# NM_005159.5(ACTC1):c.81C>T (p.Asp27=)

https://sugi.bio/variant/actc1-p-asp27

## Summary

**ACTC1 p.Asp27= (c.81C>T)** is classified **Likely benign** in ACTC1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-03-16). Very rare (popmax 0.000339%, nfe); Associated with hypertrophic cardiomyopathy.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs753552901 · 4 submitters · 5 linked conditions · very rare (popmax 0.000339%, nfe)

## For patients & families {#patients}

This is a change in the ACTC1 gene that is classified as likely benign — not considered disease-causing, submitted by 4 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.Asp27= |
| Coding change (HGVS c.) | c.81C>T |
| dbSNP | [rs753552901](https://www.ncbi.nlm.nih.gov/snp/rs753552901/) |
| Variant type | single nucleotide variant |
| Location | chr15:34794728-34794728 (GRCh38) |
| ClinVar | [VCV1171030](https://www.ncbi.nlm.nih.gov/clinvar/variation/1171030/) |

**All HGVS expressions:** `LRG_388:g.5999C>T`, `LRG_388t1:c.81C>T`, `NC_000015.10:g.34794728G>A`, `NC_000015.9:g.35086929G>A`, `NG_007553.1:g.5999C>T`, `NM_005159.5:c.81C>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 -0.852, GERP -4.66 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 7.903**. 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 **0.000339%** (nfe) · FAF95 7.9e-05% · FAF99 5.4e-05% · 4/1,179,832 in the highest group · 5/1,613,252 alleles overall — very rare (popmax 0.000339%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,466 |
| European (non-Finnish) (grpmax) | 0.000339% | 294,958 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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 2025-03-16.

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

**Submission history:** 4 submissions (2020–2025); 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 | 2020-08-17 |
| Phosphorus, Inc. | Likely benign | criteria provided, single submitter | clinical testing | 2022-01-14 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-03-16 |
| 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/), [cardiomyopathy](https://sugi.bio/atlas/disease/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, Cardiomyopathy, not specified, Atrial septal defect 5, Dilated cardiomyopathy 1R, Hypertrophic cardiomyopathy 11, HYPERTROPHIC MYOCARDIOPATHY, AllHighlyPenetrant, Cardiomyopathies, ACTC1-Related Familial Hypertrophic Cardiomyopathy.

### 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 1171030). 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.*