ACTN2 p.Ile234Phe
c.700A>T · VCV4945840
Uncertain significance
Single submitter
Classification
Uncertain significance
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
AlphaMissense
ambiguous
0.4332 · ACMG-weighted
gnomAD v4.1
Absent
absent from gnomAD v4.1
Missense predictors
1/2 damaging
REVEL, SaProt · AlphaMissense no call
Computational evidence
| Protein change | ||
| AlphaMissense | 0.4332 | ambiguous |
|---|---|---|
| REVEL | 0.931 | moderately pathogenic-leaning |
| SaProt | LLR -9.25 | tolerated |
| ⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 11 | GERP 2.4, phastCons 1 |
| Regional constraint | o/e 0.65 | unconstrained · MANE · 50 kb · p 1.6e-10 · regional, not allelic |
| Overall | ||
| CADD | 26.2 | PHRED · no single calibrated threshold — expert panels disagree |
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
gnomAD v4.1 · exomes + genomes
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
- ACTN2
- Protein
- p.Ile234Phe
- Coding
- c.700A>T
- MANE Select
- NM_001103
- Type
- single nucleotide variant
- Location
- chr1:236735637 (GRCh38)
- Gene constraint
- LOEUF 0.432 · pLI 1.00 (gnomAD)
- Structure
- AlphaFold pLDDT 84.88 · 18 PDB
- Residue 234
- the calponin-homology (ch) 2 domain; an α-helix; the 'actin-binding' region
Similar variants
- ACTN2 p.Ile234Leu Uncertain significance ★★ ⚠ same residue
- ACTN2 p.Ile234= Conflicting classifications of pathogenicity ★ same residue
- ACTN2 p.Ile234Asn Uncertain significance ★ ⚠ same residue
- ACTN2 p.Ile234Val Uncertain significance ★ ⚠ same residue
- ACTN2 p.Ala119Thr Pathogenic/Likely pathogenic ★★ same type
- ACTN2 p.Leu727Arg Pathogenic/Likely pathogenic ★★ same type
- ACTN2 p.Thr247Met Likely pathogenic ★★ same type
- ACTN2 c.1107+3G>A Uncertain significance ★★ same type
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/actn2-p-ile234phe (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown