APP p.Pro299=
c.897G>A · VCV3607527
Likely benign
Single submitter
Classification
Likely benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
ultra-rare (popmax 0.011%, sas)
Conditions
1
Alzheimer disease
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| REVEL | 0.065 | moderately benign-leaning |
|---|---|---|
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP -4.4 | GERP -3.9 |
| Overall | ||
| CADD | 8.055 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.011%
South Asian · 10/91,086 alleles
Filtering AF
0.00594%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.00453%
Overall
0.000991%
16/1,614,204 alleles · ultra-rare
exomes 13/1,461,864 · genomes 3/152,340 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| South Asiangrpmax | 0.011% | 9,109 |
| Admixed American | 0.00167% | 60,028 |
| Remaining individualsnot grpmax-eligible | 0.0016% | 62,506 |
| European (non-Finnish) | 0.000339% | 295,009 |
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
- APP
- Protein
- p.Pro299=
- Coding
- c.897G>A
- MANE Select
- NM_000484
- Type
- single nucleotide variant
- Location
- chr21:26000151 (GRCh38)
- Gene constraint
- LOEUF 0.41 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
- Structure
- AlphaFold pLDDT 68.11 · 263 PDB
- Residue 299
- the bpti/kunitz inhibitor domain; a β-strand
Similar variants
- APP p.Ala713Thr Likely pathogenic ★★ ⚠ same condition
- APP p.Asp694Asn Pathogenic ★★ ⚠ same condition
- APP p.Glu693Gln Pathogenic ★★ ⚠ same condition
- APP p.Ile716Phe Pathogenic ★★ ⚠ same condition
- APP p.Thr714Ala Pathogenic ★★ ⚠ same condition
- APP p.Val715Met Pathogenic/Likely pathogenic ★★ ⚠ same condition
- APP p.Val717Ile Pathogenic ★★ ⚠ same condition
- APP p.Val717Phe Pathogenic ★★ ⚠ same condition
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/app-p-pro299 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown