Is APP p.Val717Ile (c.2149G>A) pathogenic?

APP p.Val717Ile (c.2149G>A) is classified Pathogenic in APP (ClinVar, Multiple submitters, 12 submitters; last evaluated 2025-11-28). AlphaMissense: likely benign (0.1028); Very rare (popmax 0.00017%, nfe); Associated with Alzheimer disease type 1.

What condition is associated with APP p.Val717Ile (c.2149G>A)?

APP p.Val717Ile (c.2149G>A) is associated with Alzheimer disease type 1, Alzheimer disease, cerebral amyloid angiopathy, APP-related (ClinVar).

How common is APP p.Val717Ile (c.2149G>A) in the general population?

APP p.Val717Ile (c.2149G>A) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about APP p.Val717Ile (c.2149G>A)?

AlphaMissense predicts likely benign (score 0.1028) — an in-silico prediction, not a clinical call.

APP p.Val717Ile

Q: How is Early-onset autosomal dominant Alzheimer disease inherited?

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

c.2149G>A · rs63750264 · VCV18088

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 12 submitters

AlphaMissense

likely benign

0.1028 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Alzheimer disease type 1

Computational evidence

Protein change
AlphaMissense	0.1028	likely benign ⚠ discordant with ClinVar
REVEL	0.78	moderately pathogenic-leaning
SaProt	LLR -6.26	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	26.8	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 0.00017% European (non-Finnish) · 2/1,179,800 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,620 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.Val717Ile
Coding: c.2149G>A
MANE Select: NM_000484
dbSNP: rs63750264
Type: single nucleotide variant
Location: chr21:25891784 (GRCh38)
Gene constraint: LOEUF 0.41 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.11 · 263 PDB
Residue 717: a UniProt-annotated variant site (in ad1; increased amyloid-beta protein 42/40 ratio); a UniProt-annotated variant site (in ad1); a turn; the 'interaction with psen1' region

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

Disease context

Alzheimer disease type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Alzheimer disease cerebral amyloid angiopathy, APP-related

For Early-onset autosomal dominant Alzheimer disease (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

APP p.Val717Phe Pathogenic ★★ ⚠ same residue
APP p.Val717Gly Pathogenic ★ ⚠ same residue
APP p.Val717Leu Pathogenic ★ ⚠ same residue
APP p.Ala713Thr Likely pathogenic ★★ ⚠ same condition
APP p.Asp694Asn Pathogenic ★★ ⚠ same condition
APP p.Glu693Gln Pathogenic ★★ ⚠ same condition
APP p.Ile716Phe 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-val717ile (accessed [today's date]).

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