Is APP p.Glu665del (c.1990GAG[1]) pathogenic?

APP p.Glu665del (c.1990GAG[1]) is classified Uncertain significance in APP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-24). Very rare (popmax 0.00549%, sas); Associated with Alzheimer disease.

What condition is associated with APP p.Glu665del (c.1990GAG[1])?

APP p.Glu665del (c.1990GAG[1]) is associated with Alzheimer disease (ClinVar).

How common is APP p.Glu665del (c.1990GAG[1]) in the general population?

APP p.Glu665del (c.1990GAG[1]) is very rare (popmax 0.00549%, sas) (gnomAD).

APP p.Glu665del

c.1990GAG[1] · VCV4809004

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00549%, sas)

Conditions

Alzheimer disease

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 6.1	GERP 1.9, phastCons 1

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00549% South Asian · 5/91,076 alleles

Filtering AF 0.0021% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00136%

Overall 0.00173% 28/1,613,972 alleles · very rare exomes 28/1,461,698 · genomes 0/152,274 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00549%	18,215
Remaining individualsnot grpmax-eligible	0.0032%	31,254
Admixed American	0.00167%	60,030
European (non-Finnish)	0.00161%	62,100
African / African-American	0.00133%	75,028

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.Glu665del
Coding: c.1990GAG[1]
MANE Select: NM_000484
Type: Microsatellite
Location: chr21:25897642 (GRCh38)
Gene constraint: LOEUF 0.41 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.11 · 263 PDB
Residue 665: a UniProt-annotated variant site (in a patient with late onset alzheimer disease)

Full APP gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Alzheimer disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

APP p.Glu665Asp Uncertain significance ★★ ⚠ same residue
APP p.Glu241_Ala242insGlu Uncertain significance ★ same condition
APP p.Glu241del Uncertain significance ★ same condition
APP p.Thr278_Thr280del Uncertain significance ★ same condition
APP p.Thr279_Thr280del Uncertain significance ★ same condition
APP p.Thr279_Thr280dup Uncertain significance ★ same condition
APP p.Thr280dup Conflicting classifications of pathogenicity ★ same condition
APP c.1091-20_1091-18del Likely benign ★ 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-glu665del (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown