APP p.Lys134=
c.402A>G · rs768518732 · VCV742020
Likely benign
Multiple submitters
Classification
Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 2 submitters
gnomAD v4.1
Rare
ultra-rare (popmax 0.0736%, sas)
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| REVEL | 0.344 | indeterminate |
|---|---|---|
| Splicing | ||
| SpliceAI | <0.2 | all four deltas below 0.2 · T>A here scores Δ0.38 · evaluated, not missing |
| Constraint at this position | ||
| Conservation | phyloP -0.2 | GERP -5.1, phastCons 0.59 |
| Overall | ||
| CADD | 9.105 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0736%
South Asian · 67/91,074 alleles
Filtering AF
0.0593%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.0542%
Overall
0.00421%
68/1,613,724 alleles · ultra-rare
| Ancestry group | Frequency | 1 in |
|---|---|---|
| South Asiangrpmax | 0.0736% | 1,359 |
| Remaining individualsnot grpmax-eligible | 0.0016% | 62,482 |
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.Lys134=
- Coding
- c.402A>G
- MANE Select
- NM_000484
- dbSNP
- rs768518732
- Type
- single nucleotide variant
- Location
- chr21:26053302 (GRCh38)
- Gene constraint
- LOEUF 0.41 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
- Structure
- AlphaFold pLDDT 68.11 · 263 PDB
- Residue 134
- the e1 domain; a β-strand; the 'cubd subdomain' region; a disulfide bond
Similar variants
- APP p.Lys134Arg Likely benign ★ 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-lys134 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown