PSEN1

Chr 14AD

presenilin 1

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

NCBI Gene: 5663 ENSG00000080815 UniProt: 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]

Primary Disease Associations & Inheritance

?Acne inversa, familial, 3MIM #613737

?Cardiomyopathy, dilated, 1UMIM #613694

Alzheimer disease, type 3, with or without spastic paraparesisMIM #607822

Dementia, frontotemporalMIM #600274

Pick diseaseMIM #172700

UniProtAlzheimer disease 3

UniProtFrontotemporal dementia 1

UniProtPick disease of the brain

627

ClinVar variants

Pathogenic / LP

0.97

pLI score· haploinsufficient

Active trials

Clinical Summary— PSEN1

⚡

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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ClinVar Variants

86 Pathogenic / Likely Pathogenic· 209 VUS of 627 total submissions

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Clinical Trials

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

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

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.

0.32LOEUF

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?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.

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?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.0.12 (0.06–0.32)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.62 (0.55–0.71)

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.1.06

0≤1.21.6

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

ClinVar Variant Classifications

627 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic41

Likely Pathogenic45

VUS209

Likely Benign102

Benign23

Conflicting46

Pathogenic

Likely Pathogenic

209

VUS

102

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	3	27	11	0	41
Likely Pathogenic	1	41	3	0	45
VUS	3	118	82	6	209
Likely Benign	0	3	51	48	102
Benign	0	1	19	3	23
Conflicting	—				46
Total	7	190	166	57	466

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in 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.

Gene2Phenotype Curations

PSEN1-related dilated cardiomyopathy

disputed

ADUndeterminedUncertain

Cardiac

G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

PRESENILIN 1; PSEN1

MIM #104311 · *

?Acne inversa, familial, 3

MIM #613737