ACTN1 p.Phe440=
c.1320C>T · VCV3709548
Likely benign
Multiple submitters
Classification
Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 3 submitters
gnomAD v4.1
Rare
ultra-rare (popmax 0.0187%, nfe)
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP -3.9 | |
| Overall | ||
| CADD | 5.24 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0187%
European (non-Finnish) · 221/1,180,022 alleles
Filtering AF
0.0166%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.0159%
Overall
0.0148%
239/1,613,980 alleles · ultra-rare
exomes 218/1,461,818 · genomes 21/152,162 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| European (non-Finnish)grpmax | 0.0187% | 5,339 |
| Remaining individualsnot grpmax-eligible | 0.0128% | 7,810 |
| Finnishnot grpmax-eligible | 0.00625% | 15,996 |
| Admixed American | 0.00333% | 30,003 |
| African / African-American | 0.00267% | 37,459 |
| East Asian | 0.00223% | 44,886 |
| South Asian | 0.0011% | 91,084 |
Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.
Variant & gene context
- Gene
- ACTN1
- Protein
- p.Phe440=
- Coding
- c.1320C>T
- MANE Select
- NM_001130004
- Type
- single nucleotide variant
- Location
- chr14:68885490 (GRCh38)
- Gene constraint
- LOEUF 0.331 · pLI 1.00 (gnomAD)
- Structure
- AlphaFold pLDDT 85.39 · 4 PDB
- Residue 440
- the 'interaction with ddn' region
Similar variants
- ACTN1 p.Arg450Cys Pathogenic/Likely pathogenic ★★ same type
- ACTN1 p.Arg46Gln Pathogenic/Likely pathogenic ★★ same type
- ACTN1 p.Arg46Trp Pathogenic/Likely pathogenic ★★ same type
- ACTN1 p.Glu225Lys Pathogenic ★★ same type
- ACTN1 p.Leu547Pro Likely pathogenic ★★ same type
- ACTN1 p.Val105Ile Pathogenic/Likely pathogenic ★★ same type
- ACTN1 p.Ala255Val Uncertain significance ★★ ⚠ same type
- ACTN1 p.Ala48Val 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/actn1-p-phe440 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown