SIX5 p.Val421=
c.1263C>T · rs866476748 · VCV1638145
Likely benign
Single submitter
Classification
Likely benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
very rare (popmax 0.00364%, sas)
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Splicing | ||
| SpliceAI | <0.2 | all four deltas below 0.2 · G>T here scores Δ0.73 · evaluated, not missing |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP 1.2 | GERP -3.2, phastCons 0.002 |
| Overall | ||
| CADD | 0.47 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.00364%
South Asian · 3/82,458 alleles
Filtering AF
0.000966%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.000673%
Overall
0.00144%
22/1,530,774 alleles · very rare
exomes 21/1,378,624 · genomes 1/152,150 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| South Asiangrpmax | 0.00364% | 27,486 |
| Admixed American | 0.00208% | 48,080 |
| Finnishnot grpmax-eligible | 0.00182% | 54,948 |
| Remaining individualsnot grpmax-eligible | 0.0017% | 58,974 |
| European (non-Finnish) | 0.0014% | 71,211 |
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.Val421=
- Coding
- c.1263C>T
- MANE Select
- NM_175875
- dbSNP
- rs866476748
- Type
- single nucleotide variant
- Location
- chr19:45766696 (GRCh38)
- Gene constraint
- LOEUF 1.08 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 53.21
Similar variants
- SIX5 p.Val421Ala Uncertain significance ★ ⚠ same residue
- SIX5 p.Val421Ile 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-val421 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown