SIX5 p.Ala681=
c.2043G>A · rs370312363 · VCV1984842
Likely benign
Single submitter
Classification
Likely benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
ultra-rare (popmax 0.0143%, sas)
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 -12 | GERP -2.7 |
| Overall | ||
| CADD | 0.356 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0143%
South Asian · 13/91,070 alleles
Filtering AF
0.00844%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.00661%
Overall
0.00155%
25/1,612,666 alleles · ultra-rare
| Ancestry group | Frequency | 1 in |
|---|---|---|
| South Asiangrpmax | 0.0143% | 7,005 |
| African / African-American | 0.00534% | 18,734 |
| East Asian | 0.00223% | 44,888 |
| Admixed American | 0.00167% | 60,014 |
| European (non-Finnish) | 0.000509% | 196,604 |
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.Ala681=
- Coding
- c.2043G>A
- MANE Select
- NM_175875
- dbSNP
- rs370312363
- Type
- single nucleotide variant
- Location
- chr19:45765678 (GRCh38)
- Gene constraint
- LOEUF 1.08 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 53.21
Similar variants
- SIX5 p.Ala681Val Conflicting classifications of pathogenicity ★ ⚠ 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
- SIX5 p.Ala722Gly 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-ala681 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown