APP p.Tyr549=
c.1647C>T · rs1033116485 · VCV752834
Likely benign
Single submitter
Classification
Likely benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
very rare (popmax 0.000593%, nfe)
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Splicing | ||
| SpliceAI | <0.2 | all four deltas below 0.2 · G>C here scores Δ0.26 · evaluated, not missing |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP 5.9 | GERP 2.1, phastCons 1 |
| Overall | ||
| CADD | 9.388 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.000593%
European (non-Finnish) · 7/1,180,012 alleles
Filtering AF
0.000247%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.000159%
Overall
0.000479%
7/1,461,800 alleles · very rare
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.Tyr549=
- Coding
- c.1647C>T
- MANE Select
- NM_000484
- dbSNP
- rs1033116485
- Type
- single nucleotide variant
- Location
- chr21:25954630 (GRCh38)
- Gene constraint
- LOEUF 0.41 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
- Structure
- AlphaFold pLDDT 68.11 · 263 PDB
- Residue 549
- the e2 domain; an α-helix
Similar variants
- APP p.Tyr549Cys Uncertain significance ★ ⚠ same residue
- 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
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-tyr549 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown