# NM_005159.5(ACTC1):c.970_973del (p.Pro324fs)

https://sugi.bio/variant/actc1-p-pro324fs

## Summary

**ACTC1 p.Pro324fs (c.970_973del)** is classified **Uncertain significance** in ACTC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-27). No gnomAD frequency available for this variant; Associated with hypertrophic cardiomyopathy 11.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2504177247 · 1 submitter · 3 linked conditions · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the ACTC1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, 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.*

|  |  |
| --- | --- |
| Diagnostic panels | ACTC1 is a diagnostic-grade gene on 12 Genomics England panels |

**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.Pro324fs |
| Coding change (HGVS c.) | c.970_973del |
| MANE Select transcript | [NM_005159](https://www.ncbi.nlm.nih.gov/nuccore/NM_005159) |
| dbSNP | [rs2504177247](https://www.ncbi.nlm.nih.gov/snp/rs2504177247/) |
| Variant type | Deletion |
| Location | chr15:34791131-34791134 (GRCh38) |
| ClinVar | [VCV1999277](https://www.ncbi.nlm.nih.gov/clinvar/variation/1999277/) |

**All HGVS expressions:** `LRG_388:g.9593_9596del`, `LRG_388t1:c.970_973del`, `NC_000015.10:g.34791131_34791134del`, `NC_000015.9:g.35083332_35083335del`, `NG_007553.1:g.9593_9596del`, `NM_001406482.1:c.970_973delCCTA`, `NM_001406483.1:c.970_973delCCTA`, `NM_001406484.1:c.835_838delCCTA`, `NM_001406485.1:c.529_532delCCTA`, `NM_005159.5:c.970_973del`

## 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 7.717, GERP 2.33, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. the gene is **loss-of-function-intolerant** (LOEUF 0.511, pLI 0.97314), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **within the last 50 nt of the penultimate exon (6 of 7, 17 nt from its 3' end)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**ACTC1** population constraint: LOEUF 0.511, pLI 0.97314, missense-Z 6.3225; 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):

- **hypertrophic cardiomyopathy** — Definitive (AD)
- **dilated cardiomyopathy 1R** — Moderate (AD)
- **arrhythmogenic right ventricular cardiomyopathy** — No Known Disease Relationship (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 95.47, 93% of residues very-high.

**16 experimental structure(s)** (PDB): [8GSU](https://www.rcsb.org/structure/8GSU), [8GSW](https://www.rcsb.org/structure/8GSW), [8GT1](https://www.rcsb.org/structure/8GT1), [8GT2](https://www.rcsb.org/structure/8GT2), [8GT3](https://www.rcsb.org/structure/8GT3), [8GT4](https://www.rcsb.org/structure/8GT4) — incl. mutant structure 8GSW.

## What this gene does {#gene-function}

*Describes the biological roles of ACTC1 (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.*

**How this variant is thought to act:** ACTC1's established molecular role includes microfilament motor activity.


### Pathways affected {#pathways}

ACTC1 participates in **6 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [RHOA GTPase cycle](https://reactome.org/content/detail/R-HSA-8980692) | curated |
| [RHOB GTPase cycle](https://reactome.org/content/detail/R-HSA-9013026) | curated |
| [Regulation of CDH1 Function](https://reactome.org/content/detail/R-HSA-9764561) | curated |
| [Striated Muscle Contraction](https://reactome.org/content/detail/R-HSA-390522) | 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}

**Molecular function:** microfilament motor activity, ATP binding, myosin binding.

**Biological process:** actin filament-based movement, actin-myosin filament sliding, heart contraction.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-05-27.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-05-27 |

## Associated conditions {#conditions}

[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 11, Atrial septal defect 5, Dilated cardiomyopathy 1R, ACTC1-Related Familial Hypertrophic Cardiomyopathy.

## Similar variants {#similar}

Related ACTC1 variant pages (same residue, condition, or type): [ACTC1 p.Pro324Ser](/variant/actc1-p-pro324ser), [ACTC1 p.Asp186fs](/variant/actc1-p-asp186fs), [ACTC1 c.991-10_991-8del](/variant/actc1-c-991-minus-10-991-minus-8del), [ACTC1 c.119_129+14del](/variant/actc1-c-119-129-plus-14del), [ACTC1 c.616+4_616+7del](/variant/actc1-c-616-plus-4-616-plus-7del), [ACTC1 c.991-2del](/variant/actc1-c-991-minus-2del), [ACTC1 p.Gly148fs](/variant/actc1-p-gly148fs), [ACTC1 p.Gly345fs](/variant/actc1-p-gly345fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 1999277). 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.*