PSEN2

Chr 1AD

presenilin 2

Also known as: AD3L, AD4, CMD1V, PS2, STM2

NCBI Gene: 5664 ENSG00000143801 UniProt: P49810

Alzheimer's disease (AD) patients with an inherited form of the disease carry mutations in the presenilin proteins (PSEN1 or PSEN2) or 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 act are protease enzymes. Two alternatively spliced transcript variants encoding different isoforms of PSEN2 have been identified. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Alzheimer disease-4MIM #606889

Cardiomyopathy, dilated, 1VMIM #613697

UniProtAlzheimer disease 4

ClinVar variants

Pathogenic / LP

0.00

pLI score

Active trials

Clinical Summary— PSEN2

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Gene-Disease Validity (ClinGen)

dilated cardiomyopathy 1V · ADLimited

Limited evidence — not for standalone diagnostic reporting

⚡

Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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Clinical Trials

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

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

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.

0.74LOEUF

pLI 0.001

Z-score 2.44

OE 0.43 (0.26–0.74)

Tolerant

Typical tolerance to LoF variation

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.

0.40Z-score

OE missense 0.93 (0.84–1.03)

254 obs / 272.8 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.0.43 (0.26–0.74)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.93 (0.84–1.03)

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.1.21

0≤1.21.6

LoF obs/exp: 9 / 21.1Missense obs/exp: 254 / 272.8Syn Z: -1.77

ClinVar Variant Classifications

0 submitted variants in ClinVar

ClinVar

Protein Context — Lollipop Plot

PSEN2 · protein map & ClinVar variants

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

Gene2Phenotype Curations

PSEN2-related dilated cardiomyopathy

limited

ADUndeterminedUncertain

Cardiac

G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

PRESENILIN 2; PSEN2

MIM #600759 · *

Alzheimer disease-4

MIM #606889

Molecular basis of disorder known

Autosomal dominant

Cardiomyopathy, dilated, 1V

MIM #613697

Molecular basis of disorder known

Autosomal dominant

External Resources

Links to major genomics databases and tools

Clinical Literature

Landmark / reviewRecent case evidence

Recent Gene-Specific Literature

Gene in title · MEDLINE · newest first

Europe PMC

DNA Methylation Alteration in Early-Stage of PSEN1/PSEN2 Gene Double Knockout Mouse Models: Integrated Bioinformatics Analysis of Hippocampal Changes Underlying Age-Related Neurodegeneration.

Tang M et al.·Cell Biochem Funct

2025Functional

Presence of Alzheimer's disease variants in circular RNA of PSEN1 and PSEN2.

Johnson IP et al.·J Alzheimers Dis

2025

Benchmarking AlphaMissense pathogenicity predictions against APP, PSEN1, and PSEN2 variants of unknown significance.

Pillai J et al.·Biochem Biophys Rep

2025🔓 Open Access

Spectrum of γ-Secretase dysfunction as a unifying predictor of ADAD age at onset across PSEN1, PSEN2 and APP causal genes.

Fernández SG et al.·Mol Neurodegener

2025🔓 Open Access

UBC9 ameliorates diabetic cardiomyopathy by modulating cardiomyocyte mitophagy through NEDD4/RUNX2/PSEN2 axis.

Wu H et al.·Metabolism

2025

Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

Ovarian CancerFallopian TubePrimary Peritoneal Cancer

Study of Carboplatin and Mirvetuximab Soravtansine in First-Line Treatment of Patients Receiving Neoadjuvant Chemotherapy With Advanced-Stage Ovarian, Fallopian Tube or Primary Peritoneal Cancer

RECRUITING

NCT04606914Phase PHASE2University of Alabama at BirminghamStarted 2021-05-27

mirvetuximab soravtansine (MIRV; IMGN853)

Neurodegenerative DisordersParkinson DiseaseAlzheimer Disease

An Innovative Method in SAliva Samples for the Early Differential Diagnosis of High-impact NeuroDegenerative Diseases Through Raman Spectroscopy

ENROLLING BY INVITATION

NCT06875739Fondazione Don Carlo Gnocchi OnlusStarted 2025-02-14

Alzheimer DiseaseFamilial Alzheimer Disease (FAD)

The Chinese Familial Alzheimer's Network

RECRUITING

NCT03657732Capital Medical UniversityStarted 2005-01-10

Mild Cognitive Impairment(MCI)Alzheimer Disease, Late OnsetFamilial Alzheimer Disease (FAD)