CRB2 p.Pro46=
c.138G>A · rs758099882 · VCV2968207
Likely benign
Single submitter
Classification
Likely benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
very rare (popmax 0.00331%, sas)
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 -16 | GERP -5.3 |
| Overall | ||
| CADD | 0.063 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.00331%
South Asian · 3/90,750 alleles
Filtering AF
0.000878%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.000444%
Overall
0.000438%
7/1,597,610 alleles · very rare
exomes 6/1,445,432 · genomes 1/152,178 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| South Asiangrpmax | 0.00331% | 30,250 |
| European (non-Finnish) | 0.000343% | 291,795 |
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
- CRB2
- Protein
- p.Pro46=
- Coding
- c.138G>A
- MANE Select
- NM_173689
- dbSNP
- rs758099882
- Type
- single nucleotide variant
- Location
- chr9:123362908 (GRCh38)
- Gene constraint
- LOEUF 1.202 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 76.95 · 1 PDB
- Residue 46
- the 'required for maximum inhibition of app amyloid-beta peptide secretion' region; a UniProt-annotated variant site (in)
Similar variants
- CRB2 p.Pro46Leu Benign/Likely benign ★★ ⚠ same residue
- CRB2 p.Arg275Ter Pathogenic ★★ same type
- CRB2 p.Cys105Ter Pathogenic/Likely pathogenic ★★ same type
- CRB2 p.Gly1205Ser Pathogenic/Likely pathogenic ★★ ⚠ same type
- CRB2 p.Trp759Ter Pathogenic ★★ same type
- CRB2 p.Ala1042Thr Uncertain significance ★★ ⚠ same type
- CRB2 p.Ala1266Pro Uncertain significance ★★ ⚠ same type
- CRB2 p.Ala228Thr 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/crb2-p-pro46 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown