LRP6 p.Cys308=
c.924T>C · rs7978064 · VCV1244687
Benign
Multiple submitters
Classification
Benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 4 submitters
gnomAD v4.1
Common
common (popmax 29.6%, afr) — too common for a highly-penetrant pathogenic allele
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 4 | GERP 1.5, phastCons 1 |
| Overall | ||
| CADD | 9.409 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
29.6%
African / African-American · 22,178/74,932 alleles
Filtering AF
29.3%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 29.1%
Overall
9.98%
160,859/1,612,258 alleles · common
exomes 138,722/1,460,012 · genomes 22,137/152,246 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| African / African-Americangrpmax | 29.6% | 3 |
| Admixed American | 13.8% | 7 |
| Amishnot grpmax-eligible | 11.3% | 9 |
| Remaining individualsnot grpmax-eligible | 10% | 10 |
| European (non-Finnish) | 9.52% | 11 |
| Ashkenazi Jewishnot grpmax-eligible | 8.64% | 12 |
| Middle Eastern | 7.89% | 13 |
| Finnishnot grpmax-eligible | 7.22% | 14 |
| South Asian | 4.32% | 23 |
| East Asian | 0.604% | 166 |
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
- LRP6
- Protein
- p.Cys308=
- Coding
- c.924T>C
- MANE Select
- NM_002336
- dbSNP
- rs7978064
- Type
- single nucleotide variant
- Location
- chr12:12184032 (GRCh38)
- Gene constraint
- LOEUF 0.27 · pLI 1.00 (gnomAD)
- Structure
- AlphaFold pLDDT 79.87 · 30 PDB
- Residue 308
- the egf-like 1 domain; a β-strand; a disulfide bond
Similar variants
- LRP6 c.3207-2A>G Likely pathogenic ★★ same type
- LRP6 p.Arg335Ter Pathogenic/Likely pathogenic ★★ same type
- LRP6 p.Arg415Ter Pathogenic/Likely pathogenic ★★ same type
- LRP6 p.Arg585Ter Pathogenic/Likely pathogenic ★★ same type
- LRP6 p.Arg644Ter Pathogenic ★★ same type
- LRP6 p.Arg728Ter Pathogenic ★★ same type
- LRP6 p.Arg990Ter Pathogenic ★★ same type
- LRP6 p.Ala1304Thr 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/lrp6-p-cys308 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown