ACTA1 p.Glu59Lys
c.175G>A · rs2527439307 · VCV2582036
ClinGen expert panel — Congenital Myopathies VCEP
Likely Pathogenic for alpha-actinopathy. Applied ACMG criteria (verbatim):
PM6 PM2_Supporting PS4_Supporting PP2 PP3
Curation rationale (ClinGen, verbatim)
The NM_001100.4:c.175G>A variant in ACTA1 is a missense variant predicted to cause substitution of glutamate by lysine at amino acid 59 (p.Glu59Lys). The variant is absent from gnomAD v4.1.0 meeting PM2_Supporting. The REVEL computational prediction analysis tool gives a score of 0.855, which is above the threshold necessary to apply PP3. 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. The Z-score in gnomAD v4.1 is 4.53 (PP2). This variant has been reported in at least three probands, of which one was a de novo occurrence with unconfirmed parental relationships (PS4_Supporting, PM6; GeneDx, Harry Perkins Institute Of Medical Research, LabCorp internal data, ClinVar: SCV004040176.2, SCV004041839.1). In summary, the variant meets the criteria to be classified as likely pathogenic for autosomal dominant alpha-actinopathy. ACMG/AMP criteria met, as specified by the ClinGen Congenital Myopathies VCEP: PM6, PS4_Supporting, PM2_Supporting, PP2, PP3 (ClinGen Congenital Myopathies VCEP specifications version 2.0.0; 9/9/2024).
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.998 | likely pathogenic ✓ concordant with ClinVar |
|---|---|---|
| REVEL | 0.855 | moderately pathogenic-leaning |
| SaProt | LLR -15.86 | damaging |
| ⇒ AlphaMissense, REVEL and SaProt all call this damaging. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 7.6 | GERP 2.6, phastCons 1 |
| Regional constraint | o/e 0.33 | constrained · MANE · 1,613 bp · p 1.6e-54 · regional, not allelic |
| Overall | ||
| CADD | 28.5 | PHRED · no single calibrated threshold — expert panels disagree |
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.
Variant & gene context
- Gene
- ACTA1
- Protein
- p.Glu59Lys
- Coding
- c.175G>A
- MANE Select
- NM_001100
- dbSNP
- rs2527439307
- Type
- single nucleotide variant
- Location
- chr1:229432835 (GRCh38)
- Gene constraint
- LOEUF 0.931 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 95.21 · 5 PDB
- Residue 59
- an α-helix
Similar variants
- ACTA1 p.Glu59Val Uncertain significance ★ ⚠ same residue
- ACTA1 c.617-5C>A Likely pathogenic ★★★ same condition
- ACTA1 c.990+1G>T Pathogenic ★★★ same condition
- ACTA1 p.Asp13Asn Likely pathogenic ★★★ same condition
- ACTA1 p.Asp290His Pathogenic ★★★ same condition
- ACTA1 p.Asp58Asn Likely pathogenic ★★★ same condition
- ACTA1 p.Cys376Phe Likely pathogenic ★★★ same condition
- ACTA1 p.Cys376Ser 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-glu59lys (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown