# NM_005159.5(ACTC1):c.717G>A (p.Glu239=)

https://sugi.bio/variant/actc1-p-glu239

## Summary

**ACTC1 p.Glu239= (c.717G>A)** is classified **Likely benign** in ACTC1 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-31). Very rare (popmax 0.00801%, afr); Associated with hypertrophic cardiomyopathy 11.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs369019849 · 6 submitters · 5 linked conditions · very rare (popmax 0.00801%, afr)

## For patients & families {#patients}

This is a change in the ACTC1 gene that is classified as likely benign — not considered disease-causing, submitted by 6 submitters, and is linked to hypertrophic cardiomyopathy 11.

*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.*

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0024889/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ACTC1](https://sugi.bio/atlas/gene/ACTC1/) |
| Protein change (HGVS p.) | p.Glu239= |
| Coding change (HGVS c.) | c.717G>A |
| dbSNP | [rs369019849](https://www.ncbi.nlm.nih.gov/snp/rs369019849/) |
| Variant type | single nucleotide variant |
| Location | chr15:34792181-34792181 (GRCh38) |
| ClinVar | [VCV629731](https://www.ncbi.nlm.nih.gov/clinvar/variation/629731/) |

**All HGVS expressions:** `LRG_388:g.8546G>A`, `LRG_388t1:c.717G>A`, `NC_000015.10:g.34792181C>T`, `NC_000015.9:g.35084382C>T`, `NG_007553.1:g.8546G>A`, `NM_005159.5:c.717G>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 2.223, GERP 1.41, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 11.82**. 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 **0.00801%** (afr) · FAF95 0.00604% · FAF99 0.00557% · 6/74,950 in the highest group · 96/1,614,126 alleles overall — very rare (popmax 0.00801%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00801% | 12,492 |
| European (non-Finnish) | 0.00729% | 13,721 |
| Remaining individuals (not grpmax-eligible) | 0.0048% | 20,829 |
| Finnish (not grpmax-eligible) | 0.00156% | 64,044 |

*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 2026-01-31.

**Submitter consensus:** conflicting (5 Likely benign, 1 Likely Benign).

**Submission history:** 6 submissions (2018–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Color Diagnostics, LLC DBA Color Health | Likely benign | criteria provided, single submitter | clinical testing | 2018-10-17 |
| All of Us Research Program, National Institutes of Health | Likely Benign | criteria provided, single submitter | clinical testing | 2023-12-13 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2020-09-08 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-31 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2022-09-01 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2023-10-19 |

## Associated conditions {#conditions}

[hypertrophic cardiomyopathy 11](https://sugi.bio/atlas/disease/hypertrophic-cardiomyopathy-11/), [cardiomyopathy](https://sugi.bio/atlas/disease/cardiomyopathy/), [hypertrophic cardiomyopathy](https://sugi.bio/atlas/disease/hypertrophic-cardiomyopathy/), [atrial septal defect 5](https://sugi.bio/atlas/disease/atrial-septal-defect-5/), [dilated cardiomyopathy 1R](https://sugi.bio/atlas/disease/dilated-cardiomyopathy-1r/).

**Reported phenotype names (ClinVar):** Hypertrophic cardiomyopathy 11, Cardiomyopathy, Atrial septal defect 5, Dilated cardiomyopathy 1R, Cardiovascular phenotype, not provided, Hypertrophic cardiomyopathy, not specified, ACTC1-Related Familial Hypertrophic Cardiomyopathy, none provided.

### 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 629731). 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.*