ACTN2-related cardiac and skeletal myopathy

Summary

ACTN2-related cardiac and skeletal myopathy (MONDO:0700349) is a disease caused by ACTN2 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: ACTN2 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 3

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	ACTN2-related cardiac and skeletal myopathy
Mondo ID	MONDO:0700349
GARD	0028023
Is cancer (heuristic)	no

Also known as: ACTN2 familial isolated dilated cardiomyopathy · cardiomyopathy, dilated, 1AA, with or without LVNC · cardiomyopathy, hypertrophic, 23, with or without LVNC · CMD1AA · dilated cardiomyopathy 1AA with or without left ventricular noncompaction · dilated cardiomyopathy type 1AA · familial isolated dilated cardiomyopathy caused by mutation in ACTN2

Data availability: 3 ClinVar variants · 1 GenCC gene-disease record.

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › cardiogenetic disease › ACTN2-related cardiac and skeletal myopathy

Related subtypes (72): ventricular septal defect, hypoplastic left heart syndrome, familial cardiomyopathy, atrial septal defect, familial bicuspid aortic valve, Alagille syndrome, Holt-Oram syndrome, supravalvular aortic stenosis, tetralogy of fallot, DiGeorge syndrome, velocardiofacial syndrome, MGAT2-congenital disorder of glycosylation, dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome, heart defects-limb shortening syndrome, Sengers syndrome, CHARGE syndrome, Ehlers-Danlos syndrome, cardiac valvular type, Ellis-van Creveld syndrome, Larsen-like syndrome, B3GAT3 type, familial atrial myxoma, pericardial effusion, chronic, Peters plus syndrome, alveolar capillary dysplasia with misalignment of pulmonary veins, CHIME syndrome, TARP syndrome, cardiac valvular dysplasia, X-linked, Ehlers-Danlos syndrome, musculocontractural type, patent ductus arteriosus-bicuspid aortic valve-hand anomalies syndrome, postural orthostatic tachycardia syndrome, tricuspid atresia, patent ductus arteriosus, coronary artery disease, autosomal dominant, 1, coronary artery disease, autosomal dominant 2, COG1-congenital disorder of glycosylation, familial retinal arterial macroaneurysm, sinoatrial node dysfunction and deafness, congenital heart defects, multiple types, 3, congenital heart defects, multiple types, 2, 8q24.3 microdeletion syndrome, autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome, cardiac anomalies - developmental delay - facial dysmorphism syndrome, severe hypotonia-psychomotor developmental delay-strabismus-cardiac septal defect syndrome, transketolase deficiency, lethal left ventricular non-compaction-seizures-hypotonia-cataract-developmental delay syndrome, dextrocardia, LMNA-related cardiocutaneous progeria syndrome, dextro-looped transposition of the great arteries, familial atrioventricular septal defect, ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome, congenital vertebral-cardiac-renal anomalies syndrome, inherited mitral valve disease, Hordnes Engebretsen Knudtson syndrome, mehta lewis patton syndrome, congenital heart defects, multiple types, 5, structural congenital heart disease, multiple types - GATA4, congenital alveolar dysplasia due to FGF10, congenital alveolar dysplasia due to TBX4, GATA6-related congenital heart disease with or without pancreatic agenesis or neonatal diabetes, RBFOX2-related congenital heart disorder, ACTC1-related distal arthrogryposis with congenital heart disease, HAND1 related congenital heart defect, MYH-6 related congenital heart defects, HAND2 related congenital heart defect, congenital heart defects, multiple types, 8, with or without heterotaxy, congenital heart defects, multiple types, 9, cardiac conduction disease with or without cardiomyoopathy, fibromuscular dysplasia of the coronary arteries, TFAP2B-related congenital heart disease spectrum disorder, PLD1-related congenital heart disease, cardiogenetic rhythm disorder, TNNT2-related cardiomyopathy, NOTCH1-related AOS spectrum disorder

Subtypes (3): dilated cardiomyopathy 1AA, myopathy, congenital, with structured cores and z-line abnormalities, myopathy, distal, 6, adult-onset, autosomal dominant

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

3 retrieved; paginated sample, class counts are floors:

