ACTA1

Chr 1ADAR

actin alpha 1, skeletal muscle

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

NCBI Gene: 58 ENSG00000143632 UniProt: P68133 OMIM: 102610

The protein is an alpha actin that forms the major constituent of the contractile apparatus in skeletal muscle. Mutations cause various congenital myopathies including nemaline myopathy, congenital myopathy with excess thin myofilaments, and congenital myopathy with fiber-type disproportion, which manifest as hypotonia and muscle fiber defects. Inheritance is autosomal dominant or autosomal recessive, with pathogenicity likely resulting from dominant-negative effects.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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]

OMIM ResearchGenerating clinical summary…

DNmechanismAD/ARLOEUF 1.224 OMIM phenotypes

VCEP Guidelines: Congenital MyopathiesReleased

ClinGen Panel

Clinical Summary— ACTA1

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Gene-Disease Validity (ClinGen)

alpha-actinopathy · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

237 unique Pathogenic / Likely Pathogenic· 200 VUS of 627 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Missense constrained — critical functional residues

LoF Constraint?

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?

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?

LoF OE?0.74 (0.46–1.22)

0≤0.351.4

Missense OE?0.21 (0.17–0.26)

0≤0.61.4

Synonymous OE?0.87

0≤1.21.6

LoF obs/exp: 11 / 14.9Missense obs/exp: 55 / 260.9Syn Z: 1.11

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongACTA1-related nemaline myopathyOTHERAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.81top 10%

GOF

0.6051th %ile

LOF

0.3259th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Literature Evidence

DNEvidence for a dominant-negative effect in ACTA1 nemaline myopathy caused by abnormal folding, aggregation and altered polymerization of mutant actin isoforms1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References

1.PMID 15198992 ↗

ClinVar Variant Classifications

627 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic106

Likely Pathogenic131

VUS200

Likely Benign148

Benign18

Conflicting23

106

Pathogenic

131

Likely Pathogenic

200

VUS

148

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	18	88	0	0	106
Likely Pathogenic	18	111	2	0	131
VUS	4	165	24	7	200
Likely Benign	0	0	66	82	148
Benign	0	0	18	0	18
Conflicting	—				23
Total	40	364	110	89	626

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

View in ClinVar →

37 pathogenic / likely-pathogenic (of 43) ClinVar copy-number / structural variants overlap ACTA1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →