SIX3 p.Ala20=
c.60C>A · rs370774455 · VCV2887093
Likely benign
Single submitter
Classification
Likely benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
very rare (popmax 0.00127%, nfe)
Conditions
1
holoprosencephaly 2
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 0.61 | GERP -1.4, phastCons 1 |
| Overall | ||
| CADD | 12.3 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.00127%
European (non-Finnish) · 15/1,179,386 alleles
Filtering AF
0.000764%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.000606%
Overall
0.000938%
15/1,598,314 alleles · very rare
exomes 15/1,446,390 · genomes 0/151,924 · joint denominator
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
- SIX3
- Protein
- p.Ala20=
- Coding
- c.60C>A
- MANE Select
- NM_005413
- dbSNP
- rs370774455
- Type
- single nucleotide variant
- Location
- chr2:44942164 (GRCh38)
- Gene constraint
- LOEUF 0.387 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 70.38
Similar variants
- SIX3 p.Ala20Ser Benign ★★ same residue
- SIX3 p.Ala72Val Uncertain significance ★★ ⚠ same condition
- SIX3 p.Arg146Cys Uncertain significance ★★ ⚠ same condition
- SIX3 p.Arg201His Uncertain significance ★★ ⚠ same condition
- SIX3 p.Arg281Ser Uncertain significance ★★ same condition
- SIX3 p.Asp205His Uncertain significance ★★ ⚠ same condition
- SIX3 p.Gly103Arg Uncertain significance ★★ ⚠ same condition
- SIX3 p.Gly244Cys Uncertain significance ★★ ⚠ same condition
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/six3-p-ala20 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown