# NM_001613.4(ACTA2):c.645G>A (p.Lys215=)

https://sugi.bio/variant/acta2-p-lys215

## Summary

**ACTA2 p.Lys215= (c.645G>A)** is classified **Conflicting classifications of pathogenicity** in ACTA2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2024-11-03). Very rare (popmax 8.47e-05%, nfe); Associated with familial thoracic aortic aneurysm and aortic dissection.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs1053760032 · 4 submitters · 3 linked conditions · very rare (popmax 8.47e-05%, nfe)

## For patients & families {#patients}

This is a change in the ACTA2 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 4 submitters, and is linked to familial thoracic aortic aneurysm and aortic dissection.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant |
| Age of onset (of this condition) | Adolescent, Adult, Childhood |
| Clinical trials | 2 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | ACTA2 is a diagnostic-grade gene on 7 Genomics England panels |

**Commonly reported features of Familial thoracic aortic aneurysm and aortic dissection** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Cutis marmorata — Very frequent (99-80%)
- Abnormality of connective tissue — Very frequent (99-80%)
- Cystic medial necrosis of the aorta — Very frequent (99-80%)
- Abnormality iris morphology — Frequent (79-30%)
- Hypertension — Frequent (79-30%)
- Cardiomegaly — Frequent (79-30%)
- Aortic regurgitation — Frequent (79-30%)
- Coronaryartery atherosclerosis — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0002249/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ACTA2](https://sugi.bio/atlas/gene/ACTA2/) |
| Protein change (HGVS p.) | p.Lys215= |
| Coding change (HGVS c.) | c.645G>A |
| MANE Select transcript | [NM_001613](https://www.ncbi.nlm.nih.gov/nuccore/NM_001613) |
| dbSNP | [rs1053760032](https://www.ncbi.nlm.nih.gov/snp/rs1053760032/) |
| Variant type | single nucleotide variant |
| Location | chr10:88939670-88939670 (GRCh38) |
| ClinVar | [VCV877990](https://www.ncbi.nlm.nih.gov/clinvar/variation/877990/) |

**All HGVS expressions:** `LRG_781:g.56721G>A`, `LRG_781t1:c.645G>A`, `LRG_781t2:c.645G>A`, `NC_000010.10:g.90699427C>T`, `NC_000010.11:g.88939670C>T`, `NG_011541.1:g.56721G>A`, `NM_001141945.3:c.645G>A`, `NM_001320855.2:c.645G>A`, `NM_001406462.1:c.645G>A`, `NM_001406463.1:c.645G>A`, `NM_001406464.1:c.645G>A`, `NM_001406466.1:c.534G>A`, `NM_001406467.1:c.516G>A`, `NM_001406468.1:c.516G>A`, `NM_001406469.1:c.516G>A`, `NM_001406471.1:c.617-1428G>A`, `NM_001613.4:c.645G>A`, `NR_125373.1:n.1739C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 0.414, GERP 0.214, phastCons 0.993 — weakly conserved position
- CADD: **PHRED 16.08**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.24 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **8.47e-05%** (nfe) · 1/1,179,960 in the highest group · 1/1,461,704 alleles overall — very rare (popmax 8.47e-05%, nfe).

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**ACTA2** population constraint: LOEUF 0.472, pLI 0.99431, missense-Z 4.6189; ClinGen dosage — haploinsufficiency 1, triplosensitivity 0 (0–3 scale). *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **multisystemic smooth muscle dysfunction syndrome** — Definitive (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 95.43, 93% of residues very-high.

## What this gene does {#gene-function}

*Describes the biological roles of ACTA2 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*


### Pathways affected {#pathways}

ACTA2 participates in **6 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Developmental Lineage of Mammary Gland Myoepithelial Cells](https://reactome.org/content/detail/R-HSA-9927432) | curated |
| [NOTCH4 Intracellular Domain Regulates Transcription](https://reactome.org/content/detail/R-HSA-9013695) | curated |
| [Regulation of CDH1 Function](https://reactome.org/content/detail/R-HSA-9764561) | curated |
| [Smooth Muscle Contraction](https://reactome.org/content/detail/R-HSA-445355) | curated |
| [Activation of STAT3 by cadherin engagement](https://reactome.org/content/detail/R-HSA-9958825) | electronic |
| [Formation of the dystrophin-glycoprotein complex (DGC)](https://reactome.org/content/detail/R-HSA-9913351) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Biological process:** response to virus, glomerular mesangial cell development.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2024-11-03.

**Submitter consensus:** conflicting (2 Uncertain significance, 2 Likely benign, 1 Likely Benign).

**Submission history:** 5 submissions (2018–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-13 |
| All of Us Research Program, National Institutes of Health | Likely Benign | criteria provided, single submitter | clinical testing | 2023-11-02 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-03 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2021-04-17 |

## Associated conditions {#conditions}

[familial thoracic aortic aneurysm and aortic dissection](https://sugi.bio/atlas/disease/familial-thoracic-aortic-aneurysm-and-aortic-dissection/), [aortic aneurysm, familial thoracic 6](https://sugi.bio/atlas/disease/aortic-aneurysm-familial-thoracic-6/), [multisystemic smooth muscle dysfunction syndrome](https://sugi.bio/atlas/disease/multisystemic-smooth-muscle-dysfunction-syndrome/).

**Reported phenotype names (ClinVar):** Familial thoracic aortic aneurysm and aortic dissection, Aortic aneurysm, familial thoracic 6, Multisystemic smooth muscle dysfunction syndrome, Thoracic aortic aneurysms and dissections, FAMILIAL THORACIC AORTIC ANEURYSM WITH LIVEDO RETICULARIS AND IRIS FLOCCULI, MYDRIASIS, CONGENITAL, WITH PATENT DUCTUS ARTERIOSUS, THORACIC AORTIC ANEURYSM, AND VASCULOPATHY, SMOOTH MUSCLE DYSFUNCTION SYNDROME.

## Similar variants {#similar}

Related ACTA2 variant pages (same residue, condition, or type): [ACTA2 p.Arg118Gln](/variant/acta2-p-arg118gln), [ACTA2 p.Arg149Cys](/variant/acta2-p-arg149cys), [ACTA2 p.Arg149Leu](/variant/acta2-p-arg149leu), [ACTA2 p.Arg179Cys](/variant/acta2-p-arg179cys), [ACTA2 p.Arg179His](/variant/acta2-p-arg179his), [ACTA2 p.Arg198Cys](/variant/acta2-p-arg198cys), [ACTA2 p.Arg198His](/variant/acta2-p-arg198his), [ACTA2 p.Arg256Cys](/variant/acta2-p-arg256cys).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 877990). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*