Congenital myopathy 2a, typical, autosomal dominant

Summary

Congenital myopathy 2a, typical, autosomal dominant (MONDO:0008070) is a disease caused by ACTA1 (GenCC Definitive), with 5 cohort genes.

At a glance

• Causal gene: ACTA1 (GenCC Definitive)
• Cohort genes: 5
• ClinVar variants: 484

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital myopathy 2a, typical, autosomal dominant
Mondo ID	MONDO:0008070
MeSH	C579880, C580202
OMIM	161800
Orphanet	98904
DOID	DOID:0110927
NCIT	C129870
SNOMED CT	702349003
UMLS	C3711389
MedGen	777997
GARD	0010111
Is cancer (heuristic)	no

Also known as: ACTA1 nemaline myopathy · actin accumulation myopathy · actin accumulation myopathy (disorder) · actin myopathy · CMYO2A · congenital myopathy 2a, typical, autosomal dominant · congenital myopathy with excess of thin filaments · NEM3 · nemaline myopathy 3 · nemaline myopathy caused by mutation in ACTA1 · nemaline myopathy type 3

Data availability: 484 ClinVar variants · 4 GenCC gene-disease records · 25 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › severe congenital nemaline myopathy › congenital myopathy 2a, typical, autosomal dominant

Related subtypes (4): nemaline myopathy 2, nemaline myopathy 8, nemaline myopathy 9, nemaline myopathy 10

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

484 retrieved; paginated sample, class counts are floors:

155 uncertain significance, 123 likely benign, 84 pathogenic, 52 likely pathogenic, 28 pathogenic/likely pathogenic, 25 conflicting classifications of pathogenicity, 11 benign, 6 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1003875	NM_001100.4(ACTA1):c.983_985del (p.Lys328del)	ACTA1	Pathogenic	criteria provided, single submitter
1031829	NM_001100.4(ACTA1):c.1001C>G (p.Pro334Arg)	ACTA1	Pathogenic	reviewed by expert panel
1031830	NM_001100.4(ACTA1):c.400A>G (p.Met134Val)	ACTA1	Pathogenic	criteria provided, single submitter
1065494	NM_001100.4(ACTA1):c.226G>C (p.Gly76Arg)	ACTA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069121	NM_001100.4(ACTA1):c.155_158del (p.Lys52fs)	ACTA1	Pathogenic	criteria provided, single submitter
1072266	NM_001100.4(ACTA1):c.599A>G (p.Tyr200Cys)	ACTA1	Pathogenic	criteria provided, single submitter
1073998	NM_001100.4(ACTA1):c.841T>C (p.Tyr281His)	ACTA1	Pathogenic	criteria provided, multiple submitters, no conflicts
1074947	NM_001100.4(ACTA1):c.181C>T (p.Gln61Ter)	ACTA1	Pathogenic	criteria provided, single submitter
1333773	NM_001100.4(ACTA1):c.419C>A (p.Ala140Asp)	ACTA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1451534	NM_001100.4(ACTA1):c.400del (p.Met134fs)	ACTA1	Pathogenic	criteria provided, single submitter
1452454	NM_001100.4(ACTA1):c.509G>A (p.Gly170Asp)	ACTA1	Pathogenic	criteria provided, single submitter
1452968	NM_001100.4(ACTA1):c.124C>T (p.His42Tyr)	ACTA1	Pathogenic	reviewed by expert panel
1456499	NM_001100.4(ACTA1):c.704C>A (p.Ser235Tyr)	ACTA1	Pathogenic	criteria provided, single submitter
1457948	NM_001100.4(ACTA1):c.1049C>T (p.Ser350Leu)	ACTA1	Pathogenic	criteria provided, single submitter
1457951	NM_001100.4(ACTA1):c.846C>G (p.Asn282Lys)	ACTA1	Pathogenic	criteria provided, single submitter
1457959	NM_001100.4(ACTA1):c.169G>C (p.Gly57Arg)	ACTA1	Pathogenic	criteria provided, single submitter
1459640	NM_001100.4(ACTA1):c.436del (p.Ala146fs)	ACTA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1685499	NM_001100.4(ACTA1):c.359A>T (p.Lys120Met)	ACTA1	Pathogenic	criteria provided, single submitter
18279	NM_001100.4(ACTA1):c.287T>C (p.Leu96Pro)	ACTA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
18280	NM_001100.4(ACTA1):c.350A>G (p.Asn117Ser)	ACTA1	Pathogenic	criteria provided, multiple submitters, no conflicts
18281	NM_001100.4(ACTA1):c.49G>C (p.Gly17Arg)	ACTA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
18282	NM_001100.4(ACTA1):c.493G>T (p.Val165Leu)	ACTA1	Pathogenic	no assertion criteria provided
18283	NM_001100.4(ACTA1):c.782A>T (p.Glu261Val)	ACTA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
18285	NM_001100.4(ACTA1):c.808G>T (p.Gly270Cys)	ACTA1	Pathogenic	no assertion criteria provided
18287	NM_001100.4(ACTA1):c.7G>T (p.Asp3Tyr)	ACTA1	Pathogenic	no assertion criteria provided
18289	NM_001100.4(ACTA1):c.881A>T (p.Asp294Val)	ACTA1	Pathogenic	no assertion criteria provided
18291	NM_001100.4(ACTA1):c.1000C>T (p.Pro334Ser)	ACTA1	Pathogenic	reviewed by expert panel
18292	NM_001100.4(ACTA1):c.493G>A (p.Val165Met)	ACTA1	Pathogenic	reviewed by expert panel
196311	NM_001100.4(ACTA1):c.142G>A (p.Gly48Ser)	ACTA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1992629	NM_001100.4(ACTA1):c.794A>G (p.Gln265Arg)	ACTA1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 15 · Orphanet: 24 · 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
ACTA1	Definitive	Semidominant	congenital myopathy 2a, typical, autosomal dominant	15

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ACTA1	Orphanet:171430	Severe congenital nemaline myopathy
ACTA1	Orphanet:171433	Intermediate nemaline myopathy
ACTA1	Orphanet:171436	Typical nemaline myopathy
ACTA1	Orphanet:171439	Childhood-onset nemaline myopathy
ACTA1	Orphanet:2020	Congenital fiber-type disproportion myopathy
ACTA1	Orphanet:447977	Progressive scapulohumeroperoneal distal myopathy
ACTA1	Orphanet:97240	Zebra body myopathy
ACTA1	Orphanet:97244	Rigid spine syndrome
ACTA1	Orphanet:98904	Congenital myopathy with excess of thin filaments
COL4A1	Orphanet:36383	COL4A1/2-related familial vascular leukoencephalopathy
COL4A1	Orphanet:477749	Pontine autosomal dominant microangiopathy with leukoencephalopathy
COL4A1	Orphanet:481986	Familial schizencephaly
COL4A1	Orphanet:73229	HANAC syndrome
COL4A1	Orphanet:75326	Familial isolated retinal arteriolar tortuosity
COL4A1	Orphanet:899	Walker-Warburg syndrome
COL4A1	Orphanet:99810	Familial porencephaly
KBTBD13	Orphanet:171439	Childhood-onset nemaline myopathy
NEB	Orphanet:171430	Severe congenital nemaline myopathy
NEB	Orphanet:171433	Intermediate nemaline myopathy
NEB	Orphanet:171436	Typical nemaline myopathy
NEB	Orphanet:171439	Childhood-onset nemaline myopathy
NEB	Orphanet:33108	Lethal multiple pterygium syndrome
NEB	Orphanet:399103	Autosomal recessive distal nebulin myopathy
NEB	Orphanet:708123	Autosomal dominant distal nebulin myopathy

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ACTA1	HGNC:129	ENSG00000143632	P68133	Actin, alpha skeletal muscle	gencc,clinvar
COL4A1	HGNC:2202	ENSG00000187498	P02462	Collagen alpha-1(IV) chain	clinvar
KBTBD13	HGNC:37227	ENSG00000234438	C9JR72	Kelch repeat and BTB domain-containing protein 13	clinvar
ABCB10	HGNC:41	ENSG00000135776	Q9NRK6	ATP-binding cassette sub-family B member 10, mitochondrial	clinvar
NEB	HGNC:7720	ENSG00000183091	P20929	Nebulin	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ACTA1	Actin, alpha skeletal muscle	Actins are highly conserved proteins that are involved in various types of cell motility and are ubiquitously expressed in all eukaryotic cells.
COL4A1	Collagen alpha-1(IV) chain	Type IV collagen is the major structural component of glomerular basement membranes (GBM), forming a ‘chicken-wire’ meshwork together with laminins, proteoglycans and entactin/nidogen.
KBTBD13	Kelch repeat and BTB domain-containing protein 13	Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex.
ABCB10	ATP-binding cassette sub-family B member 10, mitochondrial	ATP-dependent transporter located in the mitochondrial inner membrane that catalyzes the export of biliverdin from the mitochondrial matrix, and plays a crucial role in hemoglobin synthesis and antioxidative stress.
NEB	Nebulin	This giant muscle protein may be involved in maintaining the structural integrity of sarcomeres and the membrane system associated with the myofibrils.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 3 · Druggable fraction: 0.2

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
Transporter	1	15.6×	0.188
Scaffold/PPI	1	3.5×	0.386
Other/Unknown	3	1.1×	0.608

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ACTA1	Other/Unknown	no		Actin, Actin_CS, Actin/actin-like_CS
COL4A1	Other/Unknown	no		Collagen_IV_NC, Collagen, CTDL_fold
KBTBD13	Other/Unknown	no		BTB/POZ_dom, Kelch_1, SKP1/BTB/POZ_sf
ABCB10	Transporter	yes	7.4.2.5	ABC_transporter-like_ATP-bd, AAA+_ATPase, ABC1_TM_dom
NEB	Scaffold/PPI	no		Nebulin_repeat, SH3_domain, Nebulin-like

Expression context

Cohort genes with no expression data: 0.

4 cohort genes 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gluteal muscle	2
diaphragm	1
skeletal muscle tissue of biceps brachii	1
placenta	1
right coronary artery	1
visceral pleura	1
hindlimb stylopod muscle	1
primordial germ cell in gonad	1
skeletal muscle tissue	1
bone marrow	1
epithelial cell of pancreas	1
trabecular bone tissue	1
biceps brachii	1
tibialis anterior	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ACTA1	203	broad	marker	gluteal muscle, skeletal muscle tissue of biceps brachii, diaphragm
COL4A1	283	ubiquitous	marker	visceral pleura, placenta, right coronary artery
KBTBD13	47	tissue_specific	yes	primordial germ cell in gonad, hindlimb stylopod muscle, skeletal muscle tissue
ABCB10	254	ubiquitous	marker	trabecular bone tissue, epithelial cell of pancreas, bone marrow
NEB	204	tissue_specific	marker	gluteal muscle, tibialis anterior, biceps brachii

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
COL4A1	2,909
ABCB10	1,885
NEB	1,402
KBTBD13	606
ACTA1	523

Intra-cohort edges

A	B	Sources
KBTBD13	NEB	string_interaction

Structural data

PDB: 4 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ABCB10	Q9NRK6	6
ACTA1	P68133	5
COL4A1	P02462	4
NEB	P20929	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
KBTBD13	C9JR72	90.56

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 31. Enrichment computed across 5 evidence-associated genes (5 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 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Striated Muscle Contraction	2	123.5×	0.003	ACTA1, NEB
Non-integrin membrane-ECM interactions	2	61.7×	0.006	ACTA1, COL4A1
Mitochondrial ABC transporters	1	571.0×	0.014	ABCB10
Muscle contraction	2	30.9×	0.014	ACTA1, NEB
Regulation of CDH1 Function	1	190.3×	0.030	ACTA1
Anchoring fibril formation	1	152.3×	0.030	COL4A1
Scavenging by Class A Receptors	1	120.2×	0.030	COL4A1
Fibronectin matrix formation	1	114.2×	0.030	COL4A1
Crosslinking of collagen fibrils	1	114.2×	0.030	COL4A1
Attachment of bacteria to epithelial cells	1	99.3×	0.031	COL4A1
Laminin interactions	1	76.1×	0.037	COL4A1
Formation of the dystrophin-glycoprotein complex (DGC)	1	61.7×	0.041	ACTA1
Collagen chain trimerization	1	51.9×	0.041	COL4A1
Signaling by PDGF	1	50.8×	0.041	COL4A1
NCAM1 interactions	1	49.6×	0.041	COL4A1
Assembly of collagen fibrils and other multimeric structures	1	40.1×	0.048	COL4A1
Collagen degradation	1	35.1×	0.049	COL4A1
Collagen biosynthesis and modifying enzymes	1	34.1×	0.049	COL4A1
Activation of STAT3 by cadherin engagement	1	32.6×	0.049	ACTA1
ECM proteoglycans	1	30.1×	0.051	COL4A1
Integrin cell surface interactions	1	26.9×	0.054	COL4A1
ABC-family protein mediated transport	1	24.3×	0.057	ABCB10
Class I MHC mediated antigen processing & presentation	1	14.0×	0.093	KBTBD13
Extracellular matrix organization	1	12.6×	0.099	ACTA1
Neddylation	1	9.5×	0.125	KBTBD13
Antigen processing: Ubiquitination & Proteasome degradation	1	7.4×	0.152	KBTBD13
Adaptive Immune System	1	6.0×	0.180	KBTBD13
Transport of small molecules	1	5.0×	0.203	ABCB10
Post-translational protein modification	1	3.8×	0.251	KBTBD13
Immune System	1	2.6×	0.342	KBTBD13

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
export from the mitochondrion	1	3370.4×	0.004	ABCB10
mitochondrial unfolded protein response	1	1685.2×	0.004	ABCB10
regulation of the force of skeletal muscle contraction	1	1123.5×	0.004	KBTBD13
positive regulation of heme biosynthetic process	1	1123.5×	0.004	ABCB10
cardiac muscle thin filament assembly	1	1123.5×	0.004	NEB
relaxation of skeletal muscle	1	1123.5×	0.004	KBTBD13
somatic muscle development	1	842.6×	0.004	NEB
regulation of actin filament length	1	842.6×	0.004	NEB
renal tubule morphogenesis	1	842.6×	0.004	COL4A1
mesenchyme migration	1	674.1×	0.005	ACTA1
skeletal muscle thin filament assembly	1	561.7×	0.005	ACTA1
positive regulation of hemoglobin biosynthetic process	1	561.7×	0.005	ABCB10
retinal blood vessel morphogenesis	1	481.5×	0.005	COL4A1
collagen-activated tyrosine kinase receptor signaling pathway	1	259.3×	0.009	COL4A1
mitochondrial transport	1	240.7×	0.009	ABCB10
blood vessel morphogenesis	1	160.5×	0.012	COL4A1
heme biosynthetic process	1	120.4×	0.014	ABCB10
skeletal muscle fiber development	1	108.7×	0.014	ACTA1
branching involved in blood vessel morphogenesis	1	105.3×	0.014	COL4A1
neuromuscular junction development	1	105.3×	0.014	COL4A1
erythrocyte development	1	105.3×	0.014	ABCB10
positive regulation of erythrocyte differentiation	1	102.1×	0.014	ABCB10
basement membrane organization	1	102.1×	0.014	COL4A1
cellular response to amino acid stimulus	1	61.3×	0.022	COL4A1
collagen fibril organization	1	44.9×	0.028	COL4A1
muscle contraction	1	41.6×	0.029	ACTA1
epithelial cell differentiation	1	35.1×	0.033	COL4A1
muscle organ development	1	33.4×	0.034	NEB
actin filament organization	1	23.7×	0.046	KBTBD13
brain development	1	15.9×	0.065	COL4A1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 5

Druggability breadth: 1 of 5 evidence-associated genes (20%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ACTA1	0	0
COL4A1	0	0
KBTBD13	0	0
ABCB10	0	0
NEB	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ABCB10	7.4.2.5	bacterial ABC-type protein transporter

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; 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	1	ABCB10
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	4	ACTA1, COL4A1, KBTBD13, NEB

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ACTA1	0	—
COL4A1	0	—
KBTBD13	0	—
ABCB10	0	—
NEB	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.