# NM_001613.4(ACTA2):c.1047C>T (p.Ala349=)

https://sugi.bio/variant/acta2-p-ala349

## Summary

**ACTA2 p.Ala349= (c.1047C>T)** is classified **Likely benign** in ACTA2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-04-23). Ultra-rare (popmax 0.0267%, afr); Associated with aortic aneurysm, familial thoracic 6.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs111352790 · 4 submitters · 2 linked conditions · ultra-rare (popmax 0.0267%, afr)

## For patients & families {#patients}

This is a change in the ACTA2 gene that is classified as likely benign — not considered disease-causing, submitted by 4 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 |

**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.Ala349= |
| Coding change (HGVS c.) | c.1047C>T |
| dbSNP | [rs111352790](https://www.ncbi.nlm.nih.gov/snp/rs111352790/) |
| Variant type | single nucleotide variant |
| Location | chr10:88935310-88935310 (GRCh38) |
| ClinVar | [VCV469082](https://www.ncbi.nlm.nih.gov/clinvar/variation/469082/) |

**All HGVS expressions:** `LRG_781:g.61081C>T`, `LRG_781t1:c.1047C>T`, `LRG_781t2:c.1047C>T`, `NC_000010.10:g.90695067G>A`, `NC_000010.11:g.88935310G>A`, `NG_011541.1:g.61081C>T`, `NM_001141945.3:c.1047C>T`, `NM_001320855.2:c.1047C>T`, `NM_001406462.1:c.1047C>T`, `NM_001406463.1:c.1047C>T`, `NM_001406464.1:c.1047C>T`, `NM_001406466.1:c.936C>T`, `NM_001406467.1:c.918C>T`, `NM_001406468.1:c.918C>T`, `NM_001406469.1:c.918C>T`, `NM_001406471.1:c.855C>T`, `NM_001613.4:c.1047C>T`, `NR_125373.1:n.935G>A`

## 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 0.199, GERP -0.808, phastCons 0.88 — weakly conserved position
- CADD: **PHRED 15.45**. 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: **not looked up on this page** — it was served without the gene's SpliceAI index, so no lookup was made. This is a gap in this page, not in the data, and says nothing about whether a splicing effect is predicted.
- Population frequency (gnomAD v4.1): grpmax **0.0267%** (afr) · FAF95 0.0177% · FAF99 0.0147% · 20/75,030 in the highest group · 31/1,613,984 alleles overall — ultra-rare (popmax 0.0267%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.0267% | 3,752 |
| Remaining individuals (not grpmax-eligible) | 0.0176% | 5,682 |

*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.*

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-04-23.

**Submitter consensus:** conflicting (3 Likely benign, 1 Likely Benign).

**Submission history:** 4 submissions (2019–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-04-23 |
| Color Diagnostics, LLC DBA Color Health | Likely benign | criteria provided, single submitter | clinical testing | 2019-06-18 |
| All of Us Research Program, National Institutes of Health | Likely Benign | criteria provided, single submitter | clinical testing | 2024-02-05 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2022-09-16 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Aortic aneurysm, familial thoracic 6, Familial thoracic aortic aneurysm and aortic dissection, FAMILIAL THORACIC AORTIC ANEURYSM WITH LIVEDO RETICULARIS AND IRIS FLOCCULI, Thoracic aortic aneurysms and dissections.

### 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 469082). 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.*