# NM_005159.5(ACTC1):c.84G>T (p.Ala28=)

https://sugi.bio/variant/actc1-p-ala28

## Summary

**ACTC1 p.Ala28= (c.84G>T)** is classified **Benign/Likely benign** in ACTC1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-11-20). Very rare (popmax 0.004%, afr); Associated with hypertrophic cardiomyopathy.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs1008290796 · 3 submitters · 4 linked conditions · very rare (popmax 0.004%, afr)

## For patients & families {#patients}

This is a change in the ACTC1 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 3 submitters, and is linked to hypertrophic cardiomyopathy.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 233 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [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.Ala28= |
| Coding change (HGVS c.) | c.84G>T |
| dbSNP | [rs1008290796](https://www.ncbi.nlm.nih.gov/snp/rs1008290796/) |
| Variant type | single nucleotide variant |
| Location | chr15:34794725-34794725 (GRCh38) |
| ClinVar | [VCV760930](https://www.ncbi.nlm.nih.gov/clinvar/variation/760930/) |

**All HGVS expressions:** `LRG_388:g.6002G>T`, `LRG_388t1:c.84G>T`, `NC_000015.10:g.34794725C>A`, `NC_000015.9:g.35086926C>A`, `NG_007553.1:g.6002G>T`, `NM_005159.5:c.84G>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 -1.154, GERP -4.66 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 10.34**. 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 **0.004%** (afr) · FAF95 0.00106% · FAF99 0.000495% · 3/74,922 in the highest group · 3/152,202 alleles overall — very rare (popmax 0.004%, afr).

*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}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2023-11-20.

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

**Submission history:** 3 submissions (2015–2023); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2023-03-19 |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2015-03-03 |
| All of Us Research Program, National Institutes of Health | Likely Benign | criteria provided, single submitter | clinical testing | 2023-11-20 |

## Associated conditions {#conditions}

[hypertrophic cardiomyopathy](https://sugi.bio/atlas/disease/hypertrophic-cardiomyopathy/), [hypertrophic cardiomyopathy 11](https://sugi.bio/atlas/disease/hypertrophic-cardiomyopathy-11/), [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, not provided, Atrial septal defect 5, Dilated cardiomyopathy 1R, Hypertrophic cardiomyopathy 11, HYPERTROPHIC MYOCARDIOPATHY, 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 760930). 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.*