2 conflicting classifications of pathogenicity, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
837873	NM_001103.4(ACTN2):c.740C>T (p.Thr247Met)	ACTN2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1467366	NM_001103.4(ACTN2):c.1861C>T (p.Arg621Cys)	ACTN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3776379	NM_001103.4(ACTN2):c.749C>T (p.Ser250Phe)	ACTN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
ACTN2	Strong	Autosomal dominant	myopathy, congenital, with structured cores and z-line abnormalities	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ACTN2	Orphanet:154	Familial isolated dilated cardiomyopathy
ACTN2	Orphanet:708129	Autosomal recessive ACTN2-related distal myopathy
ACTN2	Orphanet:708133	Autosomal dominant ACTN2-related distal myopathy

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ACTN2	HGNC:164	ENSG00000077522	P35609	Alpha-actinin-2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ACTN2	Alpha-actinin-2	F-actin cross-linking protein which is thought to anchor actin to a variety of intracellular structures.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ACTN2	Other/Unknown	no		Actinin_actin-bd_CS, CH_dom, Spectrin_repeat

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
hindlimb stylopod muscle	1
skeletal muscle tissue of biceps brachii	1
skeletal muscle tissue of rectus abdominis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ACTN2	226	broad	marker	skeletal muscle tissue of rectus abdominis, skeletal muscle tissue of biceps brachii, hindlimb stylopod muscle

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ACTN2	2,781

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ACTN2	P35609	16

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 23. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
CREB1 phosphorylation through NMDA receptor-mediated activation of RAS signaling	1	878.5×	0.008	ACTN2
Ras activation upon Ca2+ influx through NMDA receptor	1	571.0×	0.008	ACTN2
Unblocking of NMDA receptors, glutamate binding and activation	1	543.8×	0.008	ACTN2
Negative regulation of NMDA receptor-mediated neuronal transmission	1	543.8×	0.008	ACTN2
Nephrin family interactions	1	475.8×	0.008	ACTN2
Long-term potentiation	1	475.8×	0.008	ACTN2
Striated Muscle Contraction	1	308.6×	0.011	ACTN2
Assembly and cell surface presentation of NMDA receptors	1	253.8×	0.011	ACTN2
Post NMDA receptor activation events	1	203.9×	0.012	ACTN2
Activation of NMDA receptors and postsynaptic events	1	184.2×	0.012	ACTN2
Response to elevated platelet cytosolic Ca2+	1	163.1×	0.013	ACTN2
Cell-Cell communication	1	137.6×	0.013	ACTN2
MAPK1/MAPK3 signaling	1	131.3×	0.013	ACTN2
Platelet activation, signaling and aggregation	1	105.7×	0.014	ACTN2
MAPK family signaling cascades	1	102.9×	0.014	ACTN2
Neurotransmitter receptors and postsynaptic signal transmission	1	100.2×	0.014	ACTN2
Platelet degranulation	1	87.8×	0.015	ACTN2
Muscle contraction	1	77.2×	0.016	ACTN2
Transmission across Chemical Synapses	1	76.1×	0.016	ACTN2
RAF/MAP kinase cascade	1	61.1×	0.019	ACTN2
Neuronal System	1	44.3×	0.025	ACTN2
Hemostasis	1	36.0×	0.029	ACTN2
Signal Transduction	1	10.2×	0.098	ACTN2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
actin filament uncapping	1	16852.0×	9e-04	ACTN2
phospholipase C-activating angiotensin-activated signaling pathway	1	5617.3×	0.001	ACTN2
microspike assembly	1	4213.0×	0.001	ACTN2
positive regulation of endocytic recycling	1	2808.7×	0.001	ACTN2
positive regulation of potassium ion transport	1	2106.5×	0.001	ACTN2
negative regulation of potassium ion transport	1	1872.4×	0.001	ACTN2
negative regulation of protein localization to cell surface	1	1296.3×	0.002	ACTN2
muscle cell development	1	936.2×	0.002	ACTN2
cardiac muscle cell development	1	624.1×	0.003	ACTN2
focal adhesion assembly	1	526.6×	0.003	ACTN2
sarcomere organization	1	383.0×	0.004	ACTN2
regulation of membrane potential	1	230.8×	0.006	ACTN2
protein localization to plasma membrane	1	108.7×	0.011	ACTN2
regulation of apoptotic process	1	83.4×	0.013	ACTN2
actin cytoskeleton organization	1	79.1×	0.013	ACTN2
cell adhesion	1	37.5×	0.027	ACTN2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ACTN2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	ACTN2

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
ACTN2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.