# NM_005159.5(ACTC1):c.839C>G (p.Thr280Ser)

https://sugi.bio/variant/actc1-p-thr280ser

## Summary

**ACTC1 p.Thr280Ser (c.839C>G)** is classified **Uncertain significance** in ACTC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-05). AlphaMissense: likely benign (0.1867); Absent from gnomAD v4.1; Associated with cardiomyopathy.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1566967118 · 1 submitter · 1 linked condition · AlphaMissense likely benign · absent from gnomAD v4.1

## 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 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 | 333 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.Thr280Ser |
| Coding change (HGVS c.) | c.839C>G |
| MANE Select transcript | [NM_005159](https://www.ncbi.nlm.nih.gov/nuccore/NM_005159) |
| dbSNP | [rs1566967118](https://www.ncbi.nlm.nih.gov/snp/rs1566967118/) |
| Variant type | single nucleotide variant |
| Location | chr15:34791265-34791265 (GRCh38) |
| ClinVar | [VCV630098](https://www.ncbi.nlm.nih.gov/clinvar/variation/630098/) |

**All HGVS expressions:** `LRG_388:g.9462C>G`, `LRG_388t1:c.839C>G`, `NC_000015.10:g.34791265G>C`, `NC_000015.9:g.35083466G>C`, `NG_007553.1:g.9462C>G`, `NM_005159.5:c.839C>G`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.1867)
- REVEL 0.791 (moderately pathogenic-leaning) — differs from AlphaMissense
- SaProt LLR -10.611 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** REVEL and SaProt call this damaging; AlphaMissense does not
- SpliceAI predicts **acceptor loss** (Δ 0.32) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 11.902, GERP 2.33, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 26.9**. 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.*
- Regional missense constraint: **o/e 0.35** across the covering region of the MANE Select transcript (34,790,415–34,791,265), spanning 850 bp — the region is depleted of missense variation. Chi-square p 1.5e-13. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.32**, donor loss **0.00**, acceptor gain **0.01**, donor gain **0.00**. Largest is acceptor loss, 10 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.01**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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 **280** 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 Single submitter *(criteria provided, single submitter)*, last evaluated 2023-12-05.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Color Diagnostics, LLC DBA Color Health | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-12-05 |

## Associated conditions {#conditions}

[cardiomyopathy](https://sugi.bio/atlas/disease/cardiomyopathy/).

**Reported phenotype names (ClinVar):** Cardiomyopathy, Cardiomyopathies.

## Similar variants {#similar}

Related ACTC1 variant pages (same residue, condition, or type): [ACTC1 p.Thr280=](/variant/actc1-p-thr280), [ACTC1 p.Glu101Lys](/variant/actc1-p-glu101lys), [ACTC1 p.Val56Ile](/variant/actc1-p-val56ile), [ACTC1 p.Gly247Asp](/variant/actc1-p-gly247asp), [ACTC1 c.455-6G>A](/variant/actc1-c-455-minus-6g-a), [ACTC1 c.808+4A>G](/variant/actc1-c-808-plus-4a-g), [ACTC1 c.-12A>G](/variant/actc1-c-minus-12a-g), [ACTC1 c.-1G>A](/variant/actc1-c-minus-1g-a).

### 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 630098). 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.*