PSEN1

protein-coding

presenilin 1, the group of Peptidase family A22

Gene summary

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]

Previous symbols:

MANE transcript

NM_000021.4

Inheritance

ClinVar variants

P:161U:207B:74

Top phenotype

Cardiomyopathy, dilated 1U

gnomAD constraint

pLI —, LoF o/e 0.12

Max pathogenic AF

—

Genomic locus

chr14:73,136,418-73,223,691

External References & Databases

Ensembl (ENSG00000080815)

Transcript & Mutation Effects

hg38 • Region Span ~87.3 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

acne inversa, familial, 3LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0013398

Submitter: Labcorp Genetics (formerly Invitae)

Alzheimer disease 3STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011913

Submitter: Labcorp Genetics (formerly Invitae)

semantic dementiaLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0010857

Submitter: Labcorp Genetics (formerly Invitae)

Alzheimer disease 3STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011913

Submitter: Ambry Genetics

Alzheimer disease 3STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011913

Submitter: Ambry Genetics

familial dilated cardiomyopathyNO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0016333

Submitter: G2P

dilated cardiomyopathy 1ULIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0013371

Submitter: Labcorp Genetics (formerly Invitae)

Alzheimer disease 3STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011913

Submitter: Genomics England PanelApp

Pick diseaseSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008243

Submitter: Genomics England PanelApp

dilated cardiomyopathy 1UNO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0013371

Submitter: ClinGen

PSEN1 was originally evaluated for DCM by the ClinGen DCM GCEP on September 25th, 2020. Evidence of the association of this gene with DCM was re-evaluated using SOP v10 on May 29th, 2025As a result, the classification did not change. A summary of the information contributing to the classification of this gene at the time of re-evaluation is summarized herein. PSEN1 was first reported in relation to autosomal dominant dilated cardiomyopathy (DCM) in 2006 (Li et al., 2006, PMID: 17186461). There is a lack of robust human genetic evidence demonstrating this gene-disease relationship in the literature at the time of curation. All of the variants reported as disease-causing have subsequently been found at a frequency higher than would be expected for a monogenic, pathogenic effect in population reference data sets. Therefore, there is no scorable human genetic evidence. This gene-disease assertion is supported by expression studies (Gianni et al., 2010, PMID: 2019488). In summary, the evidence presented for this gene-disease relationship does not provide convincing human genetic evidence in support of or refuting the role of PSEN1 and DCM. The relationship of PSEN1 with DCM is unclear and therefore classified as disputed. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on May 29th, 2025 (SOP Version 10).

familial isolated dilated cardiomyopathySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015470

Submitter: Orphanet

semantic dementiaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0010857

Submitter: Genomics England PanelApp

early-onset autosomal dominant Alzheimer diseaseSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015140

Submitter: Orphanet

behavioral variant of frontotemporal dementiaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0017160

Submitter: Orphanet

Clinical Genomic Database (CGD)

Cardiomyopathy, dilated 1UAD

Manifestation: Cardiovascular; Dermatologic; Neurologic

Intervention: Cardiovascular

Rationale: Surveillance (eg, with echocardiography), preventive measures and medical management may be helpful to decrease morbidity

Comments: The reported onset of heart failure has been in the adult period (including in young adults), but surveillance and early treatment may be indicated prior to adulthood

Refs: 7550356; 7596406; 7585193; 9052708; 9384602; 9521418; 9544835; 11094121; 11389157; 11524469; 12891668; 12668610; 15122701; 16216949; 16033913; 17186461; 20194882; 20929727; 21495993; 21656036

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PSEN1 variants in ClinVar

29 Conditions Cataloged

Alzheimer disease 3Total: 300

Frontotemporal dementiaTotal: 245

Pick diseaseTotal: 243

Acne inversa, familial, 3Total: 239

not providedTotal: 224

not specifiedTotal: 68

Dilated cardiomyopathy 1UTotal: 29

PSEN1-related disorderTotal: 27

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000021.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			6 clinvar	59 clinvar	3 clinvar	68
missense	71 clinvar	80 clinvar	190 clinvar	11 clinvar	1 clinvar	353
nonsense	1 clinvar					1
start loss						0
frameshift	2 clinvar		1 clinvar			3
splice donor/acceptor (+/-2bp)	6 clinvar	1 clinvar	10 clinvar			17
Total	80	81	207	70	4	442

Highest pathogenic variant AF is 0.000017347858

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 165 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000021.4	RefSeq	NP_000012.1	10	MANE Select
ENST00000324501.10	Ensembl	ENSP00000326366.5	10	MANE Select
NM_007318.3	RefSeq	NP_015557.2	10	Standard
ENST00000357710.8	Ensembl	ENSP00000350342.4	10	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
psen1	Danio rerio	Structure: neuron Quality: increased amount abnormal

Gene / Model

Organism

Observed Phenotype

psen1

Danio rerio

Structure: neuron

Quality: increased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Neurotrophin signaling pathway - Homo sapiens (human)
Alzheimer,s disease - Homo sapiens (human)
Wnt signaling pathway - Homo sapiens (human)
Notch signaling pathway - Homo sapiens (human)
Human papillomavirus infection - Homo sapiens (human)

Biological Process

autophagosome assembly
negative regulation of transcription by RNA polymerase II
activation of MAPKK activity
blood vessel development
cell fate specification

Molecular Function

endopeptidase activity
aspartic-type endopeptidase activity
calcium channel activity
protein binding
beta-catenin binding

Cellular Component

Golgi membrane
kinetochore
nucleus
nuclear outer membrane
mitochondrion

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000324501
Coding exons: 10
Length: 87274
Individuals with no LoFs: 125736
Homozygous LoFs: 0
Heterozygous LoFs: 12
Defined: 125748
p: 0.0000477

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.16	159	256	0.621	0.0000138	3045
Missense (PolyPhen)		48	119.03	0.40325		1496
Synonymous	-0.441	103	97.5	1.06	0.00000540	918
Loss of Function	4.01	3	24.4	0.123	0.00000131	285

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.00014	0.000087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0.00014	0.000046	rare
European (Non-Finnish)	0.000053	0.000053	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Catalytic subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (amyloid-beta precursor protein) (PubMed:15274632, PubMed:10545183, PubMed:10593990, PubMed:10206644, PubMed:10899933, PubMed:10811883, PubMed:12679784, PubMed:12740439, PubMed:25043039, PubMed:26280335). Requires the presence of the other members of the gamma-secretase complex for protease activity (PubMed:15274632, PubMed:25043039, PubMed:26280335). Plays a role in Notch and Wnt signaling cascades and regulation of downstream processes via its role in processing key regulatory proteins, and by regulating cytosolic CTNNB1 levels (PubMed:9738936, PubMed:10593990, PubMed:10899933, PubMed:10811883). Stimulates cell-cell adhesion via its interaction with CDH1; this stabilizes the complexes between CDH1 (E-cadherin) and its interaction partners CTNNB1 (beta-catenin), CTNND1 and JUP (gamma-catenin) (PubMed:11953314). Under conditions of apoptosis or calcium influx, cleaves CDH1 (PubMed:11953314). This promotes the disassembly of the complexes between CDH1 and CTNND1, JUP and CTNNB1, increases the pool of cytoplasmic CTNNB1, and thereby negatively regulates Wnt signaling (PubMed:9738936, PubMed:11953314). Required for normal embryonic brain and skeleton development, and for normal angiogenesis (By similarity). {ECO:0000250|UniProtKB:P49769, ECO:0000269|PubMed:10206644, ECO:0000269|PubMed:10545183, ECO:0000269|PubMed:10593990, ECO:0000269|PubMed:10811883, ECO:0000269|PubMed:10899933, ECO:0000269|PubMed:11953314, ECO:0000269|PubMed:12679784, ECO:0000269|PubMed:12740439, ECO:0000269|PubMed:15274632, ECO:0000269|PubMed:15341515, ECO:0000269|PubMed:16305624, ECO:0000269|PubMed:25043039, ECO:0000269|PubMed:26280335, ECO:0000269|PubMed:9738936}.;
Disease: DISEASE: Alzheimer disease 3 (AD3) [MIM:607822]: A familial early- onset form of Alzheimer disease. Alzheimer disease is a neurodegenerative disorder characterized by progressive dementia, loss of cognitive abilities, and deposition of fibrillar amyloid proteins as intraneuronal neurofibrillary tangles, extracellular amyloid plaques and vascular amyloid deposits. The major constituents of these plaques are neurotoxic amyloid-beta protein 40 and amyloid-beta protein 42, that are produced by the proteolysis of the transmembrane APP protein. The cytotoxic C- terminal fragments (CTFs) and the caspase-cleaved products, such as C31, are also implicated in neuronal death. {ECO:0000269|PubMed:10025789, ECO:0000269|PubMed:10090481, ECO:0000269|PubMed:10200054, ECO:0000269|PubMed:10208579, ECO:0000269|PubMed:10439444, ECO:0000269|PubMed:10441572, ECO:0000269|PubMed:10447269, ECO:0000269|PubMed:10533070, ECO:0000269|PubMed:10631141, ECO:0000269|PubMed:10644793, ECO:0000269|PubMed:11027672, ECO:0000269|PubMed:11524469, ECO:0000269|PubMed:11710891, ECO:0000269|PubMed:11920851, ECO:0000269|PubMed:12048239, ECO:0000269|PubMed:12058025, ECO:0000269|PubMed:12484344, ECO:0000269|PubMed:12493737, ECO:0000269|PubMed:16305624, ECO:0000269|PubMed:20460383, ECO:0000269|PubMed:22503161, ECO:0000269|PubMed:26145164, ECO:0000269|PubMed:26280335, ECO:0000269|PubMed:26549787, ECO:0000269|PubMed:7550356, ECO:0000269|PubMed:7596406, ECO:0000269|PubMed:7651536, ECO:0000269|PubMed:8634711, ECO:0000269|PubMed:8634712, ECO:0000269|PubMed:8733303, ECO:0000269|PubMed:9172170, ECO:0000269|PubMed:9225696, ECO:0000269|PubMed:9298817, ECO:0000269|PubMed:9384602, ECO:0000269|PubMed:9507958, ECO:0000269|PubMed:9521423, ECO:0000269|PubMed:9719376, ECO:0000269|PubMed:9831473, ECO:0000269|PubMed:9833068, ECO:0000269|Ref.84}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Frontotemporal dementia (FTD) [MIM:600274]: A form of dementia characterized by pathologic finding of frontotemporal lobar degeneration, presenile dementia with behavioral changes, deterioration of cognitive capacities and loss of memory. In some cases, parkinsonian symptoms are prominent. Neuropathological changes include frontotemporal atrophy often associated with atrophy of the basal ganglia, substantia nigra, amygdala. In most cases, protein tau deposits are found in glial cells and/or neurons. {ECO:0000269|PubMed:11094121}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Cardiomyopathy, dilated 1U (CMD1U) [MIM:613694]: A disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death. {ECO:0000269|PubMed:17186461}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Acne inversa, familial, 3 (ACNINV3) [MIM:613737]: A chronic relapsing inflammatory disease of the hair follicles characterized by recurrent draining sinuses, painful skin abscesses, and disfiguring scars. Manifestations typically appear after puberty. {ECO:0000269|PubMed:20929727}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.876

Intolerance Scores

LoFtool: 0.00214
RVIS EVS: -0.34
RVIS percentile EVS: 30.37

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.964

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium