PSEN1

Chr 14

presenilin 1

Also known as: ACNINV3, AD3, CMD1U, FAD, PS-1, PS1, PSNL1, S182

NCBI Gene: 5663ENSG00000080815UniProt: P49768

Alzheimer's disease (AD) patients with an inherited form of the disease carry mutations in the presenilin proteins (PSEN1; PSEN2) or in the amyloid precursor protein (APP). These disease-linked mutations result in increased production of the longer form of amyloid-beta (main component of amyloid deposits found in AD brains). Presenilins are postulated to regulate APP processing through their effects on gamma-secretase, an enzyme that cleaves APP. Also, it is thought that the presenilins are involved in the cleavage of the Notch receptor, such that they either directly regulate gamma-secretase activity or themselves are protease enzymes. Several alternatively spliced transcript variants encoding different isoforms have been identified for this gene, the full-length nature of only some have been determined. [provided by RefSeq, Aug 2008]

GeneReviewsResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtAlzheimer disease 3
UniProtFrontotemporal dementia 1
UniProtCardiomyopathy, dilated, 1U
UniProtAcne inversa, familial, 3

Clinical highlights

Gene-disease validity (ClinGen)
dilated cardiomyopathy 1U · ADDisputedevidence questions this relationship
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.Curated gene-level mechanism — a prior for triage, not a per-variant call.
5
Active trials
221
Pubs (1 yr)
—
P/LP submissions
—
P/LP missense
0.32
LOEUF· LoF intol.
Multiple*
Mechanism· predicted
📖
GeneReview available — PSEN1
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
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 OE?0.12 (0.06–0.32)
0≤0.351.4
Missense OE?0.62 (0.55–0.71)
0≤0.61.4
Synonymous OE?1.06
0≤1.21.6
LoF obs/exp: 3 / 24.4Missense obs/exp: 159 / 256.1Syn Z: -0.44

ClinVar Variant Classifications

0 submitted variants in ClinVar

ClinVar

Protein Context — Lollipop Plot

PSEN1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients