SIX5 p.Thr552=
c.1656G>A · rs149475634 · VCV708831
Likely benign
Multiple submitters
Classification
Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 7 submitters
gnomAD v4.1
Rare
rare (popmax 0.172%, nfe)
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 -10 | GERP -3.1 |
| Overall | ||
| CADD | 1.139 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.172%
European (non-Finnish) · 2,027/1,179,226 alleles
Filtering AF
0.166%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.163%
Overall
0.13%
2,092/1,611,876 alleles · rare
| Ancestry group | Frequency | 1 in |
|---|---|---|
| European (non-Finnish)grpmax | 0.172% | 582 |
| Remaining individualsnot grpmax-eligible | 0.0545% | 1,836 |
| African / African-American | 0.0293% | 3,408 |
| Middle Eastern | 0.0165% | 6,054 |
| Admixed American | 0.00335% | 29,865 |
| South Asian | 0.00331% | 30,243 |
| Finnishnot grpmax-eligible | 0.00315% | 31,754 |
| East Asian | 0.00223% | 44,802 |
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.Thr552=
- Coding
- c.1656G>A
- MANE Select
- NM_175875
- dbSNP
- rs149475634
- Type
- single nucleotide variant
- Location
- chr19:45766065 (GRCh38)
- Gene constraint
- LOEUF 1.08 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 53.21
- Residue 552
- a UniProt-annotated variant site (in bor2; affects eya1 binding and the ability to activate gene transcription)
Similar variants
- SIX5 p.Thr552Met 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-thr552 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown