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ACTA2 Gene Mutations

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The ACTA2 gene

What does the ACTA2 gene do?

The ACTA2 gene provides instructions for producing a protein called alpha-actin, which plays a key role in the function of smooth muscle cells throughout the body. These cells are essential for the normal function of blood vessels and many organs. Changes in this gene can disrupt smooth muscle function and lead to a range of vascular and systemic conditions.

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The ACTA2 gene encodes the smooth muscle–specific isoform of α-actin, a protein that enables smooth muscle cells to contract and maintain the structure of blood vessels and organs.

 

The basic functions of smooth muscle in the organ systems are [1]:

  • Gastrointestinal tract: Moves food through the digestive system
  • Cardiovascular: Regulation of blood flow and pressure via vascular resistance
  • Renal: Regulation of urine flow
  • Genital: Contractions during pregnancy, propulsion of sperm
  • Respiratory tract: Regulation of bronchiole diameter
  • Integument: Raises hair with erector pili muscle
  • Sensory: Dilation and constriction of the pupil as well as changing lens shape

What is smooth muscle?

Smooth muscle is a type of muscle found in most internal organs, including the blood vessels, lungs, gastrointestinal system, bladder, and eye. Unlike skeletal muscle, which controls voluntary movements such as walking or lifting, smooth muscle works involuntarily, regulating essential functions. 

 

Because smooth muscle is present throughout the body, it plays a critical role in many vital processes.

What happens when there is a mutation in ACTA2?

Mutations in the ACTA2 gene can impair the normal function of smooth muscle cells. At a cellular level, ACTA2 mutations affect how actin proteins are formed and organized, reducing the ability of smooth muscle cells to contract effectively. This leads to stress within the vessel walls and organs where smooth muscle is essential.

 

This can result in:

  • Weakening or abnormal structure of blood vessels
  • Reduced ability to regulate blood flow
  • Increased risk of vascular complications

The impact of ACTA2 mutations varies depending on the specific genetic change. Because smooth muscle cells are present in multiple organs, the impact of ACTA2 mutations can extend beyond the vascular system, depending on the specific variant.

ACTA2-related conditions

ACTA2 mutations are associated with a spectrum of conditions, with varying severity depending on the specific genetic variant. These include:

  • Multisystemic Smooth Muscle Dysfunction Syndrome (MSMDS)
  • Familial Thoracic Aortic Aneurysm and Dissection (FTAAD)
  • Other vascular and smooth muscle-related disorders

Not all ACTA2 mutations lead to the same condition. Some primarily affect the vascular system, while others, such as MSMDS, impact multiple organs.

Abbreviations and interpretation:

  • +, phenotype reported in at least one individual carrying the indicated variant.
  • −, phenotype specifically evaluated and reported as absent in the cited individual(s).
  • NR, not reported, not systematically evaluated, or insufficient variant-specific evidence to classify the phenotype as present or absent. A “+” indicates a documented association and does not imply complete penetrance.
  • † The reported p.Asn117Lys family had no evidence of thoracic aortic disease at the time described. The reported p.Asp181Val individual had no evidence of aortic disease or ocular dysfunction.
  • ‡ Stroke has been reported in carriers of p.Asn117Thr, p.Asn117Ile, and p.Asn117Ser, but the available reports did not characterize the cerebrovascular anatomy sufficiently to classify these cases as the characteristic ACTA2 moyamoya-like arteriopathy.
  • § The p.Arg39His phenotype should be verified against the primary case-level publication before final submission if the “noncerebral arterial stenosis” designation is retained.
  • The PDA assignment for p.Arg39Gly should likewise be checked against the original case-level source before publication.
HGVS
protein
variant		 HGVS cDNA
variant
(NM_001613.4)		 PDA Congenital
mydriasis		 Moyamoya-like
cerebrovascular
disease		 Early-onset
thoracic aortic
disease		 Noncerebral
arterial
stenosis		 Fusiform
intracranial
aneurysm		 Supporting
references
p.(Arg179His) c.536G>A + + + + + NR PMID: 29300374, 22831780
p.(Arg179Cys) c.535C>T + + + + NR NR PMID: 29300374, 25759435
p.(Arg179Leu) c.536G>T + + + + NR NR PMID: 22831780, 29300374
p.(Arg179Ser) c.535C>A + + + + + NR PMID: 29300374
p.(Arg179Gly) c.535C>G + + + + NR NR PMID: 35567597
p.(Asn117Lys) c.351C>G + + + −† NR NR PMID: 32093627
p.(Asn117Thr) c.350A>C NR NR NR‡ + NR NR PMID: 32093627
and references therein
p.(Asn117Ile) c.350A>T NR NR NR‡ + NR NR PMID: 32093627
and references therein
p.(Asn117Ser) c.350A>G NR NR NR‡ + NR NR PMID: 32093627
and references therein
p.(Thr204Ile) c.611C>T + NR + + NR NR PMID: 35567597
p.(Arg258His) c.773G>A NR NR + + NR NR PMID: 19409525,
25759435, 32464348
p.(Arg258Cys) c.772C>T + NR + + NR NR PMID: 19409525,
25759435, 33513575
p.(Met46Arg) c.137T>G + NR + + + NR PMID: 30975232,
35567597
p.(Asp181Val) c.542A>T + −† + −† NR NR PMID: 35567597
and cited Pinto report
p.(Arg39His) c.116G>A NR NR NR + +§ NR PMID: 19409525,
25759435
p.(Arg39Gly) c.115C>G +¶ NR NR NR NR NR Previously reported phenotype;
confirm against primary source
p.(Arg39Cys) c.115C>T + NR NR + NR NR PMID: 21248741,
25759435, 35567597
p.(Lys328Asn) c.984G>T NR + NR# + NR + Ware et al.,
Pediatrics 2014;
PMID: 35567597
p.(Ile66Asn) c.197T>A NR NR NR + NR + PMID: 35567597
Other ACTA2 variants
ACTA2 & MSMDS

Why early recognition matters

Early identification of ACTA2-related conditions, especially MSMDS, is critical to:

  • Guide appropriate monitoring and care
  • Reduce the risk of serious complications
  • Avoid interventions that may increase risk (such as certain medications or anesthesia approaches)
  • Connect families and clinicians with specialized resources

Notes

Hafen BB, Shook M, Burns B. Anatomy, Smooth Muscle. [Updated 2023 Jul 17]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2026 Jan-. Available from:

https://www.ncbi.nlm.nih.gov/books/NBK532857/

*This content is not intended as a substitute for professional medical advice, diagnosis, or treatment. Should you require medical advice, please contact a qualified medical professional who is familiar with Multisystemic Smooth Muscle Dysfunction Syndrome.

© 2026 ACTA2 Alliance, All Rights Reserved.

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