Is APP p.Arg653Gln (c.1958G>A) pathogenic?

APP p.Arg653Gln (c.1958G>A) is classified Uncertain significance in APP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-10). AlphaMissense: ambiguous (0.3625); Very rare (popmax 0.00223%, eas); Associated with cerebral amyloid angiopathy, APP-related.

What condition is associated with APP p.Arg653Gln (c.1958G>A)?

APP p.Arg653Gln (c.1958G>A) is associated with cerebral amyloid angiopathy, APP-related (ClinVar).

How common is APP p.Arg653Gln (c.1958G>A) in the general population?

APP p.Arg653Gln (c.1958G>A) is very rare (popmax 0.00223%, 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.Arg653Gln (c.1958G>A)?

AlphaMissense predicts ambiguous (score 0.3625) — an in-silico prediction, not a clinical call.

APP p.Arg653Gln

c.1958G>A · VCV3781337

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3625 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

cerebral amyloid angiopathy, APP-related

Computational evidence

Protein change
AlphaMissense	0.3625	ambiguous
REVEL	0.521	indeterminate
SaProt	LLR -6.93	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 289 kb · p 2e-07 · regional, not allelic
Overall
CADD	28.3	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 0.00223% East Asian · 1/44,868 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000372% 6/1,613,704 alleles · very rare exomes 6/1,461,490 · genomes 0/152,214 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,868
Remaining individualsnot grpmax-eligible	0.0016%	62,480
South Asian	0.0011%	90,944
European (non-Finnish)	0.000254%	393,283

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.Arg653Gln
Coding: c.1958G>A
MANE Select: NM_000484
Type: single nucleotide variant
Location: chr21:25905029 (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

cerebral amyloid angiopathy, APP-related — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hereditary cerebral amyloid angiopathy (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

APP p.Arg653= Uncertain significance ★ same residue
APP p.Ala713Thr Likely pathogenic ★★ ⚠ same condition
APP p.Asp694Asn Pathogenic ★★ ⚠ same condition
APP p.Glu693Gln Pathogenic ★★ ⚠ same condition
APP p.Val717Ile Pathogenic ★★ ⚠ same condition
APP p.Arg16Gln Uncertain significance ★★ ⚠ same condition
APP p.Arg585Lys Uncertain significance ★★ ⚠ same condition
APP p.Ser346Tyr 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-arg653gln (accessed [today's date]).

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