ACTA1

Chr 1ADAR

actin alpha 1, skeletal muscle

Also known as: ACTA, ASMA, CFTD, CFTD1, CFTDM, CMYO2A, CMYO2B, CMYO2C

NCBI Gene: 58ENSG00000143632UniProt: P68133

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. [provided by RefSeq, Sep 2019]

Primary Disease Associations & Inheritance

?Myopathy, scapulohumeroperonealMIM #616852
AD
Congenital myopathy 2A, typical, autosomal dominantMIM #161800
AD
Congenital myopathy 2B, severe infantile, autosomal recessiveMIM #620265
AR
Congenital myopathy 2C, severe infantile, autosomal dominantMIM #620278
AD
660
ClinVar variants
268
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— ACTA1
🧬
Gene-Disease Validity (ClinGen)
alpha-actinopathy · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
268 Pathogenic / Likely Pathogenic· 202 VUS of 660 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Missense constrained — critical functional residues
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
1.22LOEUF
pLI 0.000
Z-score 0.93
OE 0.74 (0.46–1.22)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
4.53Z-score
OE missense 0.21 (0.17–0.26)
55 obs / 260.9 exp
Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.74 (0.46–1.22)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.21 (0.17–0.26)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.87
0≤1.21.6
LoF obs/exp: 11 / 14.9Missense obs/exp: 55 / 260.9Syn Z: 1.11

ClinVar Variant Classifications

660 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic139
Likely Pathogenic129
VUS202
Likely Benign149
Benign18
Conflicting23
139
Pathogenic
129
Likely Pathogenic
202
VUS
149
Likely Benign
18
Benign
23
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
12
84
43
0
139
Likely Pathogenic
12
107
10
0
129
VUS
4
160
31
7
202
Likely Benign
0
0
67
82
149
Benign
0
0
18
0
18
Conflicting
—23
Total2835116989660

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

ACTA1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

ACTA1-related nemaline myopathy

strong
ARUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

?Myopathy, scapulohumeroperoneal

MIM #616852

Molecular basis of disorder known

Autosomal dominant

Congenital myopathy 2A, typical, autosomal dominant

MIM #161800

Molecular basis of disorder known

Autosomal dominant

Congenital myopathy 2B, severe infantile, autosomal recessive

MIM #620265

Molecular basis of disorder known

Autosomal recessive

Congenital myopathy 2C, severe infantile, autosomal dominant

MIM #620278

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Mutations and polymorphisms of the skeletal muscle alpha-actin gene (ACTA1).
Laing NG et al.·Hum Mutat
2009
An Update on Reported Variants in the Skeletal Muscle α-Actin (ACTA1) Gene.
Clayton JS et al.·Hum Mutat
2024Review
Clinical and Histologic Findings in ACTA1-Related Nemaline Myopathy: Case Series and Review of the Literature.
Moreno CAM et al.·Pediatr Neurol
2017Review
Congenital myopathies: pathophysiological mechanisms and promising therapies.
Zhang H et al.·J Transl Med
2024Review
Dilated cardiomyopathy-associated skeletal muscle actin (ACTA1) mutation R256H disrupts actin structure and function and causes cardiomyocyte hypocontractility.
Garg A et al.·Proc Natl Acad Sci U S A
2024
Actinopathies and myosinopathies.
Goebel HH et al.·Brain Pathol
2009Review
Nemaline myopathies: a current view.
Sewry CA et al.·J Muscle Res Cell Motil
2019Review
[Congenital myopathies].
Cabello A et al.·Rev Neurol
2003Review
A review of core myopathy: central core disease, multiminicore disease, dusty core disease, and core-rod myopathy.
Ogasawara M et al.·Neuromuscul Disord
2021Review
Genotype-phenotype correlations in ACTA1 mutations that cause congenital myopathies.
Feng JJ et al.·Neuromuscul Disord
2009Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
ACTA1-related congenital myopathy in a neonate: a case report and literature review.
Zhao L et al.·Front Pediatr
2025🔓 Open AccessReview
CARE-compliant case report: Nemaline myopathy caused by the ACTA1 p.Q139H missense mutation.
Pei X et al.·Medicine (Baltimore)
2025🔓 Open AccessCase report
ACTA1 gene regulation in livestock: A multidimensional review on muscle development, meat quality, and genetic applications.
Ayuti SR et al.·Vet World
2025🔓 Open AccessReview
Like father, like son: RNA-sequencing from a 30-year-old muscle biopsy identifies a novel splice variant in ACTA1 as the cause of an attenuated nemaline myopathy phenotype.
Meyer AP et al.·Neuromuscul Disord
2025
Generation of an induced pluripotent stem cell line (NCHi023-A) from a 41-year-old male with nemaline myopathy carrying autosomal dominant ACTA1 c.809-10C>A mutation.
Hanley M et al.·Stem Cell Res
2025🔓 Open Access
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools