APP

Chr 21

amyloid beta precursor protein

Also known as: AAA, ABETA, ABPP, AD1, APPI, CTFgamma, CVAP, PN-II

NCBI Gene: 351 ENSG00000142192 UniProt: P05067

The APP protein functions as a cell surface receptor involved in neurite growth, neuronal adhesion, axonogenesis, and synaptic formation, and is cleaved by secretases to produce peptides including those that form amyloid plaques. Mutations cause autosomal dominant familial Alzheimer disease and cerebral amyloid angiopathy with various geographic variants (Dutch, Italian, Iowa, Flemish, Arctic). The gene is highly constrained against loss-of-function variants (LOEUF 0.419), reflecting its essential neuronal functions.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a cell surface receptor and transmembrane precursor protein that is cleaved by secretases to form a number of peptides. Some of these peptides are secreted and can bind to the acetyltransferase complex APBB1/TIP60 to promote transcriptional activation, while others form the protein basis of the amyloid plaques found in the brains of patients with Alzheimer disease. In addition, two of the peptides are antimicrobial peptides, having been shown to have bacteriocidal and antifungal activities. Mutations in this gene have been implicated in autosomal dominant Alzheimer disease and cerebroarterial amyloidosis (cerebral amyloid angiopathy). Multiple transcript variants encoding several different isoforms have been found for this gene. [provided by RefSeq, Aug 2014]

GeneReviews ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtAlzheimer disease 1

UniProtCerebral amyloid angiopathy, APP-related

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · cerebral amyloid angiopathy, APP-related · AD · ClinGen 2025

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

10016

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.42

LOEUF

Multiple*

Mechanism· predicted

📖

GeneReview available — APP

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.42LOEUF

pLI 0.047

Z-score 4.68

OE 0.26 (0.17–0.42)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.39Z-score

OE missense 0.82 (0.75–0.89)

369 obs / 452.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.26 (0.17–0.42)

0≤0.351.4

Missense OE?0.82 (0.75–0.89)

0≤0.61.4

Synonymous OE?1.07

0≤1.21.6

LoF obs/exp: 12 / 46.4Missense obs/exp: 369 / 452.4Syn Z: -0.70

Background carrier burden — how many people carry a rare variant somewhere in APP?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 70

913 rare PASS variants

Rare truncating (LoF)

1 in 2,700

62 rare PASS variants

Rare synonymous (reference)

1 in 91

401 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for APP. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 90	1 in 3,000
South Asian	~43k	1 in 74	1 in 2,900
Remaining (unassigned)	~30k	1 in 69	1 in 6,000
European (Finnish)	~27k	1 in 340	≈ 1 in 6,700
Admixed American	~22k	1 in 77	1 in 1,700
African / African American	~21k	1 in 72	1 in 2,800
East Asian	~20k	1 in 77	1 in 590
Ashkenazi Jewish	~13k	1 in 260	≈ 1 in 4,400
Middle Eastern	~2,884	1 in 66	≈ 1 in 930

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 18 coding exons well covered in gnomAD exomes and genomes.? see exons ↓