PSEN1

Chr 14AD

presenilin 1

NCBI Gene: 5663 ENSG00000080815 UniProt: P49768 OMIM: 104311

The presenilin 1 protein serves as the catalytic subunit of the gamma-secretase complex, which cleaves integral membrane proteins including amyloid precursor protein and Notch receptors, and also functions as a calcium-leak channel in the endoplasmic reticulum. Mutations cause autosomal dominant early-onset Alzheimer disease (often presenting before age 65), frontotemporal dementia, and Pick disease. This gene is highly constrained against loss-of-function variants (pLI 0.97, LOEUF 0.32), reflecting its essential role in normal brain development and function.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

MultiplemechanismADLOEUF 0.325 OMIM phenotypes

Clinical Summary— PSEN1

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Gene-Disease Validity (ClinGen)

dilated cardiomyopathy 1U · ADDisputed

Disputed — evidence questions this relationship

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.97). One damaged copy is likely sufficient to cause disease.

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Clinical Trials

5 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

LoF intolerant — likely haploinsufficient

LoF Constraint

0.32LOEUF

pLI 0.973

Z-score 4.01

OE 0.12 (0.06–0.32)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint

2.16Z-score

OE missense 0.62 (0.55–0.71)

159 obs / 256.1 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios

LoF OE0.12 (0.06–0.32)

0≤0.351.4

Missense OE0.62 (0.55–0.71)

0≤0.61.4

Synonymous OE1.06

0≤1.21.6

LoF obs/exp: 3 / 24.4Missense obs/exp: 159 / 256.1Syn Z: -0.44

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedPSEN1-related dilated cardiomyopathyOTHERAD

0.5477th %ile

GOF

0.5954th %ile

LOF

0.49top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, gain-of-function and dominant-negative). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFLOEUF 0.32

GOF1 literature citation

DN1 literature citation

Literature Evidence

DNTrans-dominant negative effects of pathogenic PSEN1 mutations on g-secretase activity and Ab productionPMID:23843529

GOFThere is no molecular explanation for the many presenilin 1 (PSEN1) mutations causing Alzheimer's disease, but both gain of function relating to amyloid production and loss of isolated PSEN1 function have been implied.PMID:26852951

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.