Myopathy, congenital, with structured cores and z-line abnormalities

Summary

Myopathy, congenital, with structured cores and z-line abnormalities (MONDO:0032852) 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: 103

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	myopathy, congenital, with structured cores and z-line abnormalities
Mondo ID	MONDO:0032852
OMIM	618654
DOID	DOID:0081342
UMLS	C5231445
MedGen	1684705
GARD	0025759
Is cancer (heuristic)	no

Also known as: MYOCOZ · myopathy, congenital with structured cores and z-line abnormalities

Data availability: 103 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › muscle tissue disorder › skeletal muscle disorder › myopathy › congenital myopathy › myopathy, congenital, with structured cores and z-line abnormalities

Related subtypes (53): Ullrich congenital muscular dystrophy, congenital structural myopathy, Bethlem myopathy, MYH7-related skeletal myopathy, tubular aggregate myopathy, cylindrical spirals myopathy, congenital myopathy 7A, myosin storage, autosomal dominant, intellectual disability-myopathy-short stature-endocrine defect syndrome, myopathy, myosin storage, autosomal recessive, Bailey-Bloch congenital myopathy, fingerprint body myopathy, myopathy, proximal, and ophthalmoplegia, Compton-North congenital myopathy, MEGF10-related myopathy, fetal akinesia-cerebral and retinal hemorrhage syndrome, Klippel-Feil anomaly-myopathy-facial dysmorphism syndrome, severe hypotonia-psychomotor developmental delay-strabismus-cardiac septal defect syndrome, myopathy with hexagonally cross-linked tubular arrays, benign Samaritan congenital myopathy, congenital generalized hypercontractile muscle stiffness syndrome, hyaline body myopathy, centronuclear myopathy, reducing body myopathy, myopathy, congenital, with tremor, myopathy, congenital, progressive, with scoliosis, myopathy, congenital, with respiratory insufficiency and bone fractures, myopathy, congenital proximal, with minicore lesions, myopathy, congenital, with diaphragmatic defects, respiratory insufficiency, and dysmorphic facies, congenital myopathy with reduced type 2 muscle fibers, alpha-actinopathy, SELENON-related myopathy, TPM3-related myopathy, SCN4A-related myopathy, autosomal recessive, RYR1-related myopathy, TTN-related myopathy, TPM2-related myopathy, Batten-Turner congenital myopathy, TOR1AIP1-related myopathy, congenital myopathy 11, congenital myopathy 15, congenital myopathy 18, congenital myopathy 10b, mild variant, congenital myopathy 2b, severe infantile, autosomal recessive, congenital myopathy 2c, severe infantile, autosomal dominant, congenital myopathy 20, congenital myopathy 21 with early respiratory failure, congenital myopathy 22A, classic, congenital myopathy 22B, severe fetal, congenital myopathy 25, congenital myopathy 26, congenital myopathy 27, congenital myopathy 28 with rigid spine, congenital myopathy 29 with contractures

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

103 retrieved; paginated sample, class counts are floors:

43 conflicting classifications of pathogenicity, 35 uncertain significance, 10 benign, 7 likely benign, 6 benign/likely benign, 1 pathogenic/likely pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
694345	NM_001103.4(ACTN2):c.2180T>G (p.Leu727Arg)	ACTN2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
694346	NM_001103.4(ACTN2):c.2194_2226del (p.Ala732_Ile742del)	ACTN2	Likely pathogenic	criteria provided, single submitter
1042730	NM_001103.4(ACTN2):c.21C>T (p.Gly7=)	ACTN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1220240	NM_001103.4(ACTN2):c.2069A>G (p.Asn690Ser)	ACTN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1315602	NM_001103.4(ACTN2):c.1589A>G (p.Asn530Ser)	ACTN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1395077	NM_001103.4(ACTN2):c.1342G>C (p.Glu448Gln)	ACTN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1408568	NM_001103.4(ACTN2):c.1707C>A (p.Asp569Glu)	ACTN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1416359	NM_001103.4(ACTN2):c.1025A>G (p.Glu342Gly)	ACTN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1502253	NM_001103.4(ACTN2):c.1117G>A (p.Gly373Ser)	ACTN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
179767	NM_001103.4(ACTN2):c.1899T>G (p.His633Gln)	ACTN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1803012	NM_001103.4(ACTN2):c.937A>T (p.Met313Leu)	ACTN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
18313	NM_001103.4(ACTN2):c.26A>G (p.Gln9Arg)	ACTN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1952588	NM_001103.4(ACTN2):c.2024T>C (p.Met675Thr)	ACTN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
201627	NM_001103.4(ACTN2):c.278G>A (p.Arg93Gln)	ACTN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
201647	NM_001103.4(ACTN2):c.2194G>A (p.Ala732Thr)	ACTN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
201649	NM_001103.4(ACTN2):c.2567C>T (p.Pro856Leu)	ACTN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
201651	NM_001103.4(ACTN2):c.2678A>G (p.Asp893Gly)	ACTN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
216492	NM_001103.4(ACTN2):c.1046A>T (p.Gln349Leu)	ACTN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
228435	NM_001103.4(ACTN2):c.2602G>A (p.Ala868Thr)	ACTN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
296503	NM_001103.4(ACTN2):c.983G>A (p.Arg328Gln)	ACTN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
296506	NM_001103.4(ACTN2):c.1823G>A (p.Arg608Gln)	ACTN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
373800	NM_001103.4(ACTN2):c.1984C>T (p.Arg662Trp)	ACTN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
384968	NM_001103.4(ACTN2):c.1295C>T (p.Ala432Val)	ACTN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
388855	NM_001103.4(ACTN2):c.2054T>C (p.Ile685Thr)	ACTN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
390309	NM_001103.4(ACTN2):c.1771A>G (p.Ile591Val)	ACTN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
412276	NM_001103.4(ACTN2):c.2423C>T (p.Thr808Ile)	ACTN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
412277	NM_001103.4(ACTN2):c.896G>A (p.Arg299His)	ACTN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
429493	NM_001103.4(ACTN2):c.2231C>T (p.Thr744Met)	ACTN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
43905	NM_001103.4(ACTN2):c.1384G>T (p.Ala462Ser)	ACTN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
43920	NM_001103.4(ACTN2):c.1930G>A (p.Ala644Thr)	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.