APP p.Ile716=
c.2148C>A · rs145564988 · VCV585432
Benign
Multiple submitters
Classification
Benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 3 submitters
gnomAD v4.1
Rare
rare (popmax 0.702%, afr)
Conditions
1
Alzheimer disease
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 0.47 | GERP -3.9, phastCons 0.81 |
| Overall | ||
| CADD | 3.857 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.702%
African / African-American · 527/75,026 alleles
Filtering AF
0.653%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.633%
Overall
0.0379%
611/1,614,022 alleles · rare
exomes 302/1,461,794 · genomes 309/152,228 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| African / African-Americangrpmax | 0.702% | 142 |
| Remaining individualsnot grpmax-eligible | 0.0864% | 1,157 |
| Admixed American | 0.04% | 2,500 |
| South Asian | 0.0022% | 45,535 |
| European (non-Finnish) | 0.000339% | 294,986 |
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.Ile716=
- Coding
- c.2148C>A
- MANE Select
- NM_000484
- dbSNP
- rs145564988
- Type
- single nucleotide variant
- Location
- chr21:25891785 (GRCh38)
- Gene constraint
- LOEUF 0.41 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
- Structure
- AlphaFold pLDDT 68.11 · 263 PDB
- Residue 716
- a UniProt-annotated variant site (in ad1); a turn; the 'interaction with psen1' region
Similar variants
- APP p.Ile716Phe Pathogenic ★★ ⚠ same residue
- APP p.Ile716Thr Pathogenic ★ ⚠ same residue
- APP p.Ile716Val Pathogenic ★★ same residue
- APP p.Ile716Met Likely pathogenic ★ ⚠ same residue
- APP p.Ala713Thr Likely pathogenic ★★ ⚠ same condition
- APP p.Asp694Asn Pathogenic ★★ ⚠ same condition
- APP p.Glu693Gln Pathogenic ★★ ⚠ same condition
- APP p.Thr714Ala 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-ile716 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown