# NM_001613.4(ACTA2):c.338A>G (p.Asn113Ser)

https://sugi.bio/variant/acta2-p-asn113ser

## Summary

**ACTA2 p.Asn113Ser (c.338A>G)** is classified **Uncertain significance** in ACTA2 (ClinVar, No assertion criteria, 1 submitter). AlphaMissense: likely pathogenic (0.9114); Absent from gnomAD v4.1; Associated with aortic aneurysm, familial thoracic 6.

**At a glance:** Uncertain significance · review: No assertion criteria · rsID rs397516680 · 1 submitter · 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 currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, 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.Asn113Ser |
| Coding change (HGVS c.) | c.338A>G |
| MANE Select transcript | [NM_001613](https://www.ncbi.nlm.nih.gov/nuccore/NM_001613) |
| dbSNP | [rs397516680](https://www.ncbi.nlm.nih.gov/snp/rs397516680/) |
| Variant type | single nucleotide variant |
| Location | chr10:88943828-88943828 (GRCh38) |
| ClinVar | [VCV1328395](https://www.ncbi.nlm.nih.gov/clinvar/variation/1328395/) |

**All HGVS expressions:** `LRG_781:g.52563A>G`, `LRG_781t1:c.338A>G`, `LRG_781t2:c.338A>G`, `NC_000010.10:g.90703585T>C`, `NC_000010.11:g.88943828T>C`, `NG_011541.1:g.52563A>G`, `NM_001141945.3:c.338A>G`, `NM_001320855.2:c.338A>G`, `NM_001406462.1:c.338A>G`, `NM_001406463.1:c.338A>G`, `NM_001406464.1:c.338A>G`, `NM_001406467.1:c.209A>G`, `NM_001406468.1:c.209A>G`, `NM_001406469.1:c.209A>G`, `NM_001406471.1:c.338A>G`, `NM_001613.4:c.338A>G`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.9114)
- REVEL 0.856 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -10.458 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 7.856, GERP 1.82, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 24.9**. 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: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- 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}

**Uncertain significance** — review status No assertion criteria *(no assertion criteria provided)*.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Institute of Human Genetics, Cologne University | Uncertain significance | no assertion criteria provided | clinical testing |  |

## 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, FAMILIAL THORACIC AORTIC ANEURYSM WITH LIVEDO RETICULARIS AND IRIS FLOCCULI.

## Similar variants {#similar}

Related ACTA2 variant pages (same residue, condition, or type): [ACTA2 p.Asn113Asp](/variant/acta2-p-asn113asp), [ACTA2 p.Asn113=](/variant/acta2-p-asn113), [ACTA2 p.Asn113Thr](/variant/acta2-p-asn113thr), [ACTA2 p.Asn113Tyr](/variant/acta2-p-asn113tyr), [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).

### 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 1328395). 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.*