Benign
Multiple submitters
Classification
Benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 11 submitters
gnomAD v4.1
Common
common (popmax 97.9%, eas) — too common for a highly-penetrant pathogenic allele
Conditions
1
holoprosencephaly 2
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Splicing | ||
| SpliceAI | <0.2 | no splice effect predicted · four deltas, not one · how we know |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP 2.8 | GERP -0.45, phastCons 1 |
| Overall | ||
| CADD | 12.55 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
97.9%
East Asian · 42,992/43,910 alleles
Filtering AF
97.1%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 96.8%
Overall
92.6%
1,469,448/1,586,652 alleles · common
exomes 1,326,848/1,434,578 · genomes 142,600/152,074 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| East Asiangrpmax | 97.9% | 1 |
| African / African-American | 97.4% | 1 |
| Amishnot grpmax-eligible | 95.9% | 1 |
| Admixed American | 93.1% | 1 |
| Remaining individualsnot grpmax-eligible | 92.9% | 1 |
| Ashkenazi Jewishnot grpmax-eligible | 92.6% | 1 |
| European (non-Finnish) | 92.4% | 1 |
| Finnishnot grpmax-eligible | 92.1% | 1 |
| Middle Eastern | 92% | 1 |
| South Asian | 88.5% | 1 |
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.Ala314=
- Coding
- c.942A>G
- MANE Select
- NM_005413
- dbSNP
- rs338074
- Type
- single nucleotide variant
- Location
- chr2:44944703 (GRCh38)
- Gene constraint
- LOEUF 0.387 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 70.38
- Residue 314
- the 'disordered' region
Similar variants
- 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
- SIX3 p.Gly317Ser 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-ala314 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown