Is APP p.Val225Ala (c.674T>C) pathogenic?

APP p.Val225Ala (c.674T>C) is classified Uncertain significance in APP (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-11-20). AlphaMissense: likely benign (0.0742); Ultra-rare (popmax 0.0379%, eas); Associated with cerebral amyloid angiopathy, APP-related.

What condition is associated with APP p.Val225Ala (c.674T>C)?

APP p.Val225Ala (c.674T>C) is associated with cerebral amyloid angiopathy, APP-related, Alzheimer disease, Alzheimer disease type 1 (ClinVar).

How common is APP p.Val225Ala (c.674T>C) in the general population?

APP p.Val225Ala (c.674T>C) is ultra-rare (popmax 0.0379%, eas) (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.Val225Ala (c.674T>C)?

AlphaMissense predicts likely benign (score 0.0742) — an in-silico prediction, not a clinical call.

APP p.Val225Ala

c.674T>C · rs746313873 · VCV339642

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0742 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0379%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cerebral amyloid angiopathy, APP-related

Computational evidence

Protein change
AlphaMissense	0.0742	likely benign
REVEL	0.264	benign-leaning
SaProt	LLR -6.32	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.9	GERP 1.4, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 289 kb · p 2e-07 · regional, not allelic
Overall
CADD	17.53	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0379% East Asian · 17/44,888 alleles

Filtering AF 0.0241% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0197%

Overall 0.00105% 17/1,613,910 alleles · ultra-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.Val225Ala
Coding: c.674T>C
MANE Select: NM_000484
dbSNP: rs746313873
Type: single nucleotide variant
Location: chr21:26022031 (GRCh38)
Gene constraint: LOEUF 0.41 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.11 · 263 PDB
Residue 225: the 'disordered' region

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 Alzheimer disease type 1

For Hereditary cerebral amyloid angiopathy (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

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
APP p.Val715Met Pathogenic/Likely pathogenic ★★ ⚠ same condition
APP p.Val717Ile Pathogenic ★★ ⚠ same condition
APP p.Val717Phe 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-val225ala (accessed [today's date]).

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