Is APP p.Glu241del (c.713AAG[3]) pathogenic?

APP p.Glu241del (c.713AAG[3]) is classified Uncertain significance in APP (ClinVar, Single submitter, 2 submitters; last evaluated 2025-11-25). Ultra-rare (popmax 0.0825%, mid); Associated with Alzheimer disease.

What condition is associated with APP p.Glu241del (c.713AAG[3])?

APP p.Glu241del (c.713AAG[3]) is associated with Alzheimer disease (ClinVar).

How common is APP p.Glu241del (c.713AAG[3]) in the general population?

APP p.Glu241del (c.713AAG[3]) is ultra-rare (popmax 0.0825%, mid) (gnomAD).

APP p.Glu241del

c.713AAG[3] · rs754150568 · VCV1437591

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0825%, mid)

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 2.4	GERP -2.8, phastCons 0.99
Overall
CADD	12.83	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0825% Middle Eastern · 5/6,062 alleles

Filtering AF 0.0324% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.021%

Overall 0.00471% 76/1,613,784 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0825%	1,212
Admixed American	0.0133%	7,496
Remaining individualsnot grpmax-eligible	0.0096%	10,415
Finnishnot grpmax-eligible	0.00781%	12,796
African / African-American	0.00534%	18,738
European (non-Finnish)	0.00373%	26,815
South Asian	0.00329%	30,357
East Asian	0.00223%	44,864

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.Glu241del
Coding: c.713AAG[3]
MANE Select: NM_000484
dbSNP: rs754150568
Type: Microsatellite
Location: chr21:26021981 (GRCh38)
Gene constraint: LOEUF 0.41 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.11 · 263 PDB
Residue 241: the 'disordered' region

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.Glu241_Ala242insGlu Uncertain significance ★ same residue
APP p.Glu665del 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
APP c.866-10_866-8del 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-glu241del (accessed [today's date]).

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