# NM_005159.5(ACTC1):c.523dup (p.His175fs)

https://sugi.bio/variant/actc1-p-his175fs

## Summary

**ACTC1 p.His175fs (c.523dup)** is classified **Uncertain significance** in ACTC1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2023-10-25). Very rare (popmax 0.00178%, nfe); Associated with atrial septal defect 5.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs730880389 · 4 submitters · 4 linked conditions · very rare (popmax 0.00178%, nfe)

## 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 4 submitters, and is linked to atrial septal defect 5.

*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/0024898/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.His175fs |
| Coding change (HGVS c.) | c.523dup |
| MANE Select transcript | [NM_005159](https://www.ncbi.nlm.nih.gov/nuccore/NM_005159) |
| dbSNP | [rs730880389](https://www.ncbi.nlm.nih.gov/snp/rs730880389/) |
| Variant type | Duplication |
| Location | chr15:34792500-34792501 (GRCh38) |
| ClinVar | [VCV180754](https://www.ncbi.nlm.nih.gov/clinvar/variation/180754/) |

**All HGVS expressions:** `LRG_388:g.8226dup`, `LRG_388t1:c.523dup`, `NC_000015.10:g.34792504dup`, `NC_000015.9:g.35084705dup`, `NG_007553.1:g.8226dup`, `NM_005159.4:c.523dup`, `NM_005159.5:c.523dup`

## 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 7.932, 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 **in exon 4 of 7**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00178%** (nfe) · FAF95 0.00114% · FAF99 0.000971% · 21/1,180,022 in the highest group · 22/1,461,884 alleles overall — very rare (popmax 0.00178%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00178% | 56,191 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,510 |

*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}

Residue **175** lies in an α-helix.

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 Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2023-10-25.

**Submitter consensus:** unanimous (4/4 Uncertain significance).

**Submission history:** 4 submissions (2013–2023); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-06-02 |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2013-08-06 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-07-19 |
| Color Diagnostics, LLC DBA Color Health | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-10-25 |

## Associated conditions {#conditions}

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

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

## Similar variants {#similar}

Related ACTC1 variant pages (same residue, condition, or type): [ACTC1 p.His175=](/variant/actc1-p-his175), [ACTC1 p.His175Arg](/variant/actc1-p-his175arg), [ACTC1 p.Asn227fs](/variant/actc1-p-asn227fs), [ACTC1 c.130-11dup](/variant/actc1-c-130-minus-11dup), [ACTC1 p.Asn117delinsCysSerGlnArgProArgTer](/variant/actc1-p-asn117delinscysserglnargproargter), [ACTC1 p.Asp224fs](/variant/actc1-p-asp224fs), [ACTC1 p.Phe202fs](/variant/actc1-p-phe202fs), [ACTC1 p.Glu101Lys](/variant/actc1-p-glu101lys).

### 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 180754). 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.*