SIX1 p.Val231=
c.693C>A · VCV3753556
Uncertain significance
Single submitter
Classification
Uncertain significance
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
very rare (popmax 0.000847%, nfe)
Conditions
2
branchiootic syndrome 3
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 |
|---|---|---|
| Pangolin | Δ0.30 | gain · loss 0.00 · not in the SpliceAI release · independent |
| Constraint at this position | ||
| Conservation | phyloP 2.1 | GERP -1.7, phastCons 1 |
| Overall | ||
| CADD | 7.951 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.000847%
European (non-Finnish) · 10/1,179,998 alleles
Filtering AF
0.000429%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.000312%
Overall
0.000684%
10/1,461,890 alleles · very rare
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
- SIX1
- Protein
- p.Val231=
- Coding
- c.693C>A
- MANE Select
- NM_005982
- Type
- single nucleotide variant
- Location
- chr14:60646445 (GRCh38)
- Gene constraint
- LOEUF 0.692 · pLI 0.26 · ClinGen HI 0/3 (gnomAD)
- Structure
- AlphaFold pLDDT 76.87 · 1 PDB
- Residue 231
- the 'disordered' region
Similar variants
- SIX1 p.Arg110Gln Pathogenic/Likely pathogenic ★★ same condition
- SIX1 p.Arg110Trp Pathogenic ★★ same condition
- SIX1 p.Glu125Lys Pathogenic/Likely pathogenic ★★ same condition
- SIX1 p.Tyr129Cys Pathogenic ★★ same condition
- SIX1 p.Val106Met Likely pathogenic ★★ same condition
- SIX1 p.Ala184Thr Uncertain significance ★★ same condition
- SIX1 p.Arg119His Uncertain significance ★★ ⚠ same condition
- SIX1 p.Arg140Gln Uncertain significance ★★ ⚠ 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/six1-p-val231 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown