PSEN2 p.Pro28=
c.84G>A · rs371475270 · VCV748858
Likely benign
Multiple submitters
Classification
Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 3 submitters
gnomAD v4.1
Rare
very rare (popmax 0.00667%, amr)
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 -11 | GERP -3 |
| Overall | ||
| CADD | 0.177 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.00667%
Admixed American · 4/59,994 alleles
Filtering AF
0.0047%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.00431%
Overall
0.00514%
83/1,613,948 alleles · very rare
exomes 78/1,461,742 · genomes 5/152,206 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Admixed Americangrpmax | 0.00667% | 14,999 |
| European (non-Finnish) | 0.00585% | 17,101 |
| African / African-American | 0.00534% | 18,736 |
| Remaining individualsnot grpmax-eligible | 0.0032% | 31,239 |
| Finnishnot grpmax-eligible | 0.00313% | 31,991 |
| East Asian | 0.00223% | 44,872 |
| South Asian | 0.0011% | 91,082 |
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
- PSEN2
- Protein
- p.Pro28=
- Coding
- c.84G>A
- MANE Select
- NM_000447
- dbSNP
- rs371475270
- Type
- single nucleotide variant
- Location
- chr1:226881991 (GRCh38)
- Gene constraint
- LOEUF 0.85 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 71.99 · 2 PDB
- Residue 28
- the 'disordered' region
Similar variants
- PSEN2 p.Pro28Leu Uncertain significance ★ ⚠ same residue
- PSEN2 p.Pro28Thr Uncertain significance ★ same residue
- PSEN2 p.Asn141Ile Pathogenic ★★ same type
- PSEN2 p.Thr122Pro Pathogenic/Likely pathogenic ★★ same type
- PSEN2 c.*20G>A Uncertain significance ★★ same type
- PSEN2 p.Ala237Val Uncertain significance ★★ ⚠ same type
- PSEN2 p.Ala258Thr Uncertain significance ★★ ⚠ same type
- PSEN2 p.Ala291Val 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/psen2-p-pro28 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown