Is APP p.Arg527Gln (c.1580G>A) pathogenic?

APP p.Arg527Gln (c.1580G>A) is classified Conflicting classifications of pathogenicity in APP (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-05-09). AlphaMissense: likely benign (0.279); Ultra-rare (popmax 0.034%, sas); Associated with Alzheimer disease type 1.

What condition is associated with APP p.Arg527Gln (c.1580G>A)?

APP p.Arg527Gln (c.1580G>A) is associated with Alzheimer disease type 1, Alzheimer disease (ClinVar).

How common is APP p.Arg527Gln (c.1580G>A) in the general population?

APP p.Arg527Gln (c.1580G>A) is ultra-rare (popmax 0.034%, sas) (gnomAD).

What do computational predictors say about APP p.Arg527Gln (c.1580G>A)?

AlphaMissense predicts likely benign (score 0.279) — an in-silico prediction, not a clinical call.

APP p.Arg527Gln

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.1580G>A · rs201466202 · VCV1372949

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.279 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.034%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Alzheimer disease type 1

Computational evidence

Protein change
AlphaMissense	0.279	likely benign
REVEL	0.18	moderately benign-leaning
SaProt	LLR -7.60	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 4.8	GERP 1.8, 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 0.034% South Asian · 31/91,088 alleles

Filtering AF 0.0246% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0214%

Overall 0.0039% 63/1,613,960 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.034%	2,938
Remaining individualsnot grpmax-eligible	0.0032%	31,238
European (non-Finnish)	0.00246%	40,690
Admixed American	0.00167%	59,980

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.Arg527Gln
Coding: c.1580G>A
MANE Select: NM_000484
dbSNP: rs201466202
Type: single nucleotide variant
Location: chr21:25955634 (GRCh38)
Gene constraint: LOEUF 0.41 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.11 · 263 PDB
Residue 527: the e2 domain; an α-helix; the 'collagen-binding' 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

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

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

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-arg527gln (accessed [today's date]).

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