Is APP p.Val715Ala (c.2144T>C) pathogenic?

APP p.Val715Ala (c.2144T>C) is classified Pathogenic in APP (ClinVar, No assertion criteria, 2 submitters; last evaluated 2024-04-09). AlphaMissense: likely pathogenic (0.802); Absent from gnomAD v4.1; Associated with APP-related disorder.

What condition is associated with APP p.Val715Ala (c.2144T>C)?

APP p.Val715Ala (c.2144T>C) is associated with APP-related disorder (ClinVar).

How common is APP p.Val715Ala (c.2144T>C) in the general population?

APP p.Val715Ala (c.2144T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about APP p.Val715Ala (c.2144T>C)?

AlphaMissense predicts likely pathogenic (score 0.802) — an in-silico prediction, not a clinical call.

APP p.Val715Ala

c.2144T>C · rs63750868 · VCV98238

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.802 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

APP-related disorder

Computational evidence

Protein change
AlphaMissense	0.802	likely pathogenic ✓ concordant with ClinVar
REVEL	0.941	strongly pathogenic-leaning
SaProt	LLR -6.09	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 289 kb · p 2e-07 · regional, not allelic
Overall
CADD	25.8	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

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.Val715Ala
Coding: c.2144T>C
MANE Select: NM_000484
dbSNP: rs63750868
Type: single nucleotide variant
Location: chr21:25891789 (GRCh38)
Gene constraint: LOEUF 0.41 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.11 · 263 PDB
Residue 715: a UniProt-annotated variant site (in ad1; decreased amyloid-beta protein 40/total amyloid-beta); an α-helix; the 'interaction with psen1' region

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

Disease context

APP-related disorder

Similar variants

APP p.Val715Met Pathogenic/Likely pathogenic ★★ ⚠ same residue
APP p.Leu723Pro Likely pathogenic ★ same condition
APP p.Arg268Thr Uncertain significance ★ ⚠ same condition
APP p.Glu605Gln Uncertain significance ★ ⚠ same condition
APP p.His677Arg Conflicting classifications of pathogenicity ★ ⚠ same condition
APP p.Ile63Val Uncertain significance ★ ⚠ same condition
APP p.Thr276Ala Uncertain significance ★ ⚠ same condition
APP p.Ala479Ser 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-val715ala (accessed [today's date]).

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