filament (GO:0005865), actin filament (GO:0005884), actin cytoskeleton (GO:0015629), sarcomere (GO:0030017), lamellipodium (GO:0030027), filopodium (GO:0030175), cell body (GO:0044297), extracellular exosome (GO:0070062), blood microparticle (GO:0072562), cytoplasm (GO:0005737), cytoskeleton (GO:0005856)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Muscle contraction	1
Regulation of CDH1 Expression and Function	1
Non-integrin membrane-ECM interactions	1
Adherens junctions interactions	1
Extracellular matrix organization	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
cytoskeleton	2
adenyl ribonucleotide binding	2
actin cytoskeleton	2
muscle system process	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
actin filament organization	1
skeletal myofibril assembly	1
skeletal muscle tissue development	1
myotube cell development	1
mesenchyme morphogenesis	1
tissue migration	1
structural molecule activity	1
cytoskeleton organization	1
purine ribonucleoside triphosphate binding	1
catalytic activity	1
cytoskeletal protein binding	1
anion binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
actomyosin	1
contractile actin filament bundle	1
cytoplasm	1
sarcomere	1
myofilament	1
polymeric cytoskeletal fiber	1
myofibril	1
cell leading edge	1
plasma membrane bounded cell projection	1
actin-based cell projection	1
extracellular vesicle	1
extracellular region	1
intracellular anatomical structure	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

130 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
SSH1	LIMK1	psi-mi:“MI:0915”(physical association)	0.680
ANXA8	ACTA1	psi-mi:“MI:0915”(physical association)	0.590
ACTA1	CAMK2A	psi-mi:“MI:0915”(physical association)	0.560
ZNF20	ACTA1	psi-mi:“MI:0915”(physical association)	0.560
SYNC	ACTA1	psi-mi:“MI:0915”(physical association)	0.560
PNMA5	ACTA1	psi-mi:“MI:0915”(physical association)	0.560
ASCL4	ACTA1	psi-mi:“MI:0915”(physical association)	0.560
INCA1	ACTA1	psi-mi:“MI:0915”(physical association)	0.560
LIAT1	ACTA1	psi-mi:“MI:0915”(physical association)	0.560
DMC1	POTEF	psi-mi:“MI:0914”(association)	0.530
ZNF324B	ZNF316	psi-mi:“MI:0914”(association)	0.530

BioGRID (393): ACTA1 (Two-hybrid), ACTA1 (Two-hybrid), ABL1 (Reconstituted Complex), ACTA1 (Affinity Capture-MS), ACTA1 (Affinity Capture-MS), ACTA1 (Affinity Capture-MS), ACTA1 (Affinity Capture-MS), ACTA1 (Affinity Capture-MS), ACTA1 (Affinity Capture-MS), ACTA1 (Affinity Capture-MS), ACTA1 (Affinity Capture-MS), ACTA1 (Affinity Capture-MS), ACTA1 (Affinity Capture-MS), ACTA1 (Affinity Capture-Western), MYO1C (Affinity Capture-Western)

ESM2 similar proteins: O15998, P04751, P04752, P07829, P0CJ46, P0CJ47, P10995, P12717, P20399, P26198, P27130, P41113, P49055, P53457, P53460, P53465, P53466, P53473, P53475, P53479, P53480, P53482, P62736, P62737, P62738, P62739, P62740, P68032, P68033, P68034, P68035, P68133, P68134, P68135, P68136, P68137, P68138, P68139, P68140, P68264

Diamond homologs: A2BDB0, A2WNB0, O18840, O74258, O94241, P02578, P04751, P07829, P0CM04, P0CM05, P10984, P10986, P10990, P10995, P12716, P14235, P17128, P17304, P20399, P27131, P29751, P30162, P30163, P45890, P48975, P49055, P53455, P53458, P53459, P53472, P53479, P53486, P53505, P60009, P60010, P60011, P60706, P60708, P60709, P60710

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
“MYOD1/SWI/SNF complex”	“up-regulates quantity by expression”	ACTA1	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 144 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
Golgi Associated Vesicle Biogenesis	6	12.5×	6e-03
Clathrin-mediated endocytosis	8	7.1×	6e-03

GO biological processes:

GO term	Partners	Fold	FDR
membrane organization	5	19.3×	3e-03

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	105
Likely pathogenic	98
Uncertain significance	200
Likely benign	142
Benign	17

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1003875	NM_001100.4(ACTA1):c.983_985del (p.Lys328del)	Pathogenic
1031829	NM_001100.4(ACTA1):c.1001C>G (p.Pro334Arg)	Pathogenic
1031830	NM_001100.4(ACTA1):c.400A>G (p.Met134Val)	Pathogenic
1069121	NM_001100.4(ACTA1):c.155_158del (p.Lys52fs)	Pathogenic
1072266	NM_001100.4(ACTA1):c.599A>G (p.Tyr200Cys)	Pathogenic
1073998	NM_001100.4(ACTA1):c.841T>C (p.Tyr281His)	Pathogenic
1074947	NM_001100.4(ACTA1):c.181C>T (p.Gln61Ter)	Pathogenic
128261	NM_001100.4(ACTA1):c.515C>A (p.Ala172Glu)	Pathogenic
1322764	NM_001100.4(ACTA1):c.494del (p.Val165fs)	Pathogenic
1451534	NM_001100.4(ACTA1):c.400del (p.Met134fs)	Pathogenic
1452454	NM_001100.4(ACTA1):c.509G>A (p.Gly170Asp)	Pathogenic
1452968	NM_001100.4(ACTA1):c.124C>T (p.His42Tyr)	Pathogenic
1456499	NM_001100.4(ACTA1):c.704C>A (p.Ser235Tyr)	Pathogenic
1457948	NM_001100.4(ACTA1):c.1049C>T (p.Ser350Leu)	Pathogenic
1457951	NM_001100.4(ACTA1):c.846C>G (p.Asn282Lys)	Pathogenic
1457959	NM_001100.4(ACTA1):c.169G>C (p.Gly57Arg)	Pathogenic
1685499	NM_001100.4(ACTA1):c.359A>T (p.Lys120Met)	Pathogenic
1704132	NM_001100.4(ACTA1):c.551G>A (p.Gly184Asp)	Pathogenic
18280	NM_001100.4(ACTA1):c.350A>G (p.Asn117Ser)	Pathogenic
18282	NM_001100.4(ACTA1):c.493G>T (p.Val165Leu)	Pathogenic
18284	NM_001100.4(ACTA1):c.1075A>C (p.Ile359Leu)	Pathogenic
18285	NM_001100.4(ACTA1):c.808G>T (p.Gly270Cys)	Pathogenic
18287	NM_001100.4(ACTA1):c.7G>T (p.Asp3Tyr)	Pathogenic
18289	NM_001100.4(ACTA1):c.881A>T (p.Asp294Val)	Pathogenic
18291	NM_001100.4(ACTA1):c.1000C>T (p.Pro334Ser)	Pathogenic
18292	NM_001100.4(ACTA1):c.493G>A (p.Val165Met)	Pathogenic
1992629	NM_001100.4(ACTA1):c.794A>G (p.Gln265Arg)	Pathogenic
2054260	NM_001100.4(ACTA1):c.920T>G (p.Met307Arg)	Pathogenic
2202998	NM_001100.4(ACTA1):c.611C>T (p.Thr204Ile)	Pathogenic
2203001	NM_001100.4(ACTA1):c.50G>A (p.Gly17Asp)	Pathogenic

SpliceAI

550 predictions. Top by Δscore:

Variant	Effect	Δscore
1:229431639:TGAT:T	acceptor_gain	1.0000
1:229431639:TGATC:T	acceptor_loss	1.0000
1:229431642:TC:T	acceptor_loss	1.0000
1:229431643:C:CC	acceptor_gain	1.0000
1:229431643:CTG:C	acceptor_loss	1.0000
1:229431644:T:A	acceptor_loss	1.0000
1:229431717:CCAC:C	donor_loss	1.0000
1:229431718:CAC:C	donor_loss	1.0000
1:229431719:A:AT	donor_loss	1.0000
1:229431901:ACC:A	acceptor_loss	1.0000
1:229431902:CCTGG:C	acceptor_loss	1.0000
1:229431903:C:CA	acceptor_loss	1.0000
1:229431988:GCTCA:G	donor_loss	1.0000
1:229431989:CTCA:C	donor_loss	1.0000
1:229431990:TCACC:T	donor_loss	1.0000
1:229431991:CACC:C	donor_loss	1.0000
1:229431992:A:AC	donor_gain	1.0000
1:229431992:ACCG:A	donor_loss	1.0000
1:229431993:C:CC	donor_gain	1.0000
1:229431993:CCG:C	donor_gain	1.0000
1:229432181:CTCAG:C	acceptor_gain	1.0000
1:229432182:TCAG:T	acceptor_gain	1.0000
1:229432182:TCAGC:T	acceptor_loss	1.0000
1:229432183:CAG:C	acceptor_gain	1.0000
1:229432183:CAGC:C	acceptor_gain	1.0000
1:229432184:AG:A	acceptor_gain	1.0000
1:229432184:AGCTG:A	acceptor_loss	1.0000
1:229432186:C:CC	acceptor_gain	1.0000
1:229432187:T:A	acceptor_loss	1.0000
1:229432189:C:CT	acceptor_gain	1.0000

AlphaMissense

2499 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:229431518:A:T	V372D	1.000
1:229431531:C:G	G368R	1.000
1:229431561:A:G	W358R	1.000
1:229431561:A:T	W358R	1.000
1:229431571:G:C	F354L	1.000
1:229431571:G:T	F354L	1.000
1:229431573:A:G	F354L	1.000
1:229431581:A:G	L351P	1.000
1:229431581:A:T	L351Q	1.000
1:229431585:A:G	S350P	1.000
1:229431587:G:T	A349D	1.000
1:229431588:C:G	A349P	1.000
1:229431590:A:G	L348P	1.000
1:229431593:A:T	I347N	1.000
1:229431596:G:A	S346F	1.000
1:229431596:G:T	S346Y	1.000
1:229431597:A:G	S346P	1.000
1:229431599:C:A	G345V	1.000
1:229431599:C:T	G345D	1.000
1:229431600:C:G	G345R	1.000
1:229431602:C:A	G344V	1.000
1:229431602:C:T	G344D	1.000
1:229431603:C:A	G344C	1.000
1:229431603:C:G	G344R	1.000
1:229431603:C:T	G344S	1.000
1:229431607:C:A	W342C	1.000
1:229431607:C:G	W342C	1.000
1:229431609:A:G	W342R	1.000
1:229431609:A:T	W342R	1.000
1:229431624:G:T	R337S	1.000

dbSNP variants (sampled 300 via entrez): RS1000182791 (1:229430916 C>A,T), RS1000590116 (1:229436062 T>C), RS1001342110 (1:229435737 G>C), RS1001438168 (1:229435428 G>T), RS1001993472 (1:229430797 AAAAC>A), RS1002113014 (1:229435416 A>G), RS1002263124 (1:229431085 T>C), RS1002532948 (1:229435738 G>C), RS1003128897 (1:229434339 G>A), RS1003527120 (1:229434238 C>A,G), RS1004640381 (1:229434150 C>T), RS1004750934 (1:229435791 C>A), RS1006877797 (1:229431250 G>A), RS1007095495 (1:229431710 C>T), RS1008265049 (1:229431949 G>T)

Disease associations

OMIM: gene MIM:102610 | disease phenotypes: MIM:161800, MIM:236750, MIM:620278, MIM:620265, MIM:616852, MIM:115210, MIM:256030, MIM:117000, MIM:160150, MIM:208150, MIM:255310, MIM:617468

GenCC curated gene-disease

Disease	Classification	Inheritance
congenital myopathy 2a, typical, autosomal dominant	Definitive	Semidominant
congenital myopathy with excess of thin filaments	Definitive	Semidominant
congenital myopathy 2c, severe infantile, autosomal dominant	Strong	Autosomal dominant
alpha-actinopathy	Strong	Semidominant
severe congenital nemaline myopathy	Supportive	Autosomal recessive
intermediate nemaline myopathy	Supportive	Autosomal dominant
typical nemaline myopathy	Supportive	Autosomal dominant
childhood-onset nemaline myopathy	Supportive	Autosomal dominant
congenital fiber-type disproportion myopathy	Supportive	Autosomal dominant
progressive scapulohumeroperoneal distal myopathy	Supportive	Autosomal dominant
zebra body myopathy	Supportive	Unknown
rigid spine syndrome	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (2)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
alpha-actinopathy	Definitive	AR
alpha-actinopathy	Definitive	AD

Mondo (26): congenital myopathy 2a, typical, autosomal dominant (MONDO:0008070), congenital fiber-type disproportion myopathy (MONDO:0009711), alpha-actinopathy (MONDO:0100084), non-immune hydrops fetalis (MONDO:0009369), congenital myopathy 2c, severe infantile, autosomal dominant (MONDO:0859523), congenital myopathy 2b, severe infantile, autosomal recessive (MONDO:0859517), progressive scapulohumeroperoneal distal myopathy (MONDO:0014800), familial restrictive cardiomyopathy (MONDO:0016340), neuromuscular disease (MONDO:0019056), nemaline myopathy (MONDO:0018958), dilated cardiomyopathy (MONDO:0005021), congenital myopathy (MONDO:0019952), myopathy (MONDO:0005336), centronuclear myopathy (MONDO:0018947), fetal akinesia deformation sequence (MONDO:0008824)

Orphanet (12): Congenital myopathy with excess of thin filaments (Orphanet:98904), Congenital fiber-type disproportion myopathy (Orphanet:2020), Non-immune hydrops fetalis (Orphanet:363999), Progressive scapulohumeroperoneal distal myopathy (Orphanet:447977), Familial restrictive cardiomyopathy (Orphanet:217635), Neuromuscular disease (Orphanet:68381), Nemaline myopathy (Orphanet:607), Dilated cardiomyopathy (Orphanet:217604), Congenital myopathy (Orphanet:97245), Centronuclear myopathy (Orphanet:595), Arthrogryposis multiplex congenita (Orphanet:1037), Fetal akinesia deformation sequence (Orphanet:994)

HPO phenotypes

192 total (30 of 192 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000047	Hypospadias
HP:0000054	Micropenis
HP:0000218	High palate
HP:0000239	Large fontanelles
HP:0000275	Narrow face
HP:0000276	Long face
HP:0000278	Retrognathia
HP:0000298	Mask-like facies
HP:0000303	Mandibular prognathia
HP:0000316	Hypertelorism
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000369	Low-set ears
HP:0000467	Neck muscle weakness
HP:0000470	Short neck
HP:0000473	Torticollis
HP:0000508	Ptosis
HP:0000602	Ophthalmoplegia
HP:0000678	Dental crowding
HP:0000765	Abnormal thorax morphology
HP:0000767	Pectus excavatum
HP:0000774	Narrow chest
HP:0000775	Abnormality of the diaphragm
HP:0000883	Thin ribs
HP:0001181	Adducted thumb
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001265	Hyporeflexia

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST002299_13	Chronic lymphocytic leukemia	2.000000e-08
GCST004146_14	Chronic lymphocytic leukemia	1.000000e-15

MeSH disease descriptors (8)

Descriptor	Name	Tree numbers
D002311	Cardiomyopathy, Dilated	C14.280.195.160; C14.280.238.070; C16.320.488.750
D017696	Myopathies, Nemaline	C05.651.575.290; C10.668.491.550.290
D009468	Neuromuscular Diseases	C10.668
C579880	Actin-Accumulation Myopathy (supp.)
C580202	Intranuclear Rod Myopathy (supp.)
C538349	Nemaline Myopathy 2 (supp.)
C536647	Pena Shokeir syndrome, type 1 (supp.)
C535683	Rigid spine syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Doxorubicin	affects expression, decreases expression	5
Benzo(a)pyrene	affects methylation, decreases expression, increases expression, increases methylation	4
Valproic Acid	decreases expression, increases expression, increases methylation	3
Cyclosporine	increases expression, decreases expression	3
entinostat	decreases expression, affects cotreatment	2
Vorinostat	affects cotreatment, increases expression	2
Carbamazepine	affects expression	2
Daunorubicin	decreases expression	2
Mitoxantrone	decreases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Rotenone	decreases expression, increases expression	2
Silver	increases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, increases expression	2
aristolochic acid I	increases expression	1
ginger extract	decreases expression, decreases reaction, increases abundance	1
dicrotophos	increases expression	1
propionaldehyde	increases expression	1
bisphenol A	decreases expression, decreases reaction, increases abundance	1
tris(2-butoxyethyl) phosphate	affects expression	1
4-anisidine	decreases expression	1
arsenite	increases methylation	1
butyraldehyde	increases expression	1
testosterone-3-carboxymethyloxime-bovine serum albumin conjugate	decreases expression, decreases reaction	1
perfluorooctane sulfonic acid	decreases expression	1
cylindrospermopsin	decreases expression	1
thrombin receptor-activating peptide SFLLRNPNDKY	increases secretion	1
2,7-dihydroxynaphthalene	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression, increases expression	1
nutlin 3	affects cotreatment, increases secretion	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	decreases expression, decreases reaction	1

Cellosaurus cell lines

23 cell lines: 13 induced pluripotent stem cell, 8 transformed cell line, 2 finite cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A0LG	MCRIi024-A	Induced pluripotent stem cell	Male
CVCL_A0LH	MCRIi024-A-1	Induced pluripotent stem cell	Male
CVCL_A2TF	GM27890	Transformed cell line	Female
CVCL_A2VD	GM26112	Transformed cell line	Female
CVCL_A2VF	GM26114	Transformed cell line	Male
CVCL_A2VI	GM26117	Transformed cell line	Female
CVCL_A5FA	HPIi001-A	Induced pluripotent stem cell	Female
CVCL_A5FB	HPIi001-B	Induced pluripotent stem cell	Female
CVCL_A5FC	HPIi002-A	Induced pluripotent stem cell	Female
CVCL_A5FD	HPIi002-B	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00331656	PHASE4	UNKNOWN	Comparative Study of Non-Invasive Mask Ventilation vs Cuirass Ventilation in Patients With Acute Respiratory Failure.
NCT00994552	PHASE4	UNKNOWN	Comparison of Pressure Support and Pressure Control Ventilation in Chronic Respiratory Failure
NCT00374465	PHASE4	UNKNOWN	Therapy With Verapamil or Carvedilol in Chronic Heart Failure
NCT01293903	PHASE4	COMPLETED	Study of Qiliqiangxin Capsule to Treat Dilated Cardiomyopathy
NCT01557140	PHASE4	COMPLETED	A Randomized Trial of Carvedilol in Chronic Chagas Cardiomyopathy
NCT01917149	PHASE4	COMPLETED	Supramaximal Titrated Inhibition of RAAS in Dilated Cardiomyopathy
NCT02115581	PHASE4	COMPLETED	Coenzyme Q10 Supplementation in Children With Idiopathic Dilated Cardiomyopathy
NCT06236022	PHASE4	RECRUITING	The Effects of Sirolimus in Patients With Dilated Cardiomyopathy Infected With Kaposi Sarcoma-associated Virus
NCT00839033	PHASE3	TERMINATED	Evaluation of a Mechanical Device During Acute Respiratory Failure in Patients With Neuromuscular Disorders
NCT00942227	PHASE3	COMPLETED	The Value of Traction in Treatment of Lumbar Radiculopathy
NCT00979108	PHASE3	COMPLETED	The Value of Traction in the Treatment of Cervical Radiculopathy
NCT01826487	PHASE3	COMPLETED	Phase 3 Study of Ataluren in Participants With Nonsense Mutation Duchenne Muscular Dystrophy (nmDMD)
NCT02090959	PHASE3	TERMINATED	An Extension Study of Ataluren (PTC124) in Participants With Nonsense Mutation Dystrophinopathy
NCT02436096	PHASE3	COMPLETED	A Study to Evaluate eFFIcacy and Safety of Sublingual TNX-102 SL Tablet Taken at Bedtime in Patients With fibRoMyalgia
NCT02829814	PHASE3	TERMINATED	Repeat of: A Study to Evaluate Efficacy and Safety of Sublingual TNX-102 SL Tablet Taken at Bedtime in Patients With Fibromyalgia
NCT03179631	PHASE3	COMPLETED	Long-Term Outcomes of Ataluren in Duchenne Muscular Dystrophy
NCT05126758	PHASE3	ACTIVE_NOT_RECRUITING	A Study of Deramiocel (CAP-1002) in Ambulatory and Non-Ambulatory Patients With Duchenne Muscular Dystrophy
NCT05156320	PHASE3	COMPLETED	Efficacy and Safety of Apitegromab in Patients With Later-Onset Spinal Muscular Atrophy Treated With Nusinersen or Risdiplam
NCT05337553	PHASE3	ACTIVE_NOT_RECRUITING	A Study to Evaluate the Efficacy and Safety of Taldefgrobep Alfa in Participants With Spinal Muscular Atrophy
NCT05626855	PHASE3	ACTIVE_NOT_RECRUITING	Long-Term Safety & Efficacy of Apitegromab in Patients With SMA Who Completed Previous Trials of Apitegromab
NCT06672237	PHASE3	RECRUITING	A Phase 3 Study of NTLA-2001 in ATTRv-PN
NCT00333827	PHASE3	COMPLETED	Cell Therapy In Dilated Cardiomyopathy
NCT00505154	PHASE3	COMPLETED	Effect of Rosuvastatin on Left Ventricular Remodeling
NCT01223703	PHASE3	COMPLETED	PUFAs and Left Ventricular Function in Heart Failure
NCT01583114	PHASE3	TERMINATED	PREclinical Mutation CARriers From Families With DIlated Cardiomyopathy and ACE Inhibitors
NCT01914081	PHASE3	UNKNOWN	Resveratrol: A Potential Anti- Remodeling Agent in Heart Failure, From Bench to Bedside
NCT02989181	PHASE3	UNKNOWN	Continues Positive Airway Pressure Treatment for Patients With Dilated Cardiomyopathy and Obstructive Sleep Apnea
NCT03439514	PHASE3	TERMINATED	A Study of ARRY-371797 (PF-07265803) in Patients With Symptomatic Dilated Cardiomyopathy Due to a Lamin A/C Gene Mutation
NCT05237323	PHASE3	COMPLETED	Micophenolate Mofetil Versus Azathioprine in Myocarditis
NCT05849766	PHASE3	COMPLETED	Effect of Dapagliflozin on Cardiac Structure, Function and Secondary Mitral Regurgitation in Patients with Left Ventricle Dysfunction
NCT06250257	PHASE3	RECRUITING	Bromocriptine in Dilated Cardiomyopathy Among Women of Reproductive Age
NCT01074359	PHASE2	TERMINATED	Safety and Efficacy Study of A0001 in Patients With the A3243G Mitochondrial DNA Point Mutation
NCT01371149	PHASE2	COMPLETED	Patient -Ventilator Interaction in Chronic Respiratory Failure
NCT02022072	PHASE2	TERMINATED	Evaluation of Vital Capacity
NCT03127514	PHASE2	COMPLETED	AMX0035 in Patients With Amyotrophic Lateral Sclerosis (ALS)
NCT03406780	PHASE2	COMPLETED	A Study of CAP-1002 in Ambulatory and Non-Ambulatory Patients With Duchenne Muscular Dystrophy
NCT03921528	PHASE2	COMPLETED	An Active Treatment Study of SRK-015 in Patients With Type 2 or Type 3 Spinal Muscular Atrophy
NCT05479981	PHASE2	COMPLETED	Extension of AOC 1001-CS1 (MARINA) Study in Adult Myotonic Dystrophy Type 1 (DM1) Patients
NCT06339580	PHASE2	RECRUITING	Assessment of Volume-targeted Ventilation in Patients With Neuromuscular Disease
NCT07071935	PHASE2	NOT_YET_RECRUITING	A Clinical Trial of Early Ventilation in Amyotrophic Lateral Sclerosis (EVENT ALS)