ACTA1 p.Ile73fs
c.217dup · rs1571893878 · VCV817462
ClinGen expert panel — Congenital Myopathies VCEP
Pathogenic for alpha-actinopathy. Applied ACMG criteria (verbatim):
PVS1 PM2_Supporting PM3
Curation rationale (ClinGen, verbatim)
The NM_001100.4:c.217dup (p.Ile73fs*11) variant in ACTA1 is a frameshift variant that is expected to result in nonsense-mediated mRNA decay and is present in biologically-relevant transcripts (PVS1). The variant is absent from gnomAD v4.1.0 (PM2_Supporting). There is no published data on this variant, however Invitae has reported the variant in one proband, who presented with hypotonia (SCV001201868.3). In addition, this proband carried the variant of interest in trans with a second ACTA1 variant c.782A>T (p.Glu261Val) that has been classified as pathogenic at Invitae (PM3). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive alpha-actinopathy. ACMG/AMP criteria met, as specified by the congenital myopathies VCEP: PVS1, PM2_Supporting, PM3 (ClinGen Congenital Myopathies VCEP specifications version 1; 08/07/2024).
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Consequence | frameshift | predicted loss-of-function |
|---|---|---|
| NMD | predicted | premature termination codon in exon 3 of 7 |
| Splicing | ||
| SpliceAI | — | not assessed · substitutions only |
| Constraint at this position | ||
| Conservation | phyloP 11 | GERP 2.6, phastCons 1 |
Predicted loss-of-function is descriptive, not an applied PVS1 code.
Population frequency
No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.
Variant & gene context
- Gene
- ACTA1
- Protein
- p.Ile73fs
- Coding
- c.217dup
- MANE Select
- NM_001100
- dbSNP
- rs1571893878
- Type
- Duplication
- Location
- chr1:229432792 (GRCh38)
- Gene constraint
- LOEUF 0.931 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 95.21 · 5 PDB
- Residue 73
- a β-strand
Similar variants
- ACTA1 c.809-13dup Benign ★★★ same condition
- ACTA1 c.809-18dup Benign/Likely benign ★★ same condition
- ACTA1 p.Ile73Ser Likely pathogenic ★ same residue
- ACTA1 p.Ile73Val Pathogenic ★ ⚠ same residue
- ACTA1 p.Lys330fs Uncertain significance ★ same condition
- ACTA1 c.809-13_809-12dup Likely benign ★ same condition
- ACTA1 c.617-5C>A Likely pathogenic ★★★ same condition
- ACTA1 c.990+1G>T Pathogenic ★★★ same condition
Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →
Cite Sugi Variant
Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/acta1-p-ile73fs (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown