SIX5 p.Pro699=
c.2097C>T · rs140206626 · VCV2081460
Likely benign
Single submitter
Classification
Likely benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
ultra-rare (popmax 0.0617%, 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 -8.9 | GERP -2.8 |
| Overall | ||
| CADD | 0.109 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0617%
Admixed American · 37/60,004 alleles
Filtering AF
0.0459%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.0405%
Overall
0.0174%
280/1,612,672 alleles · ultra-rare
exomes 254/1,460,374 · genomes 26/152,298 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Admixed Americangrpmax | 0.0617% | 1,622 |
| African / African-American | 0.032% | 3,126 |
| Remaining individualsnot grpmax-eligible | 0.0304% | 3,289 |
| European (non-Finnish) | 0.0166% | 6,018 |
| East Asian | 0.00446% | 22,436 |
| Finnishnot grpmax-eligible | 0.00158% | 63,162 |
| South Asian | 0.0011% | 91,026 |
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
- SIX5
- Protein
- p.Pro699=
- Coding
- c.2097C>T
- MANE Select
- NM_175875
- dbSNP
- rs140206626
- Type
- single nucleotide variant
- Location
- chr19:45765624 (GRCh38)
- Gene constraint
- LOEUF 1.08 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 53.21
Similar variants
- SIX5 p.Pro699Arg Uncertain significance ★ ⚠ same residue
- SIX5 p.Pro699Ser Uncertain significance ★ ⚠ same residue
- SIX5 p.Ala408Thr Uncertain significance ★★ ⚠ same type
- SIX5 p.Ala411Val Uncertain significance ★★ ⚠ same type
- SIX5 p.Ala584Val Uncertain significance ★★ ⚠ same type
- SIX5 p.Ala626Thr Uncertain significance ★★ ⚠ same type
- SIX5 p.Ala649Ser Uncertain significance ★★ ⚠ same type
- SIX5 p.Ala673Thr 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/six5-p-pro699 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown