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

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]

Primary Disease Associations & Inheritance

Alzheimer disease 1, familialMIM #104300

Cerebral amyloid angiopathy, Dutch, Italian, Iowa, Flemish, Arctic variantsMIM #605714

582

ClinVar variants

Pathogenic / LP

0.05

pLI score

Active trials

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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ClinVar Variants

39 Pathogenic / Likely Pathogenic· 256 VUS of 582 total submissions

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Clinical Trials

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

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

1.39Z-score

OE missense 0.82 (0.75–0.89)

369 obs / 452.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.26 (0.17–0.42)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.82 (0.75–0.89)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.07

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	2	29	0	31
Likely Pathogenic	0	6	2	0	8
VUS	3	183	61	9	256
Likely Benign	0	16	79	104	199
Benign	0	3	58	4	65
Conflicting	—				23
Total	3	210	229	117	582

APP

Primary Disease Associations & Inheritance

Population Genetics & Constraint

ClinVar Variant Classifications

Classification Summary

Curated Variants Distribution

Protein Context — Lollipop Plot

OMIM — Genotype-Phenotype Relationships

Gene Overview

ClinGen Curation

Disease Associations

External Resources

Variant Interpretation

Population Databases

Gene Resources