Is APP p.Val576Ile (c.1726G>A) pathogenic?

APP p.Val576Ile (c.1726G>A) is classified Uncertain significance in APP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-05-30). AlphaMissense: likely benign (0.0702); Ultra-rare (popmax 0.0108%, nfe); Associated with Alzheimer disease.

What condition is associated with APP p.Val576Ile (c.1726G>A)?

APP p.Val576Ile (c.1726G>A) is associated with Alzheimer disease (ClinVar).

How common is APP p.Val576Ile (c.1726G>A) in the general population?

APP p.Val576Ile (c.1726G>A) is ultra-rare (popmax 0.0108%, nfe) (gnomAD).

What do computational predictors say about APP p.Val576Ile (c.1726G>A)?

AlphaMissense predicts likely benign (score 0.0702) — an in-silico prediction, not a clinical call.

APP p.Val576Ile

c.1726G>A · rs200769792 · VCV836798

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0702 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0108%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Alzheimer disease

Computational evidence

Protein change
AlphaMissense	0.0702	likely benign
REVEL	0.405	indeterminate
SaProt	LLR -6.13	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 289 kb · p 2e-07 · regional, not allelic
Overall
CADD	23.7	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 0.0108% European (non-Finnish) · 128/1,180,014 alleles

Filtering AF 0.00928% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00871%

Overall 0.00892% 144/1,614,028 alleles · ultra-rare exomes 135/1,461,862 · genomes 9/152,166 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0176%	5,681
European (non-Finnish)grpmax	0.0108%	9,219
East Asian	0.00223%	44,894
South Asian	0.0022%	45,542
Finnishnot grpmax-eligible	0.00156%	64,030
African / African-American	0.00133%	74,916

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val576Ile
Coding: c.1726G>A
MANE Select: NM_000484
dbSNP: rs200769792
Type: single nucleotide variant
Location: chr21:25911924 (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.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-val576ile (accessed [today's date]).

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