SIX2 p.Pro258=
c.774G>C · rs150988696 · VCV1569693
Likely benign
Multiple submitters
Classification
Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 3 submitters
gnomAD v4.1
Rare
rare (popmax 0.127%, 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 -5.3 | GERP -2.5 |
| Overall | ||
| CADD | 1.46 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.127%
European (non-Finnish) · 1,498/1,180,006 alleles
Filtering AF
0.122%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.119%
Overall
0.0971%
1,567/1,614,180 alleles · rare
exomes 1,474/1,461,818 · genomes 93/152,362 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| European (non-Finnish)grpmax | 0.127% | 788 |
| Remaining individualsnot grpmax-eligible | 0.0448% | 2,232 |
| Finnishnot grpmax-eligible | 0.0328% | 3,049 |
| Ashkenazi Jewishnot grpmax-eligible | 0.027% | 3,699 |
| African / African-American | 0.0147% | 6,824 |
| Admixed American | 0.00167% | 60,030 |
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.Pro258=
- Coding
- c.774G>C
- MANE Select
- NM_016932
- dbSNP
- rs150988696
- Type
- single nucleotide variant
- Location
- chr2:45006272 (GRCh38)
- Gene constraint
- LOEUF 1.24 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 75.99
- Residue 258
- the 'disordered' region
Similar variants
- SIX2 p.Pro258Leu 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.Pro235Leu Uncertain significance ★★ ⚠ same type
- SIX2 p.Pro236Leu Uncertain significance ★★ ⚠ same type
- SIX2 p.Pro250Leu 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-pro258 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown