ACTN2

Summary

ACTN2 (actinin alpha 2, HGNC:164) is a protein-coding gene on chromosome 1q43, encoding Alpha-actinin-2 (P35609). F-actin cross-linking protein which is thought to anchor actin to a variety of intracellular structures.

Alpha actinins belong to the spectrin gene superfamily which represents a diverse group of cytoskeletal proteins, including the alpha and beta spectrins and dystrophins. Alpha actinin is an actin-binding protein with multiple roles in different cell types. In nonmuscle cells, the cytoskeletal isoform is found along microfilament bundles and adherens-type junctions, where it is involved in binding actin to the membrane. In contrast, skeletal, cardiac, and smooth muscle isoforms are localized to the Z-disc and analogous dense bodies, where they help anchor the myofibrillar actin filaments. This gene encodes a muscle-specific, alpha actinin isoform that is expressed in both skeletal and cardiac muscles. Several transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 88 — RefSeq curated summary.

At a glance

• Gene–disease (curated): ACTN2-related cardiac and skeletal myopathy (Definitive, ClinGen) — +6 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 1,875 total — 18 pathogenic, 19 likely-pathogenic
• Phenotypes (HPO): 54
• MANE Select transcript: NM_001103

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:164
Approved symbol	ACTN2
Name	actinin alpha 2
Location	1q43
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000077522
Ensembl biotype	protein_coding
OMIM	102573
Entrez	88

Gene structure

Transcript identifiers

Ensembl transcripts: 56 — 37 protein_coding, 13 retained_intron, 4 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000366578, ENST00000461367, ENST00000492101, ENST00000492634, ENST00000494762, ENST00000542672, ENST00000651091, ENST00000651187, ENST00000651275, ENST00000651781, ENST00000651786, ENST00000652096, ENST00000682015, ENST00000682490, ENST00000682692, ENST00000682966, ENST00000683075, ENST00000683111, ENST00000683322, ENST00000683805, ENST00000684050, ENST00000684122, ENST00000684286, ENST00000684502, ENST00000684763, ENST00000879531, ENST00000879532, ENST00000879533, ENST00000879534, ENST00000879535, ENST00000879536, ENST00000879537, ENST00000879538, ENST00000967348, ENST00000967349, ENST00000967350, ENST00000967351, ENST00000967352, ENST00000967353, ENST00000967354, ENST00000967355, ENST00000967356, ENST00000967357, ENST00000967358, ENST00000967359, ENST00000967360, ENST00000967361, ENST00000967362, ENST00000967363, ENST00000967364, ENST00000967365, ENST00000967366, ENST00000967367, ENST00000967368, ENST00000967369, ENST00000967370

RefSeq mRNA: 2 — MANE Select: NM_001103 NM_001103, NM_001278343

CCDS: CCDS1613, CCDS60455

Canonical transcript exons

ENST00000366578 — 21 exons

Exon	Start	End
ENSE00000908080	236751470	236751652
ENSE00000908082	236753947	236754081
ENSE00001442092	236762461	236764631
ENSE00001820573	236686499	236686799
ENSE00003486984	236755019	236755198
ENSE00003506339	236759724	236759789
ENSE00003528697	236739302	236739532
ENSE00003535150	236761015	236761173
ENSE00003535405	236720105	236720191
ENSE00003539831	236735635	236735720
ENSE00003548721	236757486	236757632
ENSE00003553097	236725933	236726020
ENSE00003611529	236717858	236717972
ENSE00003612377	236718894	236719013
ENSE00003624483	236731233	236731314
ENSE00003633662	236727678	236727756
ENSE00003643789	236742896	236743043
ENSE00003672038	236737122	236737214
ENSE00003722922	236749124	236749264
ENSE00003722977	236747667	236747775
ENSE00003739119	236744626	236744776

Expression profiles

Bgee: expression breadth ubiquitous, 226 present calls, max score 99.85.

FANTOM5 (CAGE): breadth broad, TPM avg 37.5968 / max 5363.2815, expressed in 593 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
9247	36.4489	568
9262	0.5498	79
9246	0.2390	82
9251	0.2001	56
202017	0.0725	21
9261	0.0515	27
9264	0.0212	9
9263	0.0137	5

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	99.85	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	99.83	gold quality
hindlimb stylopod muscle	UBERON:0004252	99.82	gold quality
biceps brachii	UBERON:0001507	99.80	gold quality
gluteal muscle	UBERON:0002000	99.80	gold quality
apex of heart	UBERON:0002098	99.80	gold quality
gastrocnemius	UBERON:0001388	99.77	gold quality
heart right ventricle	UBERON:0002080	99.77	gold quality
skeletal muscle tissue	UBERON:0001134	99.76	gold quality
triceps brachii	UBERON:0001509	99.75	gold quality
left ventricle myocardium	UBERON:0006566	99.75	gold quality
deltoid	UBERON:0001476	99.74	gold quality
body of tongue	UBERON:0011876	99.70	gold quality
diaphragm	UBERON:0001103	99.69	gold quality
tibialis anterior	UBERON:0001385	99.67	gold quality
myocardium	UBERON:0002349	99.66	gold quality
vastus lateralis	UBERON:0001379	99.65	gold quality
cardiac ventricle	UBERON:0002082	99.64	gold quality
heart left ventricle	UBERON:0002084	99.64	gold quality
quadriceps femoris	UBERON:0001377	99.63	gold quality
cardiac muscle of right atrium	UBERON:0003379	99.60	gold quality
cardiac atrium	UBERON:0002081	99.58	gold quality
right atrium auricular region	UBERON:0006631	99.57	gold quality
muscle organ	UBERON:0001630	98.54	gold quality
heart	UBERON:0000948	98.36	gold quality
muscle of leg	UBERON:0001383	98.09	gold quality
vena cava	UBERON:0004087	97.57	gold quality
muscle tissue	UBERON:0002385	97.44	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	96.51	gold quality
nucleus accumbens	UBERON:0001882	95.15	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-11268	no	1505.71
E-CURD-10	no	219.72
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

83 targeting ACTN2, 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-7110-3P	100.00	73.18	2486
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-5682	99.89	72.56	1005
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-137-3P	99.87	74.74	2401

Literature-anchored findings (GeneRIF, showing 33)

• Spectrin-like repeats from dystrophin and alpha-actinin-2 are not functionally interchangeable. (PMID:12140183)
• Association of Ca2+-activated K+ channel with alpha-actinin2 localizes channel to entry of external Ca(2+) source, which regulates channel function. (PMID:17110593)
• actinin-2 participate in sequestering parafibromin in the cytoplasmic compartment. (PMID:18687124)
• ACTN2 expression is affected by the content of alpha-actinin-3. (PMID:19150855)
• demonstrate that proper membrane localization of a small-conductance Ca(2+)-activated K(+) channel (SK2 or K(Ca)2.2) is dependent on its interacting protein, alpha-actinin2, a major F-actin crosslinking protein. (PMID:19815520)
• BPAG1-b was detectable in vitro and in vivo as a high molecular mass protein in striated and heart muscle cells, co-localizing with alpha-actinin-2 and partially with the cytolinker plectin as well as with the intermediate filament protein desmin. (PMID:19932097)
• This is the first genome-wide linkage analysis that shows mutations in ACTN2 cause HCM (PMID:20022194)
• This study generated the genomic sequences of K88-positive and F18-positive porcine enteroteoxigenic E. coli (ETEC) strains and examined the phylogenetic distribution of clinical porcine ETEC strains and their plasmid-associated genetic content. (PMID:22081385)
• data provide functional evidence that the primary sequences of alpha-actinin-2 and alpha-actinin-3 evolved differences to optimize their functions (PMID:22253474)
• Findigs show that the F-actin-binding protein alpha-actinin-2 targets CaMKIIalpha to F-actin in cells by binding to the CaMKII regulatory domain. (PMID:22427672)
• study strengthens the hypothesis that ACTN2 influences caries risk. (PMID:24810274)
• The novel heterozygous missense sequence variant ACTN2 cosegregated with a complex cardiomyopathic trait, characterized by the interplay of midapical, nonobstructive HCM, early onset of AF and AV block, as well as regional LV noncompaction. (PMID:25173926)
• Clinical evaluation of an Australian family revealed diverse cardiac pathologies in four affected members and genetic testing of the exome identified a pathogenic ACTN2 heterozygous variant (Ala119Thr) that co-segregated with disease. (PMID:25224718)
• Study reports a complete high-resolution structure of the 200 kDa alpha-actinin-2 dimer from striated muscle and explore its functional implications on the biochemical and cellular level. (PMID:25433700)
• the interaction between GNE and alpha-actinin 1 and alpha-actinin 2 occur at different sites in the alpha-actinin molecules and that for alpha-actinin 2 the interaction site is located at the C-terminus of the protein. (PMID:27023225)
• The full length mEos2 tagged protein expressed in adult cardiomyocytes shows that both mutations additionally affect Z-disc localization and dynamic behaviour (PMID:27287556)
• These results provide new insights into the regulation of SK2 channel trafficking by the cytoskeletal proteins FLNA and alpha-actinin2, involving distinct recycling pathways (PMID:27779751)
• A dual-beam optical tweezers measured the mechanics of alpha-actinin 2 and rabbit titin interaction at the single-molecule level. Depending on the direction of force application, the unbinding forces can more than triple. Multiple alpha-actinin/Z-repeat interactions cooperate to ensure long-term stable titin anchoring, while allowing the individual components to exchange dynamically. (PMID:28096424)
• A novel, likely pathogenic mutation (c.959T>G/p.L320R) of ACTN2 was identified in all individuals affected with dilated cardiomyopathy (DCM) and/or ventricular tachycardia. This study not only expands the spectrum of ACTN2 mutations and contributes to the genetic diagnosis and counseling of families with DCM and arrhythmia, but also provides a new case with overlap phenotype caused by an ACTN2 variant. (PMID:30630173)
• our data demonstrate that specific mutations in the well-known Z-line regulator alpha-actinin-2 can cause a skeletal muscle disorder (PMID:30701273)
• A unique missense mutation in ACTN2 was identified that is linked to a new genetically determined distal myopathy. (PMID:30900782)
• Cardiac MLC2 kinase is localized to the Z-disc and interacts with alpha-actinin2. (PMID:31467300)
• CTN2 (rs6655267) and MPPED2 (rs536007) are not associated with primary dentition caries. MPPED2 (rs11031093, G Allele) is marginally associated. (PMID:32040219)
• A putative causal variant associated with heart failure, in a cardiac muscle specific regulatory region activated during cardiomyocyte differentiation, binds to actinin alpha 2 (ACTN2) gene enhancer. Genome-editing in human embryonic stem cell-derived cardiomyocytes confirms the influence of the identified regulatory region in the expression of ACTN2. (PMID:32111823)
• Differential regulation of Actn2 and Actn3 expression during unfolded protein response in C2C12 myotubes. (PMID:32451822)
• Sleeping Beauty insertional mutagenesis screen identifies the pro-metastatic roles of CNPY2 and ACTN2 in hepatocellular carcinoma tumor progression. (PMID:33482578)
• Mono- and Biallelic Protein-Truncating Variants in Alpha-Actinin 2 Cause Cardiomyopathy Through Distinct Mechanisms. (PMID:34802252)
• ACTN2 Mutant Causes Proteopathy in Human iPSC-Derived Cardiomyocytes. (PMID:36078153)
• Mutation update for the ACTN2 gene. (PMID:36116040)
• Cardiomyopathy-associated variants alter the structure and function of the alpha-actinin-2 actin-binding domain. (PMID:37271035)
• Disruption of Z-Disc Function Promotes Mechanical Dysfunction in Human Myocardium: Evidence for a Dual Myofilament Modulatory Role by Alpha-Actinin 2. (PMID:37834023)
• Recurring homozygous ACTN2 variant (p.Arg506Gly) causes a recessive myopathy. (PMID:38311799)
• Actn2 defects accelerates H9c2 hypertrophy via ERK phosphorylation under chronic stress. (PMID:38990270)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	actn2b	ENSDARG00000071090
mus_musculus	Actn2	ENSMUSG00000052374
rattus_norvegicus	Actn2	ENSRNOG00000017833
caenorhabditis_elegans		WBGENE00000228

Paralogs (36): SYNE2 (ENSG00000054654), SPTB (ENSG00000070182), ACTN1 (ENSG00000072110), DSP (ENSG00000096696), DRP2 (ENSG00000102385), SPTBN1 (ENSG00000115306), MACF1 (ENSG00000127603), FLNC (ENSG00000128591), ACTN4 (ENSG00000130402), SYNE1 (ENSG00000131018), MICAL2 (ENSG00000133816), DTNA (ENSG00000134769), MICAL1 (ENSG00000135596), FLNB (ENSG00000136068), SPTBN5 (ENSG00000137877), DTNB (ENSG00000138101), GAS2L3 (ENSG00000139354), DST (ENSG00000151914), UTRN (ENSG00000152818), SPTBN4 (ENSG00000160460), SPTA1 (ENSG00000163554), CLMN (ENSG00000165959), PKHD1 (ENSG00000170927), SPTBN2 (ENSG00000173898), SYNE3 (ENSG00000176438), PLEC (ENSG00000178209), SMTNL2 (ENSG00000188176), FLNA (ENSG00000196924), SPTAN1 (ENSG00000197694), DMD (ENSG00000198947), PKHD1L1 (ENSG00000205038), DYTN (ENSG00000232125), MICAL3 (ENSG00000243156), ACTN3 (ENSG00000248746), EPPK1 (ENSG00000261150), GAS2L2 (ENSG00000270765)

Protein

Protein identifiers

Alpha-actinin-2 — P35609 (reviewed: P35609)

Alternative names: Alpha-actinin skeletal muscle isoform 2, F-actin cross-linking protein

All UniProt accessions (9): P35609, A0A494C031, A0A494C033, A0A494C060, A0A494C0Q3, A0A494C166, A0A494C1A0, A0A804HI95, A0A804HKG0

UniProt curated annotations — full annotation on UniProt →

Function. F-actin cross-linking protein which is thought to anchor actin to a variety of intracellular structures. This is a bundling protein.

Subunit / interactions. Homodimer; antiparallel. Also forms heterodimers with ACTN3. Interacts with ADAM12, MYOZ1, MYOZ2 and MYOZ3. Interacts via its C-terminal region with the LDB3 PDZ domain. Interacts with XIRP2. Interacts with DST isoform 1 (via N-terminus). Interacts with PARVB. Interacts with SYNPO2.

Subcellular location. Cytoplasm. Myofibril. Sarcomere. Z line.

Tissue specificity. Expressed in both skeletal and cardiac muscle.

Post-translational modifications. Ubiquitinated by FBXL22, leading to proteasomal degradation.

Disease relevance. Cardiomyopathy, familial hypertrophic, 23, with or without left ventricular non-compaction (CMH23) [MIM:612158] A hereditary heart disorder characterized by ventricular hypertrophy, which is usually asymmetric and often involves the interventricular septum. The symptoms include dyspnea, syncope, collapse, palpitations, and chest pain. They can be readily provoked by exercise. The disorder has inter- and intrafamilial variability ranging from benign to malignant forms with high risk of cardiac failure and sudden cardiac death. The disease is caused by variants affecting the gene represented in this entry. Cardiomyopathy, dilated, 1AA, with or without left ventricular non-compaction (CMD1AA) [MIM:612158] A disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death. The disease is caused by variants affecting the gene represented in this entry. Congenital myopathy 8 (CMYO8) [MIM:618654] An autosomal dominant muscular disorder characterized by progressive early-onset muscle weakness, gait difficulties, loss of ambulation, and respiratory insufficiency. Morphological and ultrastructural analyses of muscle biopsies reveal type 1 fiber predominance, multiple structured cores forming a circular arrangement beneath the sarcolemma, and jagged Z-lines. The disease is caused by variants affecting the gene represented in this entry. Myopathy, distal, 6, adult onset, autosomal dominant (MPD6) [MIM:618655] An autosomal dominant muscular disorder characterized by adult onset of asymmetric distal muscle weakness, primarily affecting the lower limbs and resulting in gait difficulties. Some patients develop involvement of proximal and upper limb muscles. The disease is caused by variants affecting the gene represented in this entry. Defects in ACTN2 may be the cause of an autosomal recessive myopathy characterized by asymmetric, progressive muscle weakness predominantly affecting the lower extremities. Patients do not manifest cardiomyopathy or respiratory insufficiency. Muscle biopsy reveals disruption of the inter-myofibrillar architecture, type I fiber predominance and atrophy.

Similarity. Belongs to the alpha-actinin family.

Isoforms (2)

UniProt ID	Names	Canonical?
P35609-1	1	yes
P35609-2	2

RefSeq proteins (2): NP_001094, NP_001265272 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001589	Actinin_actin-bd_CS	Conserved_site
IPR001715	CH_dom	Domain
IPR002017	Spectrin_repeat	Repeat
IPR002048	EF_hand_dom	Domain
IPR011992	EF-hand-dom_pair	Homologous_superfamily
IPR014837	EF-hand_Ca_insen	Domain
IPR018159	Spectrin/alpha-actinin	Repeat
IPR036872	CH_dom_sf	Homologous_superfamily

Pfam: PF00307, PF00435, PF08726, PF13499

UniProt features (83 total): helix 38, sequence variant 12, turn 8, strand 7, binding site 6, domain 4, repeat 4, chain 1, modified residue 1, splice variant 1, region of interest 1

Structure

Experimental structures (PDB)

16 structures.

PDB	Method	Resolution (Å)
6SWT	X-RAY DIFFRACTION	1.2
6TS3	X-RAY DIFFRACTION	1.28
7B56	X-RAY DIFFRACTION	1.45
7B55	X-RAY DIFFRACTION	1.6
5A37	X-RAY DIFFRACTION	1.88
5A38	X-RAY DIFFRACTION	1.9
7B57	X-RAY DIFFRACTION	1.95
5A36	X-RAY DIFFRACTION	2
5A4B	X-RAY DIFFRACTION	2.01
1QUU	X-RAY DIFFRACTION	2.5
7A8T	X-RAY DIFFRACTION	2.69
1HCI	X-RAY DIFFRACTION	2.8
7ANK	X-RAY DIFFRACTION	3.2
4D1E	X-RAY DIFFRACTION	3.5
7A8U	X-RAY DIFFRACTION	3.8
1H8B	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P35609-F1	84.88	0.47

Functional residue map

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

Ligand- & substrate-binding residues (6): 766; 770; 777; 802; 804; 808

Post-translational modifications (1): 237

Function

Pathways and Gene Ontology

Reactome pathways

23 pathways

ID	Pathway
R-HSA-114608	Platelet degranulation
R-HSA-373753	Nephrin family interactions
R-HSA-390522	Striated Muscle Contraction
R-HSA-438066	Unblocking of NMDA receptors, glutamate binding and activation
R-HSA-442982	Ras activation upon Ca2+ influx through NMDA receptor
R-HSA-5673001	RAF/MAP kinase cascade
R-HSA-9609736	Assembly and cell surface presentation of NMDA receptors
R-HSA-9617324	Negative regulation of NMDA receptor-mediated neuronal transmission
R-HSA-9620244	Long-term potentiation
R-HSA-109582	Hemostasis
R-HSA-112314	Neurotransmitter receptors and postsynaptic signal transmission
R-HSA-112315	Transmission across Chemical Synapses
R-HSA-112316	Neuronal System
R-HSA-1500931	Cell-Cell communication
R-HSA-162582	Signal Transduction
R-HSA-397014	Muscle contraction
R-HSA-438064	Post NMDA receptor activation events
R-HSA-442742	CREB1 phosphorylation through NMDA receptor-mediated activation of RAS signaling
R-HSA-442755	Activation of NMDA receptors and postsynaptic events
R-HSA-5683057	MAPK family signaling cascades
R-HSA-5684996	MAPK1/MAPK3 signaling
R-HSA-76002	Platelet activation, signaling and aggregation
R-HSA-76005	Response to elevated platelet cytosolic Ca2+

MSigDB gene sets: 445 (showing top): BROWNE_HCMV_INFECTION_30MIN_DN, GOBP_POTASSIUM_ION_TRANSPORT, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOCC_SECRETORY_GRANULE, REACTOME_PLATELET_ACTIVATION_SIGNALING_AND_AGGREGATION, GOBP_FOCAL_ADHESION_ASSEMBLY, GOBP_RESPONSE_TO_ANGIOTENSIN, GOBP_STRIATED_MUSCLE_CELL_DIFFERENTIATION, KEGG_TIGHT_JUNCTION, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_POSITIVE_REGULATION_OF_PROTEIN_CONTAINING_COMPLEX_DISASSEMBLY, GOBP_POSITIVE_REGULATION_OF_ORGANELLE_ORGANIZATION, GOBP_SARCOMERE_ORGANIZATION, GOBP_POSITIVE_REGULATION_OF_POTASSIUM_ION_TRANSPORT

GO Biological Process (20): cell adhesion (GO:0007155), microspike assembly (GO:0030035), actin cytoskeleton organization (GO:0030036), regulation of membrane potential (GO:0042391), regulation of apoptotic process (GO:0042981), negative regulation of potassium ion transport (GO:0043267), positive regulation of potassium ion transport (GO:0043268), sarcomere organization (GO:0045214), focal adhesion assembly (GO:0048041), actin filament uncapping (GO:0051695), muscle cell development (GO:0055001), cardiac muscle cell development (GO:0055013), protein localization to plasma membrane (GO:0072659), phospholipase C-activating angiotensin-activated signaling pathway (GO:0086097), negative regulation of protein localization to cell surface (GO:2000009), positive regulation of endocytic recycling (GO:2001137), positive regulation of DNA-templated transcription (GO:0045893), anatomical structure formation involved in morphogenesis (GO:0048646), postsynaptic actin cytoskeleton organization (GO:0098974), positive regulation of cation channel activity (GO:2001259)

GO Molecular Function (20): transcription coactivator activity (GO:0003713), integrin binding (GO:0005178), calcium ion binding (GO:0005509), phosphatidylinositol-4,5-bisphosphate binding (GO:0005546), cytoskeletal protein binding (GO:0008092), structural constituent of muscle (GO:0008307), protein domain specific binding (GO:0019904), LIM domain binding (GO:0030274), titin binding (GO:0031432), identical protein binding (GO:0042802), transmembrane transporter binding (GO:0044325), actin filament binding (GO:0051015), FATZ binding (GO:0051373), titin Z domain binding (GO:0070080), structural constituent of postsynaptic actin cytoskeleton (GO:0098973), channel activator activity (GO:0099103), actin binding (GO:0003779), protein binding (GO:0005515), protein-containing complex binding (GO:0044877), metal ion binding (GO:0046872)

GO Cellular Component (24): extracellular region (GO:0005576), cytosol (GO:0005829), cytoskeleton (GO:0005856), actin filament (GO:0005884), focal adhesion (GO:0005925), Z disc (GO:0030018), cell junction (GO:0030054), filopodium (GO:0030175), cortical actin cytoskeleton (GO:0030864), platelet alpha granule lumen (GO:0031093), pseudopodium (GO:0031143), cell projection (GO:0042995), dendritic spine (GO:0043197), extracellular exosome (GO:0070062), postsynaptic density membrane (GO:0098839), postsynaptic actin cytoskeleton (GO:0098871), glutamatergic synapse (GO:0098978), postsynaptic density, intracellular component (GO:0099092), cytoplasm (GO:0005737), plasma membrane (GO:0005886), actin cytoskeleton (GO:0015629), sarcomere (GO:0030017), synapse (GO:0045202), plasma membrane bounded cell projection (GO:0120025)

Reactome top-level categories

Rollup of top-11 pathways:

Category	Pathways
Activation of NMDA receptors and postsynaptic events	4
Post NMDA receptor activation events	2
Response to elevated platelet cytosolic Ca2+	1
Cell-Cell communication	1
Muscle contraction	1
CREB1 phosphorylation through NMDA receptor-mediated activation of RAS signaling	1
MAPK1/MAPK3 signaling	1
Transmission across Chemical Synapses	1
Neuronal System	1
Neurotransmitter receptors and postsynaptic signal transmission	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
protein binding	4
cytoskeletal protein binding	3
actin cytoskeleton	3
potassium ion transport	2
regulation of potassium ion transport	2
protein-containing complex binding	2
protein domain specific binding	2
binding	2
postsynapse	2
postsynaptic density	2
cellular process	1
plasma membrane bounded cell projection assembly	1
cytoskeleton organization	1
actin filament-based process	1
monoatomic ion transmembrane transport	1
regulation of biological quality	1
apoptotic process	1
regulation of programmed cell death	1
negative regulation of monoatomic ion transport	1
positive regulation of monoatomic ion transport	1
myofibril assembly	1
actomyosin structure organization	1
cell-substrate junction assembly	1
cell-matrix adhesion	1
positive regulation of actin filament depolymerization	1
muscle cell differentiation	1
cell development	1
striated muscle cell development	1
cardiac cell development	1
cardiac muscle cell differentiation	1
protein localization to membrane	1
protein localization to cell periphery	1
phospholipase C-activating G protein-coupled receptor signaling pathway	1
angiotensin-activated signaling pathway	1
protein localization to cell surface	1
negative regulation of protein localization	1
regulation of protein localization to cell surface	1
positive regulation of intracellular transport	1
endocytic recycling	1

Protein interactions and networks

STRING

2138 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ACTN2	TTN	Q8WZ42	992
ACTN2	MYOZ2	Q9NPC6	962
ACTN2	MYOZ1	Q9NP98	961
ACTN2	LDB3	O75112	947
ACTN2	PDLIM3	Q53GG5	922
ACTN2	MYOT	Q9UBF9	910
ACTN2	MYPN	Q86TC9	902
ACTN2	TCAP	O15273	899
ACTN2	CSRP3	P50461	874
ACTN2	TNNT2	P45379	866
ACTN2	GRIN2B	Q13224	865
ACTN2	VCL	P18206	833
ACTN2	MYH7	P12883	831
ACTN2	ACTA1	P02568	818
ACTN2	MYH6	P13533	812

IntAct

435 interactions, top by confidence:

A	B	Type	Score
ACTN2	ACTN2	psi-mi:“MI:0915”(physical association)	0.870
PDLIM1	ACTN4	psi-mi:“MI:0914”(association)	0.800
SNAI1	ACTN2	psi-mi:“MI:0915”(physical association)	0.780
SAXO1	ACTN2	psi-mi:“MI:0915”(physical association)	0.780
ACTN2	MYOZ2	psi-mi:“MI:0915”(physical association)	0.780
RTP5	ACTN2	psi-mi:“MI:0915”(physical association)	0.780
BRMS1L	ACTN2	psi-mi:“MI:0915”(physical association)	0.780
ACTN2	MICALL2	psi-mi:“MI:0915”(physical association)	0.780
ACTN2	SNAI1	psi-mi:“MI:0915”(physical association)	0.780
ACTN2	SAXO1	psi-mi:“MI:0915”(physical association)	0.780
MYOZ2	ACTN2	psi-mi:“MI:0915”(physical association)	0.780
ACTN2	RTP5	psi-mi:“MI:0915”(physical association)	0.780
ACTN2	BRMS1L	psi-mi:“MI:0915”(physical association)	0.780
MICALL2	ACTN2	psi-mi:“MI:0915”(physical association)	0.780

BioGRID (208): ACTN2 (Two-hybrid), MOS (Two-hybrid), SNAI1 (Two-hybrid), SP100 (Two-hybrid), PDLIM3 (Two-hybrid), MYOZ2 (Two-hybrid), MICALL2 (Two-hybrid), BRMS1L (Two-hybrid), FAM154A (Two-hybrid), RTP5 (Two-hybrid), ACTN2 (Two-hybrid), ACTN2 (Affinity Capture-MS), ACTN2 (Two-hybrid), ACTN2 (Co-fractionation), ACTN2 (Co-fractionation)

ESM2 similar proteins: A5D7D1, L7UZ85, O43707, O88990, P05094, P11277, P12814, P15508, P18091, P20111, P26232, P30997, P35609, P46940, P57780, Q00078, Q00963, Q01082, Q08043, Q0E908, Q0III9, Q13576, Q2PFV7, Q3B7N2, Q3UQ44, Q3ZC55, Q4QR29, Q4WVG0, Q5M7J9, Q5R416, Q5RCS6, Q61301, Q62018, Q62261, Q6DEU9, Q6INS3, Q6NXC0, Q6PD62, Q7G188, Q7PKQ5

Diamond homologs: A5D7D1, D3ZEN0, D3ZHA0, D3ZHV2, D3ZQL6, E1BBG2, F1MF74, F1RA39, F6QZ15, G3MWR8, G3V7L1, L7UZ85, M9MRD1, O13728, O15020, O43707, O75369, O76329, O88990, O94851, O97592, P05094, P05095, P07751, P11277, P11530, P11531, P11532, P11533, P12814, P13395, P13466, P15508, P16086, P16546, P18091, P20111, P21333, P30427, P35609

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

1875 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	18
Likely pathogenic	19
Uncertain significance	858
Likely benign	604
Benign	109

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
147606	GRCh38/hg38 1q42.3-43(chr1:235387992-237270632)x3	Pathogenic
148480	GRCh38/hg38 1q43-44(chr1:236556082-248918469)x1	Pathogenic
1527626	GRCh37/hg19 1q42.2-43(chr1:232226609-241010904)	Pathogenic
1711168	GRCh37/hg19 1q42.2-44(chr1:233012994-249206918)x1	Pathogenic
1808740	GRCh37/hg19 1q42.2-43(chr1:232732121-243338216)x1	Pathogenic
189516	NM_001103.4(ACTN2):c.2276G>C (p.Arg759Thr)	Pathogenic
189517	NM_001103.4(ACTN2):c.1883A>G (p.Glu628Gly)	Pathogenic
201635	NM_001103.4(ACTN2):c.2527-1G>A	Pathogenic
201650	NM_001103.4(ACTN2):c.2578C>T (p.Gln860Ter)	Pathogenic
253636	GRCh37/hg19 1q42.2-44(chr1:234050864-249213059)x3	Pathogenic
2685865	GRCh37/hg19 1q42.13-43(chr1:230231959-238032346)x1	Pathogenic
3063443	GRCh37/hg19 1q42.2-43(chr1:233813555-240578304)x1	Pathogenic
3247621	NC_000001.10:g.(?235275379)(236899040_?)del	Pathogenic
393997	GRCh37/hg19 1q42.2-44(chr1:231670870-249213000)x3	Pathogenic
4075274	NM_001103.4(ACTN2):c.210dup (p.Lys71Ter)	Pathogenic
441651	GRCh37/hg19 1q42.2-43(chr1:234605553-240932205)x1	Pathogenic
441937	GRCh37/hg19 1q42.3-44(chr1:235797384-249224684)x1	Pathogenic
685476	GRCh37/hg19 1q42.3-44(chr1:235582580-249224684)x3	Pathogenic
1326967	NM_001103.4(ACTN2):c.698-2A>G	Likely pathogenic
1333296	NM_001103.4(ACTN2):c.311T>A (p.Leu104Ter)	Likely pathogenic
1343346	NM_001103.4(ACTN2):c.1167_1169delinsA (p.Leu390fs)	Likely pathogenic
1678113	NM_001103.4(ACTN2):c.2301+1G>T	Likely pathogenic
1678144	NM_001103.4(ACTN2):c.796del (p.Ala266fs)	Likely pathogenic
189519	NM_001103.4(ACTN2):c.683T>C (p.Met228Thr)	Likely pathogenic
3068664	NM_001103.4(ACTN2):c.239C>G (p.Ser80Ter)	Likely pathogenic
3254576	NM_001103.4(ACTN2):c.1378C>T (p.Gln460Ter)	Likely pathogenic
429420	NM_001103.4(ACTN2):c.352G>T (p.Gly118Cys)	Likely pathogenic
4528932	NM_001103.4(ACTN2):c.448+1115_615+666del	Likely pathogenic
4530632	NM_001103.4(ACTN2):c.1840-1G>A	Likely pathogenic
4531403	NM_001103.4(ACTN2):c.1661del (p.Leu554fs)	Likely pathogenic

SpliceAI

3390 predictions. Top by Δscore:

Variant	Effect	Δscore
1:236686796:G:GT	donor_gain	1.0000
1:236686797:A:T	donor_gain	1.0000
1:236686797:AAGGT:A	donor_loss	1.0000
1:236686799:GGT:G	donor_loss	1.0000
1:236717853:TGCA:T	acceptor_loss	1.0000
1:236717854:GCAG:G	acceptor_loss	1.0000
1:236717855:CA:C	acceptor_loss	1.0000
1:236717856:A:AG	acceptor_gain	1.0000
1:236717857:G:GC	acceptor_gain	1.0000
1:236717857:GA:G	acceptor_gain	1.0000
1:236717857:GAC:G	acceptor_gain	1.0000
1:236717857:GACC:G	acceptor_gain	1.0000
1:236717857:GACCT:G	acceptor_gain	1.0000
1:236717932:G:GT	donor_gain	1.0000
1:236717937:GCCT:G	donor_gain	1.0000
1:236717960:G:GT	donor_gain	1.0000
1:236717970:CAGG:C	donor_loss	1.0000
1:236717972:GG:G	donor_loss	1.0000
1:236717974:T:G	donor_loss	1.0000
1:236719011:AAG:A	donor_loss	1.0000
1:236719012:AG:A	donor_loss	1.0000
1:236719013:GGT:G	donor_loss	1.0000
1:236719014:G:C	donor_loss	1.0000
1:236719015:T:A	donor_loss	1.0000
1:236720097:A:AG	acceptor_gain	1.0000
1:236720098:C:G	acceptor_gain	1.0000
1:236720100:TGCAG:T	acceptor_loss	1.0000
1:236720101:GCA:G	acceptor_loss	1.0000
1:236720102:CA:C	acceptor_loss	1.0000
1:236720103:A:AC	acceptor_loss	1.0000

AlphaMissense

5985 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:236686781:G:C	W36C	1.000
1:236686781:G:T	W36C	1.000
1:236686792:A:C	Q40P	1.000
1:236686793:G:C	Q40H	1.000
1:236686793:G:T	Q40H	1.000
1:236717861:T:C	F44L	1.000
1:236717862:T:C	F44S	1.000
1:236717862:T:G	F44C	1.000
1:236717863:C:A	F44L	1.000
1:236717863:C:G	F44L	1.000
1:236717870:T:A	W47R	1.000
1:236717870:T:C	W47R	1.000
1:236717871:G:C	W47S	1.000
1:236717872:G:C	W47C	1.000
1:236717872:G:T	W47C	1.000
1:236717873:T:C	C48R	1.000
1:236717874:G:A	C48Y	1.000
1:236717875:T:G	C48W	1.000
1:236717882:C:G	H51D	1.000
1:236717886:T:C	L52P	1.000
1:236717936:G:C	G69R	1.000
1:236717936:G:T	G69C	1.000
1:236717937:G:A	G69D	1.000
1:236717937:G:T	G69V	1.000
1:236717946:T:A	L72H	1.000
1:236717946:T:C	L72P	1.000
1:236717955:T:C	L75P	1.000
1:236717958:T:C	L76S	1.000
1:236717958:T:G	L76W	1.000
1:236718921:G:A	G90E	1.000

dbSNP variants (sampled 300 via entrez): RS1000009390 (1:236729417 G>A), RS1000026426 (1:236685843 G>A), RS1000101176 (1:236690062 T>C,G), RS1000142016 (1:236702098 G>A), RS1000196078 (1:236694763 T>C), RS1000292193 (1:236761934 G>A), RS1000301617 (1:236687166 C>T), RS1000315178 (1:236733064 C>G), RS1000337105 (1:236733667 C>T), RS1000392646 (1:236738291 G>A), RS1000406168 (1:236704768 A>G), RS1000424015 (1:236738569 C>T), RS1000434332 (1:236698179 T>C), RS1000454799 (1:236737787 A>G), RS1000457581 (1:236727749 T>A,G)

Disease associations

OMIM: gene MIM:102573 | disease phenotypes: MIM:612158, MIM:192600, MIM:618654, MIM:618655, MIM:600996, MIM:604772, MIM:117000, MIM:214500, MIM:604169, MIM:187500, MIM:194200, MIM:115200

GenCC curated gene-disease

Disease	Classification	Inheritance
myopathy, congenital, with structured cores and z-line abnormalities	Strong	Autosomal dominant
ACTN2-related cardiac and skeletal myopathy	Strong	Autosomal dominant
dilated cardiomyopathy 1AA	Moderate	Autosomal dominant
intrinsic cardiomyopathy	Moderate	Autosomal dominant
familial isolated dilated cardiomyopathy	Supportive	Autosomal dominant
heart conduction disease	Limited	Autosomal dominant
myopathy, distal, 6, adult-onset, autosomal dominant	Limited	Unknown

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
ACTN2-related cardiac and skeletal myopathy	Definitive	AD

Mondo (28): dilated cardiomyopathy 1AA (MONDO:0012808), familial hypertrophic cardiomyopathy (MONDO:0024573), myopathy, congenital, with structured cores and z-line abnormalities (MONDO:0032852), myopathy, distal, 6, adult-onset, autosomal dominant (MONDO:0032853), catecholaminergic polymorphic ventricular tachycardia 1 (MONDO:0011484), cardiomyopathy (MONDO:0004994), intrinsic cardiomyopathy (MONDO:0000591), ACTN2-related cardiac and skeletal myopathy (MONDO:0700349), hypertrophic cardiomyopathy (MONDO:0005045), dilated cardiomyopathy (MONDO:0005021), cardiomyopathy, familial hypertrophic, 23, with or without ventricular noncompaction (MONDO:0800347), hypertrophic cardiomyopathy 1 (MONDO:0008647), ventricular fibrillation (MONDO:0000190), central core myopathy (MONDO:0007294), neuromuscular disease (MONDO:0019056)

Orphanet (15): Familial isolated dilated cardiomyopathy (Orphanet:154), Rare familial disorder with hypertrophic cardiomyopathy (Orphanet:99739), Catecholaminergic polymorphic ventricular tachycardia (Orphanet:3286), Rare cardiomyopathy (Orphanet:167848), Rare hypertrophic cardiomyopathy (Orphanet:217569), Dilated cardiomyopathy (Orphanet:217604), Central core disease (Orphanet:597), Neuromuscular disease (Orphanet:68381), Chédiak-Higashi syndrome (Orphanet:167), Left ventricular noncompaction (Orphanet:54260), Tetralogy of Fallot (Orphanet:3303), Familial dilated cardiomyopathy (Orphanet:217607), Familial dilated cardiomyopathy with conduction defect due to LMNA mutation (Orphanet:300751), NON RARE IN EUROPE: Familial isolated hypertrophic cardiomyopathy (Orphanet:155), NON RARE IN EUROPE: Wolff-Parkinson-White syndrome (Orphanet:907)

HPO phenotypes

54 total (30 of 54 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000218	High palate
HP:0000407	Sensorineural hearing impairment
HP:0000597	Ophthalmoparesis
HP:0000969	Edema
HP:0001288	Gait disturbance
HP:0001290	Generalized hypotonia
HP:0001324	Muscle weakness
HP:0001635	Congestive heart failure
HP:0001639	Hypertrophic cardiomyopathy
HP:0001640	Cardiomegaly
HP:0001644	Dilated cardiomyopathy
HP:0001678	Atrioventricular block
HP:0001695	Cardiac arrest
HP:0001706	Endocardial fibroelastosis
HP:0001712	Left ventricular hypertrophy
HP:0001727	Thromboembolic stroke
HP:0002093	Respiratory insufficiency
HP:0002460	Distal muscle weakness
HP:0002650	Scoliosis
HP:0002792	Reduced vital capacity
HP:0002875	Exertional dyspnea
HP:0003198	Myopathy
HP:0003236	Elevated circulating creatine kinase concentration
HP:0003457	EMG abnormality
HP:0003557	Increased variability in muscle fiber diameter
HP:0003621	Juvenile onset
HP:0003693	Distal amyotrophy
HP:0003701	Proximal muscle weakness
HP:0003736	Autophagic vacuoles

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST002126_16	Periodontitis (CDC/AAP)	3.000000e-06
GCST009391_795	Metabolite levels	7.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0010395	sphingomyelin 22:0 measurement

MeSH disease descriptors (14)

Descriptor	Name	Tree numbers
D009202	Cardiomyopathies	C14.280.238
D002311	Cardiomyopathy, Dilated	C14.280.195.160; C14.280.238.070; C16.320.488.750
D002312	Cardiomyopathy, Hypertrophic	C14.280.238.100; C14.280.484.048.750.070.160
D024741	Cardiomyopathy, Hypertrophic, Familial	C14.280.238.100.500; C14.280.484.048.750.070.160.500; C16.320.160
D002609	Chediak-Higashi Syndrome	C11.270.040.772; C15.378.553.774.257; C16.320.798.375; C20.673.774.257; C20.673.795.375
D008133	Long QT Syndrome	C14.280.067.565; C14.280.123.625; C16.131.240.400.715; C23.550.073.547
D020512	Myopathy, Central Core	C05.651.575.300; C10.668.491.550.300
D009468	Neuromuscular Diseases	C10.668
D013771	Tetralogy of Fallot	C14.240.400.849; C14.280.400.849; C16.131.240.400.849
D014693	Ventricular Fibrillation	C14.280.067.922; C23.550.073.922
D014927	Wolff-Parkinson-White Syndrome	C14.280.067.780.977; C14.280.123.750.977; C16.131.240.400.980
C563409	Arrhythmogenic Right Ventricular Dysplasia, Familial, 2 (supp.)
C567407	Cardiomyopathy, Dilated, 1AA (supp.)
C536231	familial dilated cardiomyopathy (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects cotreatment, decreases methylation, increases expression	2
Benzo(a)pyrene	affects methylation, increases methylation	2
Cadmium	decreases expression, increases abundance, increases expression	2
Cocaine	increases expression	2
Doxorubicin	affects expression, increases expression	2
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
glycidyl methacrylate	increases expression	1
ascorbate-2-phosphate	affects binding, affects cotreatment, increases expression	1
sodium arsenite	increases expression	1
benzo(e)pyrene	increases methylation	1
4-(2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic acid	affects cotreatment, decreases expression	1
S-(1,2-dichlorovinyl)cysteine	decreases reaction, increases expression	1
JP8 aviation fuel	decreases expression	1
monomethylarsonous acid	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
Chir 99021	affects cotreatment, decreases expression, affects binding, increases expression	1
abrine	increases expression	1
bisphenol S	decreases methylation	1
XAV939	affects binding, affects cotreatment, increases expression, decreases expression	1
incobotulinumtoxinA	decreases expression	1
LDN 193189	affects cotreatment, increases expression	1
3-(4-pyridyl)-1H-indole	affects cotreatment, decreases expression	1
Sunitinib	decreases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Acetaminophen	decreases expression	1
Ascorbic Acid	affects binding, affects cotreatment, decreases expression	1
Heroin	decreases expression	1
Hydrocortisone	affects cotreatment, decreases expression	1
Lead	affects expression	1
Lipopolysaccharides	increases expression, decreases reaction	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00348530	PHASE4	UNKNOWN	Carvedilol Versus Verapamil in Chronic Heart Failure Secondary to Non-Ischemic Cardiomyopathy
NCT00371891	PHASE4	COMPLETED	Ontario Multidetector Computed Tomographic (MDCT) Coronary Angiography Study (OMCAS)
NCT00401856	PHASE4	COMPLETED	CMR to Assess Fibrosis in Cardiomyopathy Using Eplerenone
NCT00559338	PHASE4	COMPLETED	Impact of Nesiritide Infusion for Decompensated Heart Failure in the Emergency Department
NCT00606775	PHASE4	UNKNOWN	The Preventive Efficacy of Carvedilol on Cardiac Dysfunction in Duchenne Muscular Dystrophy
NCT00658203	PHASE4	COMPLETED	Clinical Evaluation on Advanced Resynchronization
NCT00701220	PHASE4	COMPLETED	Statin Therapy for Ischemic and Nonischemic Cardiomyopathy
NCT00800761	PHASE4	COMPLETED	Intensive Combined Chelation Therapy for Iron-Induced Cardiac Disease in Patients With Thalassemia Major
NCT00806390	PHASE4	TERMINATED	Prevention of Anthracycline or Trastuzumab Induced Cardiomyopathy by Metoprolol
NCT01006473	PHASE4	COMPLETED	Exercise Training in Chagas Cardiomyopathy
NCT01261065	PHASE4	COMPLETED	Mechanisms of Improvement With Beta-Blocker Treatment in Heart Failure
NCT01345188	PHASE4	COMPLETED	Ranolazine in Ischemic Cardiomyopathy
NCT01868841	PHASE4	COMPLETED	123-I mIBG (AdreView) Heart-to-Mediastinal (H/M) Ratio and SPECT Imaging on a Small Field of View-High Efficiency Cardiac SPECT System
NCT02640846	PHASE4	UNKNOWN	Effects of Levosimendan, Milrinone and Norepinephrine on Left and Right Ventricular Function in Septic Shock
NCT03228823	PHASE4	UNKNOWN	Prospective Assessment of Premature Ventricular Contractions Suppression in Cardiomyopathy(PAPS)
NCT04323852	PHASE4	COMPLETED	Can Vitamin D Reduce Heart Muscle Damage After Bypass Surgery?
NCT05034432	PHASE4	RECRUITING	The PIVATAL Study -Study of Ventricular Arrhythmia (VTA) Ablation in Left Ventricular Assist Device (LVAD) Patients
NCT05718128	PHASE4	RECRUITING	Clinical Study of Endocardial Myocardial Biopsy
NCT06964464	PHASE4	RECRUITING	Comparative Effectiveness of Carvedilol Versus Metoprolol Succinate in Heart Failure Patients With an Implantable Cardioverter Defibrillator
NCT00170183	PHASE3	COMPLETED	Brain Natriuretic Peptide (BNP) to Preserve Renal Function in Hospitalized Patients With Heart Failure
NCT00270387	PHASE3	COMPLETED	A Study of Short-Term Outcomes and Economic Impact For Patients With Worsening Congestive Heart Failure When Natrecor (Nesiritide) is Added to Standard-Care Therapy, Compared to Administration of Placebo With Standard-Care Therapy
NCT00321295	PHASE3	COMPLETED	Biventricular Pacing In Patients With Left Ventricular Dysfunction After Cardiovascular Surgery
NCT00483197	PHASE3	UNKNOWN	VentrAssistTM LVAD as a Bridge to Cardiac Transplantation - Pivotal Trial
NCT00490321	PHASE3	UNKNOWN	VentrAssistTM LVAD for the Treatment of Advanced Heart Failure - Destination Therapy
NCT00626028	PHASE3	COMPLETED	Comparison of Inhaled Nitric Oxide and Oxygen in Participants Reactivity During Acute Pulmonary Vasodilator Testing
NCT01013714	PHASE3	UNKNOWN	Cardiac Sympathetic Denervation for Prevention of Ventricular Tachyarrhythmias
NCT01217827	PHASE3	COMPLETED	Implantable Cardioverter-Defibrillator Use in the VA System
NCT01648634	PHASE3	COMPLETED	Nebivolol for the Prevention of Left Ventricular Systolic Dysfunction in Patients With Duchenne Muscular Dystrophy
NCT02924285	PHASE3	COMPLETED	Catheter Ablation Versus Amiodarone for Therapy of Premature Ventricular Contractions in Patients With Structural Heart Disease
NCT03860935	PHASE3	COMPLETED	Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy
NCT04166331	PHASE3	COMPLETED	Adjunctive DobutAmine in sePtic Cardiomyopathy With Tissue Hypoperfusion
NCT05175066	PHASE3	COMPLETED	Bisoprolol Administration to Prevent Anthracycline-induced Cardiotoxicity
NCT05237323	PHASE3	COMPLETED	Micophenolate Mofetil Versus Azathioprine in Myocarditis
NCT06158698	PHASE3	RECRUITING	CMP-MYTHiC Trial and Registry - CardioMyoPathy With MYocarditis THerapy With Colchicine
NCT06563895	PHASE3	RECRUITING	Acoramidis Transthyretin Amyloidosis Prevention Trial in the Young (ACT-EARLY) Study in Asymptomatic Carriers of a Pathogenic TTR Variant
NCT06846086	PHASE3	RECRUITING	Cardioprotective Effects of Melatonin in Patients With Cardiomyopathy
NCT07116473	PHASE3	NOT_YET_RECRUITING	To Evaluate the Long-term Safety and Tolerability of Acoramidis in Participants With Newly Diagnosed ATTR-CM (ACT-EARLY OLE)
NCT05122975	PHASE2	TERMINATED	Treatment of an Inherited Ventricular Arrhythmia
NCT06005428	PHASE2	TERMINATED	Effectiveness of CRD-4730 in Participants With Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)
NCT00185250	PHASE2	COMPLETED	Betaferon/ Betaseron (Interferon Beta-1b) in Patients With Chronic Viral Cardiomyopathy