SIX5 p.Ala498=
c.1494A>G · rs755015539 · VCV2892543
Likely benign
Single submitter
Classification
Likely benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
ultra-rare (popmax 0.012%, 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 -0.12 | GERP -1.6, phastCons 0.83 |
| Overall | ||
| CADD | 8.652 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.012%
Admixed American · 6/49,950 alleles
Filtering AF
0.0052%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.00352%
Overall
0.00144%
22/1,531,258 alleles · ultra-rare
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Admixed Americangrpmax | 0.012% | 8,325 |
| Remaining individualsnot grpmax-eligible | 0.00169% | 59,102 |
| European (non-Finnish) | 0.00132% | 75,699 |
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.Ala498=
- Coding
- c.1494A>G
- MANE Select
- NM_175875
- dbSNP
- rs755015539
- Type
- single nucleotide variant
- Location
- chr19:45766465 (GRCh38)
- Gene constraint
- LOEUF 1.08 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 53.21
Similar variants
- 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
- SIX5 p.Ala722Gly Uncertain significance ★★ ⚠ same type
- SIX5 p.Asp698Glu 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-ala498 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown