SIX2 p.Pro241=
c.723G>A · rs776407664 · VCV2961892
Likely benign
Multiple submitters
Classification
Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 2 submitters
gnomAD v4.1
Rare
very rare (popmax 0.01%, amr)
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 -1.3 | GERP 0.2 |
| Overall | ||
| CADD | 7.999 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.01%
Admixed American · 6/60,002 alleles
Filtering AF
0.00428%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.00295%
Overall
0.00217%
35/1,613,802 alleles · very rare
exomes 33/1,461,568 · genomes 2/152,234 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Admixed Americangrpmax | 0.01% | 10,000 |
| East Asian | 0.00446% | 22,446 |
| South Asian | 0.00439% | 22,769 |
| African / African-American | 0.00267% | 37,470 |
| European (non-Finnish) | 0.00178% | 56,183 |
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.Pro241=
- Coding
- c.723G>A
- MANE Select
- NM_016932
- dbSNP
- rs776407664
- Type
- single nucleotide variant
- Location
- chr2:45006323 (GRCh38)
- Gene constraint
- LOEUF 1.24 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 75.99
- Residue 241
- the 'disordered' region; a UniProt-annotated variant site (in a renal hypodysplasia patient)
Similar variants
- SIX2 p.Pro241Leu Benign/Likely benign ★★ 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.Pro258Leu 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-pro241 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown