APP p.Ala154=
c.462C>G · rs200398369 · VCV1159952
Likely benign
Multiple submitters
Classification
Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 2 submitters
gnomAD v4.1
Rare
very rare (popmax 8.5e-05%, nfe)
Conditions
1
Alzheimer disease
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| REVEL | 0.06 | moderately benign-leaning |
|---|---|---|
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 3.2 | GERP 2, phastCons 1 |
| Overall | ||
| CADD | 11.37 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
8.5e-05%
European (non-Finnish) · 1/1,177,026 alleles
Overall
6.86e-05%
1/1,458,550 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.Ala154=
- Coding
- c.462C>G
- MANE Select
- NM_000484
- dbSNP
- rs200398369
- Type
- single nucleotide variant
- Location
- chr21:26053242 (GRCh38)
- Gene constraint
- LOEUF 0.41 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
- Structure
- AlphaFold pLDDT 68.11 · 263 PDB
- Residue 154
- the e1 domain; an α-helix; the 'cubd subdomain' region; a disulfide bond
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-ala154 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown