Is APP p.Arg460= (c.1380A>G) pathogenic?

APP p.Arg460= (c.1380A>G) is classified Uncertain significance in APP (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-13). Ultra-rare (popmax 0.0178%, eas); Associated with Alzheimer disease.

What condition is associated with APP p.Arg460= (c.1380A>G)?

APP p.Arg460= (c.1380A>G) is associated with Alzheimer disease (ClinVar).

How common is APP p.Arg460= (c.1380A>G) in the general population?

APP p.Arg460= (c.1380A>G) is ultra-rare (popmax 0.0178%, eas) (gnomAD).

APP p.Arg460=

c.1380A>G · rs745834578 · VCV339638

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0178%, eas)

Conditions

Alzheimer disease

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.038	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.1	GERP -5, phastCons 0.002
Overall
CADD	8.902	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0178% East Asian · 8/44,886 alleles

Filtering AF 0.00883% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00641%

Overall 0.000496% 8/1,613,908 alleles · ultra-rare exomes 7/1,461,878 · genomes 1/152,030 · joint denominator

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.Arg460=
Coding: c.1380A>G
MANE Select: NM_000484
dbSNP: rs745834578
Type: single nucleotide variant
Location: chr21:25975148 (GRCh38)
Gene constraint: LOEUF 0.41 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.11 · 263 PDB
Residue 460: the e2 domain; an α-helix

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-arg460 (accessed [today's date]).

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