Is APP p.Glu693Lys (c.2077G>A) pathogenic?

APP p.Glu693Lys (c.2077G>A) is classified Pathogenic in APP (ClinVar, Single submitter, 3 submitters; last evaluated 2025-08-20). AlphaMissense: ambiguous (0.4093); Absent from gnomAD v4.1; Associated with Alzheimer disease.

What condition is associated with APP p.Glu693Lys (c.2077G>A)?

APP p.Glu693Lys (c.2077G>A) is associated with Alzheimer disease, ABeta amyloidosis, Italian type (ClinVar).

How common is APP p.Glu693Lys (c.2077G>A) in the general population?

APP p.Glu693Lys (c.2077G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about APP p.Glu693Lys (c.2077G>A)?

AlphaMissense predicts ambiguous (score 0.4093) — an in-silico prediction, not a clinical call.

APP p.Glu693Lys

c.2077G>A · rs63750579 · VCV18099

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4093 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Alzheimer disease

Computational evidence

Protein change
AlphaMissense	0.4093	ambiguous
REVEL	0.774	moderately pathogenic-leaning
SaProt	LLR -7.78	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 289 kb · p 2e-07 · regional, not allelic
Overall
CADD	29.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: APP
Protein: p.Glu693Lys
Coding: c.2077G>A
MANE Select: NM_000484
dbSNP: rs63750579
Type: single nucleotide variant
Location: chr21:25891856 (GRCh38)
Gene constraint: LOEUF 0.41 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.11 · 263 PDB
Residue 693: a UniProt-annotated variant site (in ad1); a UniProt-annotated variant site (in caa-app; italian type); a UniProt-annotated variant site (in caa-app; dutch type); a β-strand

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

Also linked: ABeta amyloidosis, Italian type

Similar variants

APP p.Glu693Gln Pathogenic ★★ ⚠ same residue
APP p.Glu693= Likely benign ★ same residue
APP p.Glu693Gly Pathogenic ⚠ same residue
APP p.Ala713Thr Likely pathogenic ★★ ⚠ same condition
APP p.Asp694Asn Pathogenic ★★ ⚠ same condition
APP p.Ile716Phe Pathogenic ★★ ⚠ same condition
APP p.Thr714Ala Pathogenic ★★ ⚠ same condition
APP p.Val715Met Pathogenic/Likely 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-glu693lys (accessed [today's date]).

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