APP

Chr 21AD

amyloid beta precursor protein

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

NCBI Gene: 351 ENSG00000142192 UniProt: P05067 OMIM: 104760

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.

OMIM 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]

OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.422 OMIM phenotypes

Clinical Summary— APP

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Gene-Disease Validity (ClinGen)

cerebral amyloid angiopathy, APP-related · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.26) despite low pLI — interpret in context.

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Clinical Trials

12 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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

This gene — mechanism propensity

0.78top 25%

GOF

0.6930th %ile

LOF

0.3843th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median · 1 literature citation

GOFprediction above median · 1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNMutations at or near binding sites not only reduced both the surface fraction of APP and membrane cholesterol levels in a dominant negative manner, but also increased synaptic vulnerability to moderate membrane cholesterol reduction.1

GOFWe demonstrate that pathological PS1 loss-of-function impinges on neurite formation through a selective APP gain-of-function that could impact on axodendritic connectivity and contribute to aberrant axonal sprouting observed in AD patients.2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References