APP p.Tyr588=
c.1764C>T · VCV4946000
Likely benign
Single submitter
Classification
Likely benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
ultra-rare (popmax 0.0164%, mid)
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 -5.4 | GERP -3.6 |
| Overall | ||
| CADD | 1.191 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0164%
Middle Eastern · 1/6,084 alleles
Filtering AF
0.000738%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.000276%
Overall
0.000372%
6/1,614,048 alleles · ultra-rare
exomes 4/1,461,878 · genomes 2/152,170 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Middle Easterngrpmax | 0.0164% | 6,084 |
| East Asian | 0.00445% | 22,450 |
| African / African-American | 0.00133% | 74,912 |
| European (non-Finnish) | 0.000169% | 590,016 |
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.Tyr588=
- Coding
- c.1764C>T
- MANE Select
- NM_000484
- Type
- single nucleotide variant
- Location
- chr21:25911886 (GRCh38)
- Gene constraint
- LOEUF 0.41 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
- Structure
- AlphaFold pLDDT 68.11 · 263 PDB
Similar variants
- APP p.Ala713Thr Likely pathogenic ★★ ⚠ same type
- APP p.Asp694Asn Pathogenic ★★ ⚠ same type
- APP p.Glu693Gln Pathogenic ★★ ⚠ same type
- APP p.Ile716Phe Pathogenic ★★ ⚠ same type
- APP p.Thr714Ala Pathogenic ★★ ⚠ same type
- APP p.Val715Met Pathogenic/Likely pathogenic ★★ ⚠ same type
- APP p.Val717Ile Pathogenic ★★ ⚠ same type
- APP p.Val717Phe Pathogenic ★★ ⚠ 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/app-p-tyr588 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown