# NM_001100.4(ACTA1):c.1000C>T (p.Pro334Ser)

https://sugi.bio/variant/acta1-p-pro334ser

## Summary

**ACTA1 p.Pro334Ser (c.1000C>T)** is classified **Pathogenic** in ACTA1 (ClinVar, Expert panel, 5 submitters; last evaluated 2024-10-25). AlphaMissense: likely pathogenic (0.958); Absent from gnomAD v4.1; Associated with alpha-actinopathy.

**At a glance:** Pathogenic · review: Expert panel · rsID rs121909531 · 5 submitters · 5 linked conditions · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the ACTA1 gene that is considered disease-causing, submitted by 5 submitters, and is linked to alpha-actinopathy.

*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/0026038/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ACTA1](https://sugi.bio/atlas/gene/ACTA1/) |
| Protein change (HGVS p.) | p.Pro334Ser |
| Coding change (HGVS c.) | c.1000C>T |
| MANE Select transcript | [NM_001100](https://www.ncbi.nlm.nih.gov/nuccore/NM_001100) |
| dbSNP | [rs121909531](https://www.ncbi.nlm.nih.gov/snp/rs121909531/) |
| Variant type | single nucleotide variant |
| Location | chr1:229431633-229431633 (GRCh38) |
| ClinVar | [VCV18291](https://www.ncbi.nlm.nih.gov/clinvar/variation/18291/) |

**All HGVS expressions:** `LRG_429:g.7464C>T`, `LRG_429t1:c.1000C>T`, `NC_000001.10:g.229567380G>A`, `NC_000001.11:g.229431633G>A`, `NG_006672.1:g.7464C>T`, `NM_001100.4:c.1000C>T`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.958) — concordant with the pathogenic call
- REVEL 0.919 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -14.193 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 9.823, GERP 2.61, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 27.2**. 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 0.33** across the covering region of the MANE Select transcript (229,431,502–229,433,115), spanning 1,613 bp — the region is depleted of missense variation. Chi-square p 1.6e-54. 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}

**ACTA1** population constraint: LOEUF 0.931, pLI 3.1036e-06, missense-Z 6.0949. *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):

- **alpha-actinopathy** — Definitive (AR)
- **alpha-actinopathy** — Definitive (AD)

## Protein context {#protein}

Residue **334** lies in a UniProt-annotated variant site (in cmyo2c).

AlphaFold model confidence (whole protein): pLDDT 95.21, 92% of residues very-high.

**5 experimental structure(s)** (PDB): [7RNS](https://www.rcsb.org/structure/7RNS), [7RNU](https://www.rcsb.org/structure/7RNU), [7RNV](https://www.rcsb.org/structure/7RNV), [9DUU](https://www.rcsb.org/structure/9DUU), [9DUV](https://www.rcsb.org/structure/9DUV).

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

*Describes the biological roles of ACTA1 (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.*


### Pathways affected {#pathways}

ACTA1 participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [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}

**Biological process:** skeletal muscle thin filament assembly.

## Clinical significance {#significance}

**Pathogenic** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2024-10-25.

**Submitter consensus:** conflicting (2 Pathogenic, 2 Likely pathogenic, 1 not provided).

**Submission history:** 5 submissions (2004–2024); classifications have differed over time.

**ClinGen expert panel:** Pathogenic — Congenital Myopathies VCEP (alpha-actinopathy). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `PM2_Supporting`, `PS3`, `PP2`, `PP3`, `PP4`, `PM5`.
Inheritance: Autosomal dominant inheritance.

> **Curation rationale (ClinGen, verbatim):** The c.1000C>T (NM_001100.4(ACTA1):c.1000C>T (p.Pro334Ser)) variant in ACTA1 is a missense variant predicted to cause substitution of proline by serine at amino acid 334 (p.Pro334Ser). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). ACTA1, in which the variant was identified, is defined by the ClinGen Congenital Myopathies VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). The computational predictor REVEL gives a score of 0.919, which is above the threshold of 0.7, evidence that correlates with impact to ACTA1 function (PP3). 2 different missense variants, [p.Pro334Leu, (VCV000532770); p.Pro334Arg, (VCV001031829)], in the same codon have been classified as likely pathogenic for autosomal dominant alpha-actinopathy by the ClinGen Congenital Myopathies VCEP (PM5). One patient with the p.Pro334Ser variant displayed fiber type disproportion, which is highly specific for alpha-actinopathy (PP4, PMID: 15468086 & University of Western Australia internal data). Localization analysis of the mutant in myotubes showed no incorporation into nascent sarcomeres. Analysis in fibroblasts showed diffuse cytoplasmic myc-actin staining (PMID: 19206168; PS3). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant alpha-actinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PM2_supporting, PP2, PP3, PM5, PP4, PS3 (ClinGen Congenital Myopathies VCEP Specifications Version 2.0; 10/25/24).
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50031 · approved 2024-10-25 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/0700c61d-d15f-4e6d-b5eb-4aacac32eeb5).*
*These are ClinGen's applied codes, reported verbatim — Sugi Variant does not re-tally or combine them into its own classification.*

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneReviews | not provided | no classification provided | literature only |  |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2004-11-01 |
| Solve-RD Consortium | Likely pathogenic | no assertion criteria provided | provider interpretation | 2022-06-01 |
| ClinGen Congenital Myopathies Variant Curation Expert Panel, ClinGen | Pathogenic | reviewed by expert panel | curation | 2024-10-25 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-07-06 |

## Associated conditions {#conditions}

[alpha-actinopathy](https://sugi.bio/atlas/disease/alpha-actinopathy/), [congenital myopathy 2a, typical, autosomal dominant](https://sugi.bio/atlas/disease/congenital-myopathy-2a-typical-autosomal-dominant/), [congenital fiber-type disproportion myopathy](https://sugi.bio/atlas/disease/congenital-fiber-type-disproportion-myopathy/), [progressive scapulohumeroperoneal distal myopathy](https://sugi.bio/atlas/disease/progressive-scapulohumeroperoneal-distal-myopathy/), [congenital myopathy 2c, severe infantile, autosomal dominant](https://sugi.bio/atlas/disease/congenital-myopathy-2c-severe-infantile-autosomal-dominant/).

**Reported phenotype names (ClinVar):** Alpha-actinopathy, Congenital myopathy with fiber type disproportion, Actin accumulation myopathy, Congenital myopathy 2c, severe infantile, autosomal dominant, Progressive scapulohumeroperoneal distal myopathy, Actinopathy, Myopathy, scapulohumeroperoneal, CONGENITAL MYOPATHY 2A, TYPICAL, AUTOSOMAL DOMINANT, Nemaline myopathy type 3, Myopathy, actin, congenital, with excess of thin myofilaments.

## Same-residue context {#hotspot}

Residue **334** carries **2 other pathogenic ClinVar variants** — a recurrently-mutated position: [ACTA1 p.Pro334Arg](/variant/acta1-p-pro334arg), [ACTA1 p.Pro334Leu](/variant/acta1-p-pro334leu). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related ACTA1 variant pages (same residue, condition, or type): [ACTA1 p.Pro334Arg](/variant/acta1-p-pro334arg), [ACTA1 p.Pro334Leu](/variant/acta1-p-pro334leu), [ACTA1 p.Pro334Ala](/variant/acta1-p-pro334ala), [ACTA1 p.Pro334fs](/variant/acta1-p-pro334fs), [ACTA1 c.617-5C>A](/variant/acta1-c-617-minus-5c-a), [ACTA1 c.990+1G>T](/variant/acta1-c-990-plus-1g-t), [ACTA1 p.Asp13Asn](/variant/acta1-p-asp13asn), [ACTA1 p.Asp290His](/variant/acta1-p-asp290his).

### 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 18291). 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.*