Benign/Likely benign
Multiple submitters
Classification
Benign/Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 4 submitters
gnomAD v4.1
Rare
low-frequency (popmax 3.09%, afr)
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| REVEL | 0.299 | indeterminate |
|---|---|---|
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 6.6 | phastCons 1 |
| Overall | ||
| CADD | 12.08 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
3.09%
African / African-American · 2,317/75,044 alleles
Filtering AF
2.98%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 2.94%
Overall
0.168%
2,707/1,614,196 alleles · low-frequency
exomes 1,302/1,461,868 · genomes 1,405/152,328 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| African / African-Americangrpmax | 3.09% | 32 |
| Admixed American | 0.32% | 313 |
| Middle Eastern | 0.231% | 433 |
| Remaining individualsnot grpmax-eligible | 0.205% | 488 |
| European (non-Finnish) | 0.00458% | 21,852 |
| South Asian | 0.0022% | 45,544 |
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.Pro644=
- Coding
- c.1932C>T
- MANE Select
- NM_001130004
- dbSNP
- rs181465
- Type
- single nucleotide variant
- Location
- chr14:68882479 (GRCh38)
- Gene constraint
- LOEUF 0.331 · pLI 1.00 (gnomAD)
- Structure
- AlphaFold pLDDT 85.39 · 4 PDB
- Residue 644
- 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-pro644 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown