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ACTA2

actin alpha 2, smooth muscle

The ACTA2 gene provides instructions for producing smooth muscle alpha-2 actin, a key protein involved in the contraction of smooth muscles found in various internal organs and blood vessel walls. The ACTA2 gene is crucial for the function of smooth muscle cells throughout the body, particularly in the cardiovascular system.

Chromosome 10q23.31 Autosomal dominant HGNC:130 Tier B
ACTA2 10q23.31 p arm q arm 10

ACTA2 is located on the long (q) arm of chromosome 10, at band 10q23.31. Arm ratio per GRCh38 - banding schematic.

Explore chromosome 10 in the library →

Overview

The ACTA2 gene, also known as actin alpha 2, smooth muscle, encodes a protein critical for the contractility of smooth muscles. These muscles are involuntary and line many internal organs, such as blood vessels, the stomach, and intestines. Understanding the ACTA2 gene and its protein product, smooth muscle alpha-2 actin, is important for comprehending conditions that affect muscle function and blood vessel health, including hereditary forms of aortic disease.

What the gene does

The ACTA2 gene provides the blueprint for smooth muscle alpha-2 actin, a component of the broader actin protein family. Actin proteins are fundamental to cell movement and the ability of muscles to tense or contract. Specifically, smooth muscle alpha-2 actin is found in smooth muscle cells, which are integral to the structure and function of internal organs, including the arteries that transport blood from the heart. Within these smooth muscle cells, smooth muscle alpha-2 actin forms the core structures known as sarcomeres, which are essential for muscle contraction. This involuntary contraction and relaxation mechanism is vital for normal physiological functions, such as maintaining blood vessel shape against the pressure of pumped blood, rather than allowing them to overstretch. Abnormalities in this protein can therefore affect the structural integrity and functionality of tissues where smooth muscles are prevalent.

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Chromosome location

The ACTA2 gene is situated on chromosome 10, specifically at position 10q23.31. This genomic location refers to the long arm (q) of chromosome 10, within region 23 and sub-band 31. Genes located in this region are part of the complex genetic blueprint that dictates human development and physiological function. Understanding the precise chromosomal location aids in genetic mapping and the identification of potential links between genetic alterations and health conditions.

Protein structure

Domain architecture has not been experimentally characterised in detail for this protein.

Key variants

Genetic changes, or variants, within the ACTA2 gene can impact the structure and function of the smooth muscle alpha-2 actin protein. These variants may lead to altered protein activity, potentially affecting the contractility of smooth muscles throughout the body. While some variants may have no discernible effect, others can be pathogenic, meaning they are associated with an increased risk for specific inherited conditions. The clinical significance of any identified ACTA2 variant requires careful evaluation by healthcare professionals.

716
Total variants catalogued in ClinVar
View all on ClinVar →
39 Pathogenic / Likely pathogenic 349 Uncertain significance 292 Benign / Likely benign 36 Conflicting or other

Sample of pathogenic variants

10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.

Variant (HGVS) Protein change Classification Evidence Associated condition
c.115C>G
single nucleotide variant
 p.Arg39Gly Pathogenic/Likely pathogenic ★★☆☆ Familial thoracic aortic aneurysm and aortic dissection
c.115C>T
single nucleotide variant
 p.Arg39Cys Pathogenic/Likely pathogenic ★★☆☆ ACTA2-related disorder
c.116G>A
single nucleotide variant
 p.Arg39His Pathogenic/Likely pathogenic ★★☆☆ ACTA2-related disorder
c.130-2del
Deletion
 - Pathogenic/Likely pathogenic ★★☆☆ ACTA2-related disorder
c.138G>T
single nucleotide variant
 p.Met46Ile Pathogenic/Likely pathogenic ★★☆☆ Aortic aneurysm, familial thoracic 6
c.353G>A
single nucleotide variant
 p.Arg118Gln Pathogenic/Likely pathogenic ★★☆☆ ACTA2-related disorder
c.445C>T
single nucleotide variant
 p.Arg149Cys Pathogenic ★★☆☆ Aortic aneurysm, familial thoracic 6
c.446G>T
single nucleotide variant
 p.Arg149Leu Pathogenic/Likely pathogenic ★★☆☆ Aortic aneurysm, familial thoracic 6
c.535C>T
single nucleotide variant
 p.Arg179Cys Pathogenic ★★☆☆ Aortic aneurysm, familial thoracic 6
c.536G>A
single nucleotide variant
 p.Arg179His Pathogenic ★★☆☆ Multisystemic smooth muscle dysfunction syndrome

Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.

Associated conditions

Variants in the ACTA2 gene are primarily associated with conditions affecting smooth muscle function, particularly within the cardiovascular system. The most notable condition linked to ACTA2 is familial thoracic aortic aneurysm and dissection, where the aorta, the body's main artery, can weaken and bulge. Additionally, ACTA2 variants can be implicated in multisystemic smooth muscle dysfunction syndrome, a broader disorder impacting smooth muscle activity across various organs.

Inheritance pattern

Conditions caused by pathogenic ACTA2 variants typically follow autosomal dominant inheritance.

♀ Affected parent 1 altered copy ♂ Unaffected parent 2 typical copies Affected Unaffected Unaffected Affected Affected Carrier Unaffected Circles = females · Squares = males

Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.

UK clinical status

In the UK, the ACTA2 gene is recognised on several NHS Genomic Medicine Service (GMS) pathways and PanelApp gene panels, indicating its clinical significance. It is classified as green for conditions such as Cerebral Vascular Malformations, DDG2P (Developmental Disorders Genotype-to-Phenotype), Foetal Anomalies, Gastrointestinal Neuromuscular Disorders, Paediatric Pseudo-obstruction Syndrome, and Thoracic Aortic Aneurysm or Dissection (both general and GMS specific PanelApp entries). This widespread green status confirms that ACTA2 has strong evidence for a gene-disease association within these clinical contexts.

Green-listed
High evidence · clinically actionable in NHS testing
Included in NHS GMS signed-off panels
Cerebral vascular malformations · R336 NHS GMS → Fetal anomalies · R21 NHS GMS → Paediatric pseudo-obstruction syndrome · R438 NHS GMS → Thoracic aortic aneurysm or dissection (GMS) · R125 NHS GMS → DDG2P NHS GMS →
NHS Genomic Medicine Service Jeen carrier screening

Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory

Diet & lifestyle considerations

Maintaining a heart-healthy lifestyle may contribute to overall cardiovascular well-being, especially for individuals with genetic predispositions affecting the aorta. Research suggests that a balanced diet, regular physical activity, and avoiding smoking can support cardiovascular health in the general population. For those with ACTA2-related conditions, specific lifestyle modifications might be recommended by their healthcare provider to manage their condition, but these are not preventative measures for genetic conditions.

Supplement considerations

There is currently no conclusive evidence to suggest that specific dietary supplements can prevent or treat conditions associated with ACTA2 gene variants. While some supplements are marketed for cardiovascular health, their efficacy in the context of inherited aortic diseases or smooth muscle dysfunction has not been established. Individuals considering any supplements should consult with a healthcare professional to discuss potential benefits and risks, especially if they have a diagnosed genetic condition.

Frequently asked questions

What is the primary function of the ACTA2 gene?

The ACTA2 gene provides instructions for making smooth muscle alpha-2 actin, a protein essential for the contraction of smooth muscles found in internal organs and blood vessel walls, helping them maintain shape and function.

What health conditions are associated with ACTA2 gene variants?

Variants in the ACTA2 gene are mainly linked to familial thoracic aortic aneurysm and dissection, a condition affecting the aorta, and multisystemic smooth muscle dysfunction syndrome, which impacts smooth muscle function throughout the body.

How is ACTA2 status determined in the UK healthcare system?

In the UK, the ACTA2 gene is listed on several NHS PanelApp gene panels as 'green', indicating strong evidence for its association with conditions like thoracic aortic aneurysm, cerebral vascular malformations, and various smooth muscle disorders, guiding genetic testing and diagnosis.

Can lifestyle changes prevent ACTA2-related conditions?

While a healthy lifestyle, including diet and exercise, supports general cardiovascular health, there is no evidence that it can prevent the development of genetic conditions associated with ACTA2 variants. Lifestyle advice for individuals with such conditions should come from a healthcare provider.

Is ACTA2 an actionable gene?

Yes, ACTA2 is classified as an ACMG SF v3.2 Tier 1 actionable gene, meaning that genetic variants in this gene can have significant health implications and there are generally established medical interventions or surveillance recommendations for individuals with such variants.

References

  1. Pyeritz RE. Heritable thoracic aortic disorders. Current opinion in cardiology. 2014. PMID: 24284977
  2. Jondeau G, Boileau C. Genetics of thoracic aortic aneurysms. Current atherosclerosis reports. 2012. PMID: 22415348
  3. Grond-Ginsbach C, Pjontek R, Aksay SS. Spontaneous arterial dissection: phenotype and molecular pathogenesis. Cellular and molecular life sciences : CMLS. 2010. PMID: 20155481
  4. Milewicz DM, Carlson AA, Regalado ES. Genetic testing in aortic aneurysm disease: PRO. Cardiology clinics. 2010. PMID: 20452526
  5. Milewicz DM, Østergaard JR, Ala-Kokko LM. De novo ACTA2 mutation causes a novel syndrome of multisystemic smooth muscle dysfunction. American journal of medical genetics. Part A. 2010. PMID: 20734336
  6. Morisaki H, Akutsu K, Ogino H. Mutation of ACTA2 gene as an important cause of familial and nonfamilial nonsyndromatic thoracic aortic aneurysm and/or dissection (TAAD). Human mutation. 2009. PMID: 19639654
  7. El-Hamamsy I, Yacoub MH. Cellular and molecular mechanisms of thoracic aortic aneurysms. Nature reviews. Cardiology. 2009. PMID: 19884902
  8. Milewicz DM, Guo DC, Tran-Fadulu V. Genetic basis of thoracic aortic aneurysms and dissections: focus on smooth muscle cell contractile dysfunction. Annual review of genomics and human genetics. 2008. PMID: 18544034
  9. Guo DC, Pannu H, Tran-Fadulu V. Mutations in smooth muscle alpha-actin (ACTA2) lead to thoracic aortic aneurysms and dissections. Nature genetics. 2007. PMID: 17994018
  10. Adam MP, Bick S, Mirzaa GM. Heritable Thoracic Aortic Disease Overview. 1993. PMID: 20301299
Educational content. This page is not medical or genetic advice, is not individually reviewed by a clinician for each reader, and should not replace a consultation with a qualified healthcare professional or genetic counsellor. If you are considering genetic testing or acting on a test result, book a consultation.
Data sources Last updated 11 October 2026. Content compiled from HGNC · MedlinePlus Genetics · ClinGen · Genomics England PanelApp · NHS National Genomic Test Directory · ClinVar · UniProt · AlphaFold .