SIX3 p.Asp331Glu
c.993T>G · VCV3774938
Uncertain significance
Single submitter
Classification
Uncertain significance
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
AlphaMissense
likely pathogenic
0.6767 · ACMG-weighted
gnomAD v4.1
Absent
absent from gnomAD v4.1
Missense predictors
1/2 damaging
AlphaMissense, SaProt · REVEL no call
Computational evidence
| Protein change | ||
| AlphaMissense | 0.6767 | likely pathogenic |
|---|---|---|
| REVEL | 0.33 | indeterminate |
| SaProt | LLR -6.06 | tolerated |
| ⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call. | ||
| Splicing | ||
| SpliceAI | Δ0.55 | donor gain · deltas |
| Pangolin | Δ0.63 | gain · loss 0.00 · agrees with SpliceAI · independent |
| Constraint at this position | ||
| Conservation | phyloP 5 | GERP -0.6, phastCons 1 |
| Regional constraint | o/e 1.18 | unconstrained · MANE · 189 bp · p 0.083 · regional, not allelic |
| Overall | ||
| CADD | 28.3 | PHRED · no single calibrated threshold — expert panels disagree |
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
gnomAD v4.1 · exomes + genomes
Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.
Variant & gene context
- Gene
- SIX3
- Protein
- p.Asp331Glu
- Coding
- c.993T>G
- MANE Select
- NM_005413
- Type
- single nucleotide variant
- Location
- chr2:44944754 (GRCh38)
- Gene constraint
- LOEUF 0.387 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 70.38
- Residue 331
- the 'disordered' region
Similar variants
- SIX3 p.Asp331= Likely benign same residue
- SIX3 p.Ala72Val Uncertain significance ★★ ⚠ same type
- SIX3 p.Arg146Cys Uncertain significance ★★ ⚠ same type
- SIX3 p.Arg201His Uncertain significance ★★ ⚠ same type
- SIX3 p.Arg281Ser Uncertain significance ★★ same type
- SIX3 p.Asp205His Uncertain significance ★★ ⚠ same type
- SIX3 p.Gly103Arg Uncertain significance ★★ ⚠ same type
- SIX3 p.Gly244Cys 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/six3-p-asp331glu (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown