Is APP p.Asp694Asn (c.2080G>A) pathogenic?

APP p.Asp694Asn (c.2080G>A) is classified Pathogenic in APP (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-10-20). AlphaMissense: likely benign (0.2397); Very rare (popmax 8.47e-05%, nfe); Associated with cerebral amyloid angiopathy, APP-related.

What condition is associated with APP p.Asp694Asn (c.2080G>A)?

APP p.Asp694Asn (c.2080G>A) is associated with cerebral amyloid angiopathy, APP-related, Alzheimer disease, ABeta amyloidosis, Iowa type (ClinVar).

How common is APP p.Asp694Asn (c.2080G>A) in the general population?

APP p.Asp694Asn (c.2080G>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

How is Hereditary cerebral amyloid angiopathy inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about APP p.Asp694Asn (c.2080G>A)?

AlphaMissense predicts likely benign (score 0.2397) — an in-silico prediction, not a clinical call.

APP p.Asp694Asn

c.2080G>A · rs63749810 · VCV18101

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.2397 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cerebral amyloid angiopathy, APP-related

Computational evidence

Protein change
AlphaMissense	0.2397	likely benign ⚠ discordant with ClinVar
REVEL	0.712	pathogenic-leaning
SaProt	LLR -7.26	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
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	27.4	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

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,179,998 alleles

Overall 6.84e-05% 1/1,461,816 alleles · very rare

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.Asp694Asn
Coding: c.2080G>A
MANE Select: NM_000484
dbSNP: rs63749810
Type: single nucleotide variant
Location: chr21:25891853 (GRCh38)
Gene constraint: LOEUF 0.41 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.11 · 263 PDB
Residue 694: a UniProt-annotated variant site (in caa-app; iowa type); a β-strand

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

Disease context

cerebral amyloid angiopathy, APP-related — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Alzheimer disease ABeta amyloidosis, Iowa type

For Hereditary cerebral amyloid angiopathy (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

APP p.Ala713Thr Likely pathogenic ★★ ⚠ same condition
APP p.Glu693Gln Pathogenic ★★ ⚠ same condition
APP p.Ile716Phe Pathogenic ★★ ⚠ same condition
APP p.Thr714Ala Pathogenic ★★ ⚠ same condition
APP p.Val715Met Pathogenic/Likely pathogenic ★★ ⚠ same condition
APP p.Val717Ile Pathogenic ★★ ⚠ same condition
APP p.Val717Phe Pathogenic ★★ ⚠ same condition
APP c.*7G>A Uncertain significance ★★ 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-asp694asn (accessed [today's date]).

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