APP p.Arg486=
c.1458G>A · VCV4692826
Uncertain significance
Single submitter
Classification
Uncertain significance
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
very rare (popmax 0.00667%, amr)
Conditions
1
Alzheimer disease
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal. | ||
| REVEL | 0.453 | indeterminate |
|---|---|---|
| Splicing | ||
| SpliceAI | Δ0.28 | donor gain · deltas |
| Pangolin | Δ0.35 | loss · gain 0.23 · SpliceAI calls gain · independent |
| Constraint at this position | ||
| Conservation | phyloP 6 | GERP 2.7, phastCons 1 |
| Overall | ||
| CADD | 22.6 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.00667%
Admixed American · 4/59,966 alleles
Filtering AF
0.00226%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.00135%
Overall
0.000496%
8/1,613,648 alleles · very rare
exomes 6/1,461,788 · genomes 2/151,860 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Admixed Americangrpmax | 0.00667% | 14,991 |
| European (non-Finnish) | 0.000339% | 294,989 |
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.Arg486=
- Coding
- c.1458G>A
- MANE Select
- NM_000484
- Type
- single nucleotide variant
- Location
- chr21:25975070 (GRCh38)
- Gene constraint
- LOEUF 0.41 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
- Structure
- AlphaFold pLDDT 68.11 · 263 PDB
- Residue 486
- the e2 domain
Similar variants
- APP p.Arg486Gln Uncertain significance ★★ ⚠ same residue
- 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
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-arg486 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown