# NM_001100.4(ACTA1):c.84_85insT (p.Pro29fs)

https://sugi.bio/variant/acta1-p-pro29fs

## Summary

**ACTA1 p.Pro29fs (c.84_85insT)** is classified **Pathogenic** in ACTA1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-04-12). Very rare (popmax 0.00833%, amr); Associated with congenital myopathy 2a, typical, autosomal dominant.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs753923758 · 2 submitters · 1 linked condition · very rare (popmax 0.00833%, amr)

## For patients & families {#patients}

This is a change in the ACTA1 gene that is considered disease-causing, submitted by 2 submitters, and is linked to congenital myopathy 2a, typical, autosomal dominant.

*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 |
| Diagnostic panels | ACTA1 is a diagnostic-grade gene on 8 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0010111/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.Pro29fs |
| Coding change (HGVS c.) | c.84_85insT |
| MANE Select transcript | [NM_001100](https://www.ncbi.nlm.nih.gov/nuccore/NM_001100) |
| dbSNP | [rs753923758](https://www.ncbi.nlm.nih.gov/snp/rs753923758/) |
| Variant type | Insertion |
| Location | chr1:229433031-229433032 (GRCh38) |
| ClinVar | [VCV464132](https://www.ncbi.nlm.nih.gov/clinvar/variation/464132/) |

**All HGVS expressions:** `LRG_429:g.6065_6066insT`, `LRG_429t1:c.84_85insT`, `NC_000001.10:g.229568778_229568779insA`, `NC_000001.11:g.229433031_229433032insA`, `NG_006672.1:g.6065_6066insT`, `NM_001100.4:c.84_85insT`

## Computational & population evidence {#evidence}

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

- **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 11.722, GERP 2.57, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.931, pLI 3.1036e-06. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 2 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 insertion 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 **0.00833%** (amr) · FAF95 0.00323% · FAF99 0.00206% · 5/60,032 in the highest group · 5/1,461,544 alleles overall — very rare (popmax 0.00833%, amr).

*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}


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 Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-04-12.

**Submitter consensus:** unanimous (2/2 Pathogenic).

**Submission history:** 2 submissions (2024–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-08-03 |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2026-04-12 |

## Associated conditions {#conditions}

[congenital myopathy 2a, typical, autosomal dominant](https://sugi.bio/atlas/disease/congenital-myopathy-2a-typical-autosomal-dominant/).

**Reported phenotype names (ClinVar):** Actin accumulation myopathy, not provided, none provided, CONGENITAL MYOPATHY 2A, TYPICAL, AUTOSOMAL DOMINANT, Nemaline myopathy type 3, Myopathy, actin, congenital, with excess of thin myofilaments, Myopathy, actin, congenital, with cores, Nemaline myopathy 3, with intranuclear rods.

## Similar variants {#similar}

Related ACTA1 variant pages (same residue, condition, or type): [ACTA1 c.809-14_809-13insA](/variant/acta1-c-809-minus-14-809-minus-13insa), [ACTA1 c.809-14_809-13insT](/variant/acta1-c-809-minus-14-809-minus-13inst), [ACTA1 c.809-16_809-15insA](/variant/acta1-c-809-minus-16-809-minus-15insa), [ACTA1 c.809-16_809-15insG](/variant/acta1-c-809-minus-16-809-minus-15insg), [ACTA1 c.809-18_809-17insG](/variant/acta1-c-809-minus-18-809-minus-17insg), [ACTA1 c.809-18_809-17insT](/variant/acta1-c-809-minus-18-809-minus-17inst), [ACTA1 c.617-5C>A](/variant/acta1-c-617-minus-5c-a), [ACTA1 c.990+1G>T](/variant/acta1-c-990-plus-1g-t).

### 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 464132). 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.*