SIX2 p.Pro235=
c.705G>A · rs146943650 · VCV2184901
Benign/Likely benign
Multiple submitters
Classification
Benign/Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 2 submitters
gnomAD v4.1
Rare
rare (popmax 0.32%, afr)
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 -1.9 | GERP -2.5 |
| Overall | ||
| CADD | 5.623 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.32%
African / African-American · 240/75,068 alleles
Filtering AF
0.286%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.274%
Overall
0.0173%
280/1,613,954 alleles · rare
exomes 144/1,461,622 · genomes 136/152,332 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| African / African-Americangrpmax | 0.32% | 313 |
| Middle Eastern | 0.033% | 3,031 |
| Remaining individualsnot grpmax-eligible | 0.0144% | 6,944 |
| East Asian | 0.0134% | 7,479 |
| Admixed American | 0.00666% | 15,007 |
| South Asian | 0.00329% | 30,362 |
| European (non-Finnish) | 0.00136% | 73,740 |
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
- SIX2
- Protein
- p.Pro235=
- Coding
- c.705G>A
- MANE Select
- NM_016932
- dbSNP
- rs146943650
- Type
- single nucleotide variant
- Location
- chr2:45006341 (GRCh38)
- Gene constraint
- LOEUF 1.24 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 75.99
- Residue 235
- the 'disordered' region
Similar variants
- SIX2 p.Pro235Leu Uncertain significance ★★ ⚠ same residue
- SIX2 p.Asn280Ser Uncertain significance ★★ ⚠ same type
- SIX2 p.Gly220Val Uncertain significance ★★ ⚠ same type
- SIX2 p.Gly261Ser Uncertain significance ★★ ⚠ same type
- SIX2 p.Pro236Leu Uncertain significance ★★ ⚠ same type
- SIX2 p.Pro250Leu Uncertain significance ★★ ⚠ same type
- SIX2 p.Pro258Leu Uncertain significance ★★ ⚠ same type
- SIX2 p.Ser212Trp 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/six2-p-pro235 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown