Is APP p.Ala15Val (c.44C>T) pathogenic?

APP p.Ala15Val (c.44C>T) is classified Likely benign in APP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-31). AlphaMissense: likely benign (0.1306); Ultra-rare (popmax 0.0416%, eas); Associated with Alzheimer disease.

What condition is associated with APP p.Ala15Val (c.44C>T)?

APP p.Ala15Val (c.44C>T) is associated with Alzheimer disease (ClinVar).

How common is APP p.Ala15Val (c.44C>T) in the general population?

APP p.Ala15Val (c.44C>T) is ultra-rare (popmax 0.0416%, eas) (gnomAD).

What do computational predictors say about APP p.Ala15Val (c.44C>T)?

AlphaMissense predicts likely benign (score 0.1306) — an in-silico prediction, not a clinical call.

APP p.Ala15Val

c.44C>T · rs913925398 · VCV1102353

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1306 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0416%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Alzheimer disease

Computational evidence

Protein change
AlphaMissense	0.1306	likely benign
REVEL	0.254	benign-leaning
SaProt	LLR -7.94	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 4.4	GERP 0.87, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 289 kb · p 2e-07 · regional, not allelic
Overall
CADD	22.2	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 0.0416% East Asian · 17/40,914 alleles

Filtering AF 0.0264% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0217%

Overall 0.0013% 20/1,538,764 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0416%	2,407
African / African-American	0.00137%	73,038
South Asian	0.00119%	83,884
European (non-Finnish)	8.72e-05%	1,146,437

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.Ala15Val
Coding: c.44C>T
MANE Select: NM_000484
dbSNP: rs913925398
Type: single nucleotide variant
Location: chr21:26170577 (GRCh38)
Gene constraint: LOEUF 0.41 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.11 · 263 PDB

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

Similar variants

APP p.Ala15= Likely benign ★ 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
APP p.Val715Met Pathogenic/Likely pathogenic ★★ ⚠ same condition
APP p.Val717Ile 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-ala15val (accessed [today's date]).

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