Benign
Single submitter
Classification
Benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Common
common (popmax 19.7%, mid) — too common for a highly-penetrant pathogenic allele
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Splicing | ||
| Splice region | donor +331 | deep intronic (+331 nt into the intron) |
|---|---|---|
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 0.6 | GERP 0.6 |
| Non-coding constraint | Z 0.91 | 1 kb window · o/e 0.92 · regional · uncalibrated |
| Overall | ||
| CADD | 6.084 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
19.7%
Middle Eastern · 58/294 alleles
Filtering AF
16.4%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 16%
Overall
12.3%
18,672/151,984 alleles · common
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Middle Easterngrpmax | 19.7% | 5 |
| Ashkenazi Jewishnot grpmax-eligible | 18.3% | 5 |
| East Asian | 17.3% | 6 |
| African / African-American | 16.1% | 6 |
| Admixed American | 15.4% | 6 |
| Remaining individualsnot grpmax-eligible | 15.3% | 7 |
| South Asian | 12% | 8 |
| European (non-Finnish) | 9.33% | 11 |
| Finnishnot grpmax-eligible | 7.39% | 14 |
| Amishnot grpmax-eligible | 3.63% | 28 |
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
- ACTN2
- Coding
- c.126+331G>C
- MANE Select
- NM_001103
- dbSNP
- rs644401
- Type
- single nucleotide variant
- Location
- chr1:236687130 (GRCh38)
- Gene constraint
- LOEUF 0.432 · pLI 1.00 (gnomAD)
- Structure
- AlphaFold pLDDT 84.88 · 18 PDB
Similar variants
- 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
- ACTN2 c.1108-10A>G Uncertain significance ★★ same type
- ACTN2 c.1255+1G>C Uncertain significance ★★ same type
- ACTN2 c.126+2T>G Uncertain significance ★★ same type
- ACTN2 c.127-3C>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-c-126-plus-331g-c (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown