# NM_005159.5(ACTC1):c.622C>A (p.Arg208Ser)

https://sugi.bio/variant/actc1-p-arg208ser

## Summary

**ACTC1 p.Arg208Ser (c.622C>A)** is classified **Uncertain significance** in ACTC1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-12-15). AlphaMissense: likely pathogenic (0.9963); Absent from gnomAD v4.1; Associated with dilated cardiomyopathy 1R.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs727505179 · 3 submitters · 3 linked conditions · AlphaMissense likely pathogenic · 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 3 submitters, and is linked to dilated cardiomyopathy 1R.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant, Autosomal recessive, Mitochondrial inheritance |
| Age of onset (of this condition) | All ages |
| 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/0015661/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.Arg208Ser |
| Coding change (HGVS c.) | c.622C>A |
| MANE Select transcript | [NM_005159](https://www.ncbi.nlm.nih.gov/nuccore/NM_005159) |
| dbSNP | [rs727505179](https://www.ncbi.nlm.nih.gov/snp/rs727505179/) |
| Variant type | single nucleotide variant |
| Location | chr15:34792276-34792276 (GRCh38) |
| ClinVar | [VCV2574201](https://www.ncbi.nlm.nih.gov/clinvar/variation/2574201/) |

**All HGVS expressions:** `LRG_388:g.8451C>A`, `LRG_388t1:c.622C>A`, `NC_000015.10:g.34792276G>T`, `NC_000015.9:g.35084477G>T`, `NG_007553.1:g.8451C>A`, `NM_001406482.1:c.622C>A`, `NM_001406483.1:c.622C>A`, `NM_001406484.1:c.487C>A`, `NM_001406485.1:c.181C>A`, `NM_005159.5:c.622C>A`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.9963)
- REVEL 0.876 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -14.008 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 11.907, GERP 2.33, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 31.0**. 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 0.16** across the covering region of the MANE Select transcript (34,791,266–34,793,379), spanning 2,113 bp — the region is depleted of missense variation. Chi-square p 8.3e-37. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- 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 **208** 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 2024-12-15.

**Submitter consensus:** unanimous (3/3 Uncertain significance).

**Submission history:** 3 submissions (2022–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-01-31 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-12-15 |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-05-02 |

## Associated conditions {#conditions}

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

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

## Similar variants {#similar}

Related ACTC1 variant pages (same residue, condition, or type): [ACTC1 p.Arg208Cys](/variant/actc1-p-arg208cys), [ACTC1 p.Arg208His](/variant/actc1-p-arg208his), [ACTC1 p.Glu101Lys](/variant/actc1-p-glu101lys), [ACTC1 p.Val56Ile](/variant/actc1-p-val56ile), [ACTC1 p.Ala297Ser](/variant/actc1-p-ala297ser), [ACTC1 p.Gly247Asp](/variant/actc1-p-gly247asp), [ACTC1 p.Thr128Ile](/variant/actc1-p-thr128ile), [ACTC1 c.455-6G>A](/variant/actc1-c-455-minus-6g-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 2574201). 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.*