# NM_001613.4(ACTA2):c.55T>C (p.Cys19Arg)

https://sugi.bio/variant/acta2-p-cys19arg

## Summary

**ACTA2 p.Cys19Arg (c.55T>C)** is classified **Likely pathogenic** in ACTA2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-11). AlphaMissense: likely pathogenic (0.9982); Absent from gnomAD v4.1; Associated with aortic aneurysm, familial thoracic 6.

**At a glance:** Likely pathogenic · review: Multiple submitters · rsID rs2133273980 · 2 submitters · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the ACTA2 gene that is considered likely disease-causing, submitted by 2 submitters, and is linked to aortic aneurysm, familial thoracic 6.

*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) | Unknown |
| Age of onset (of this condition) | Infancy |
| Diagnostic panels | ACTA2 is a diagnostic-grade gene on 7 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015527/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.Cys19Arg |
| Coding change (HGVS c.) | c.55T>C |
| MANE Select transcript | [NM_001613](https://www.ncbi.nlm.nih.gov/nuccore/NM_001613) |
| dbSNP | [rs2133273980](https://www.ncbi.nlm.nih.gov/snp/rs2133273980/) |
| Variant type | single nucleotide variant |
| Location | chr10:88948876-88948876 (GRCh38) |
| ClinVar | [VCV1054067](https://www.ncbi.nlm.nih.gov/clinvar/variation/1054067/) |

**All HGVS expressions:** `LRG_781:g.47515T>C`, `LRG_781t1:c.55T>C`, `LRG_781t2:c.55T>C`, `NC_000010.10:g.90708633A>G`, `NC_000010.11:g.88948876A>G`, `NG_011541.1:g.47515T>C`, `NM_001141945.3:c.55T>C`, `NM_001320855.2:c.55T>C`, `NM_001406462.1:c.55T>C`, `NM_001406463.1:c.55T>C`, `NM_001406464.1:c.55T>C`, `NM_001406466.1:c.55T>C`, `NM_001406467.1:c.55T>C`, `NM_001406468.1:c.55T>C`, `NM_001406469.1:c.55T>C`, `NM_001406471.1:c.55T>C`, `NM_001613.4:c.55T>C`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.9982) — concordant with the pathogenic call
- REVEL 0.764 (pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -14.519 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 7.969, GERP 0.737, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 27.7**. 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.*
- Regional missense constraint: **o/e 0.47** across the covering region of the MANE Select transcript (88,935,226–88,948,930), spanning 13,704 bp. Chi-square p 5.8e-32. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (A>C, Δ0.34 donor 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-03-11.

**Submitter consensus:** unanimous (2/2 Likely pathogenic).

**Submission history:** 2 submissions (2021–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-03-11 |
| Blueprint Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2021-07-28 |

## Associated conditions {#conditions}

[aortic aneurysm, familial thoracic 6](https://sugi.bio/atlas/disease/aortic-aneurysm-familial-thoracic-6/).

**Reported phenotype names (ClinVar):** Aortic aneurysm, familial thoracic 6, ACTA2-related disorder, FAMILIAL THORACIC AORTIC ANEURYSM WITH LIVEDO RETICULARIS AND IRIS FLOCCULI, ACTA2-related condition, ACTA2-related disorders.

## Similar variants {#similar}

Related ACTA2 variant pages (same residue, condition, or type): [ACTA2 p.Cys19Ser](/variant/acta2-p-cys19ser), [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).

### 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 1054067). 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.*