PSEN1

Summary

PSEN1 (presenilin 1, HGNC:9508) is a protein-coding gene on chromosome 14q24.2, encoding Presenilin-1 (P49768). 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).

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.

Source: NCBI Gene 5663 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Alzheimer disease 3 (Strong, GenCC) — +7 more curated relationships
• GWAS associations: 4
• Clinical variants (ClinVar): 620 total — 80 pathogenic, 45 likely-pathogenic
• Phenotypes (HPO): 125
• Druggable target: yes — 8 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_000021

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9508
Approved symbol	PSEN1
Name	presenilin 1
Location	14q24.2
Locus type	gene with protein product
Status	Approved
Aliases	FAD, S182, PS1, PS-1, PSNL1
Ensembl gene	ENSG00000080815
Ensembl biotype	protein_coding
OMIM	104311
Entrez	5663

Gene structure

Transcript identifiers

Ensembl transcripts: 115 — 65 protein_coding, 24 nonsense_mediated_decay, 17 retained_intron, 9 protein_coding_CDS_not_defined

ENST00000324501, ENST00000357710, ENST00000394157, ENST00000394164, ENST00000406768, ENST00000553447, ENST00000553599, ENST00000553855, ENST00000554131, ENST00000554995, ENST00000555254, ENST00000555386, ENST00000555867, ENST00000556011, ENST00000556066, ENST00000556533, ENST00000556864, ENST00000556951, ENST00000557037, ENST00000557293, ENST00000557356, ENST00000557511, ENST00000559361, ENST00000560005, ENST00000697912, ENST00000697913, ENST00000697914, ENST00000697915, ENST00000700265, ENST00000700266, ENST00000700267, ENST00000700268, ENST00000700269, ENST00000700270, ENST00000700271, ENST00000700272, ENST00000700273, ENST00000700302, ENST00000700303, ENST00000700304, ENST00000700305, ENST00000700306, ENST00000700307, ENST00000700308, ENST00000700309, ENST00000700310, ENST00000700311, ENST00000700312, ENST00000700313, ENST00000700314, ENST00000700315, ENST00000700316, ENST00000700317, ENST00000700318, ENST00000700319, ENST00000700320, ENST00000700321, ENST00000700322, ENST00000700323, ENST00000700324, ENST00000700374, ENST00000700375, ENST00000700376, ENST00000700377, ENST00000700378, ENST00000700379, ENST00000700388, ENST00000700389, ENST00000700390, ENST00000700391, ENST00000700404, ENST00000700405, ENST00000700406, ENST00000700407, ENST00000700408, ENST00000700409, ENST00000700410, ENST00000700430, ENST00000700431, ENST00000700432, ENST00000700433, ENST00000700434, ENST00000700435, ENST00000700436, ENST00000700437, ENST00000700467, ENST00000700468, ENST00000700469, ENST00000894158, ENST00000894159, ENST00000894160, ENST00000894161, ENST00000894162, ENST00000894163, ENST00000894164, ENST00000894165, ENST00000894166, ENST00000894167, ENST00000894168, ENST00000894169, ENST00000894170, ENST00000894171, ENST00000894172, ENST00000894173, ENST00000938816, ENST00000938817, ENST00000950359, ENST00000950360, ENST00000950361, ENST00000950362, ENST00000950363, ENST00000950364, ENST00000950365, ENST00000950366, ENST00000950367

RefSeq mRNA: 2 — MANE Select: NM_000021 NM_000021, NM_007318

CCDS: CCDS9812, CCDS9813

Canonical transcript exons

ENST00000324501 — 12 exons

Exon	Start	End
ENSE00001343124	73147795	73147876
ENSE00002555450	73219134	73223691
ENSE00003621038	73170797	73171047
ENSE00003972119	73136507	73136583
ENSE00003979367	73198031	73198129
ENSE00003979369	73173566	73173707
ENSE00003979370	73206386	73206472
ENSE00003979376	73211769	73211942
ENSE00003979377	73217126	73217244
ENSE00003979382	73147967	73148106
ENSE00003979383	73192644	73192864
ENSE00003979391	73186853	73186920

Expression profiles

Bgee: expression breadth ubiquitous, 287 present calls, max score 96.94.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 28.0209 / max 534.6852, expressed in 1809 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
140514	27.6483	1809
140516	0.3725	135

Top tissues by expression

293 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
middle frontal gyrus	UBERON:0002702	96.94	gold quality
corpus callosum	UBERON:0002336	96.16	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	96.11	gold quality
monocyte	CL:0000576	95.92	gold quality
mononuclear cell	CL:0000842	95.65	gold quality
leukocyte	CL:0000738	95.61	gold quality
spinal cord	UBERON:0002240	95.24	gold quality
adrenal tissue	UBERON:0018303	94.89	gold quality
rectum	UBERON:0001052	94.87	gold quality
calcaneal tendon	UBERON:0003701	94.78	gold quality
ileal mucosa	UBERON:0000331	94.73	gold quality
sural nerve	UBERON:0015488	94.11	gold quality
amniotic fluid	UBERON:0000173	93.99	gold quality
blood	UBERON:0000178	93.69	gold quality
colonic epithelium	UBERON:0000397	93.35	gold quality
gall bladder	UBERON:0002110	93.16	gold quality
inferior vagus X ganglion	UBERON:0005363	92.97	gold quality
ganglionic eminence	UBERON:0004023	92.93	gold quality
granulocyte	CL:0000094	92.79	gold quality
islet of Langerhans	UBERON:0000006	92.74	gold quality
stromal cell of endometrium	CL:0002255	92.59	gold quality
palpebral conjunctiva	UBERON:0001812	92.50	gold quality
duodenum	UBERON:0002114	92.43	gold quality
skin of leg	UBERON:0001511	92.25	gold quality
cortical plate	UBERON:0005343	92.20	gold quality
colonic mucosa	UBERON:0000317	92.15	gold quality
medial globus pallidus	UBERON:0002477	91.95	gold quality
endothelial cell	CL:0000115	91.90	gold quality
jejunal mucosa	UBERON:0000399	91.89	gold quality
mucosa of transverse colon	UBERON:0004991	91.80	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

4 targets.

Target	Regulation
ABCC1	Unknown
PFKFB3	Activation
PTEN	Activation
SLC40A1	Repression

Upstream regulators (CollecTRI, top): ATF4, CREB1, DNMT1, ELK1, ETS1, ETS2, ETV1, ETV5, GABPA, GLI3, ID1, JUN, MYOD1, NOTCH1, RBPJ, SP1, SSRP1, TP53, ZFHX2, ZNF436, ZNF699

miRNA regulators (miRDB)

159 targeting PSEN1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4713-3P	100.00	65.92	505
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-10401-5P	99.99	65.79	948
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-22-3P	99.93	68.13	917

Literature-anchored findings (GeneRIF, showing 40)

• Binding of the APP protease inhibitor pepstatin to presenilin 1 (PS1) is decreased in cells of a heterozygous carrier of the PS1 exon 9 deletion, suggesting that the PS1 mutation alters the inhibitor binding site. (PMID:11444983)
• Here we present a novel cell-based reporter gene assay for the quantification of PS-controlled gamma-secretase cleavage of the Alzheimer amyloid precursor protein (APP). (PMID:11744687)
• variable expression not a major determinant of risk for late-onset Alzheimer’s disease (PMID:11757955)
• enhancement of amyloid beta protein by Herp, and endoplasmic reticulum stress-inducible protein (PMID:11799129)
• The PSEN1 mutation (P264L causes disease that begins with spastic paraparesis and is associated with dementia that is not of the Alzheimer type. (PMID:11836371)
• inhibition of endoproteolysis by gamma-secretase inhibitors (PMID:11876645)
• Notch receptor cleavage depends on but is not directly executed by presenilins (PMID:11891288)
• Wild-type and mutated presenilins 2 trigger p53-dependent apoptosis and down-regulate presenilin 1 expression in HEK293 human cells and in murine neurons (PMID:11904448)
• Neurotoxic mechanisms triggered by Alzheimer’s disease-linked mutant M146L presenilin 1: involvement of NO synthase via a novel pertussis toxin target. (PMID:11905990)
• Accelerated plaque accumulation, associative learning deficits, and up-regulation of alpha 7 nicotinic receptor protein in transgenic mice co-expressing mutant human presenilin 1 and amyloid precursor proteins (PMID:11912199)
• It seems this novel missense substitution of serine for glycine, occurred at codon 266 in exon 8 of presenilin 1 is pathogenic, and findings provide a new clue to the etiology of the familial early onset dementia. (PMID:11920851)
• The presence of a human presenilin 1 gene, normal or with an Alzheimer’s disease mutation, leads to enhanced plasticity in the mouse brain. (PMID:11927360)
• requirement for maturation and cell surface accumulation of nicastrin (PMID:11943765)
• Alternative transcripts of presenilin 1 are associated with sporadic frontotemporal dementia, deletions having been identified within the exon 4-8 region. (PMID:11973477)
• Expression of PS1 was found throughout myeloid development from CD34+ stem cells to platelets and neutrophils, and colocalized with amyloid precursor protein in cell-specific granules, suggesting a conserved function across different tissues. (PMID:11987239)
• mutations of leucine 166 in presenilin-1 equally affect the generation of the Notch and APP intracellular domains independent of their effect on Abeta 42 production (PMID:12048239)
• regulation by nicastrin and role in determining amyloid beta-peptide production via complex formation (PMID:12048259)
• expression induced by interleukin-1beta and amyloid beta 42 peptide is potentiated by hypoxia in primary human neural cells (PMID:12050157)
• interaction with GFAP epsilon (PMID:12058025)
• Very early-onset familial Alzheimer’s disease linked to G206V mutation in PS1 (PMID:12112163)
• mutations in PSEN1 increase Abeta42 production, inhibit cleavage of APP and notch (PMID:12119298)
• presenilin 1 has a role in PI signal transduction, higher calcium, and apoptosis (PMID:12121968)
• Presenilins are targeted as a biologically active complex with Nicastrin through the secretory pathway to the cell surface, suggesting a dual function of Presenilins in gamma-secretase processing and in trafficking. (PMID:12147673)
• The genotype frequency of the Glu318Gly mutation in all Alzheimer’s disease cases and controls in the Australian population was 2.8%. (PMID:12192622)
• PS1/gamma-secretase contains PEN-2 and requires it for presenilin expression (PMID:12198112)
• Presenilin-1 mutations alter K+ currents in the human neuroblastoma cell line, SH-SY5Y. (PMID:12218704)
• In PS1 human-mutant knockin mice, PS1 is expressed in microglia & the M146V mutation confers a heightened sensitivity to LPS, as indicated by superinduction of inducible nitric oxide synthase & activation of MAP kinases. (PMID:12230303)
• PS1 functions as a scaffold that rapidly couples beta-catenin phosphorylation through two sequential kinase activities independent of the Wnt-regulated Axin/CK1alpha complex. (PMID:12297048)
• These data indicate that mammalian APH-1 (mAPH-1) along with presenilin 1 and nicastrin is probably a functional component of the gamma-secretase complex required for the intramembrane proteolysis of APP and Notch (PMID:12297508)
• Presenilin1 mediates a dual intramembranous gamma-secretase cleavage of Notch-1. (PMID:12374741)
• The PSEN1 gene -4,752 C/T polymorphism modifies the risk for AD. (PMID:12413003)
• regulates intracellular trafficking and cell surface delivery of beta-amyloid precursor protein (PMID:12435726)
• tetradecanoylphorbol acetate appears to activate the transcription of the PS1 gene by a mechanism which does not require the -10 Ets motif or the -6 CREB/AP1 motif (PMID:12444985)
• Presenilin 1 regulates the glycosylation and intracellular trafficking of APP and select membrane proteins. (PMID:12460547)
• Gamma-secretase activity is not involved in presenilin 1-mediated regulation of beta-catenin. (PMID:12470641)
• regulation of proteolytic processing by PEN-2 and APH-1 (PMID:12522139)
• The missense mutation in exon 5 of presenilin-1 (PS-1) gene, found in this Alzheimer’s disease family, may be one of the responsible PS-1 gene mutations for familial Alzheimer disease in Chinese. (PMID:12609057)
• Our present findings suggest important implications for understanding CD44-dependent signal transduction and a potential role of PS/gamma-secretase activity in the functional regulation of adhesion molecules. (PMID:12629514)
• APH-1 stabilizes the presenilin holoprotein in the complex, whereas PEN-2 is required for endoproteolytic processing of presenilin and conferring gamma-secretase activity to the complex. (PMID:12660785)
• these studies provide evidence that the increased risk for AD associated with PSEN1 may result from genetic variations in the regulatory region, leading to altered expression levels of PSEN1 in neurons. (PMID:12668610)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	psen1	ENSDARG00000004870
mus_musculus	Psen1	ENSMUSG00000019969
rattus_norvegicus	Psen1	ENSRNOG00000009110
drosophila_melanogaster	Psn	FBGN0284421
caenorhabditis_elegans		WBGENE00004769

Paralogs (1): PSEN2 (ENSG00000143801)

Protein

Protein identifiers

Presenilin-1 — P49768 (reviewed: P49768)

Alternative names: Protein S182

All UniProt accessions (32): P49768, A0A024R6A3, A0A0S2Z4D2, A0A8V8TLT5, A0A8V8TPK5, A0A8V8TPL0, A0A8V8TPL5, A0A8V8TQ30, A0A8V8TQ36, A0A8V8TQ53, A0A8V8TQ54, A0A8V8TQ58, A0A8V8TQ90, A0A8V8TQ93, A0A8V8TQT3, A0A8V8TQU7, A0A8V8TQU9, A0A8V8TQV2, A0A8V8TR50, A0A8V8TR52, A0A8V8TR55, G3V2B1, G3V2G7, G3V3P0, G3V3Z0, G3V449, G3V490, G3V4M0, G3V4P4, G3V519, H0YM52, H0YNU4

UniProt curated annotations — full annotation on UniProt →

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). Requires the presence of the other members of the gamma-secretase complex for protease activity. 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. 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). Under conditions of apoptosis or calcium influx, cleaves CDH1. 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. Required for normal embryonic brain and skeleton development, and for normal angiogenesis. Mediates the proteolytic cleavage of EphB2/CTF1 into EphB2/CTF2. The holoprotein functions as a calcium-leak channel that allows the passive movement of calcium from endoplasmic reticulum to cytosol and is therefore involved in calcium homeostasis. Involved in the regulation of neurite outgrowth. Is a regulator of presynaptic facilitation, spike transmission and synaptic vesicles replenishment in a process that depends on gamma-secretase activity. It acts through the control of SYT7 presynaptic expression.

Subunit / interactions. Homodimer. The functional gamma-secretase complex is composed of at least four polypeptides: a presenilin homodimer (PSEN1 or PSEN2), nicastrin (NCSTN), APH1 (APH1A/APH1B) and PEN2. Such minimal complex is sufficient for secretase activity. Other components which are associated with the complex include SLC25A64, SLC5A7, PHB and PSEN1 isoform 3. As part of the gamma-secretase complex, interacts with CRB2 (via transmembrane domain). Predominantly heterodimer of a N-terminal (NTF) and a C-terminal (CTF) endoproteolytical fragment. Associates with proteolytic processed C-terminal fragments C83 and C99 of the amyloid precursor protein (APP) (via transmembrane domain). Associates with NOTCH1 (via transmembrane domain). Associates with cadherin/catenin adhesion complexes through direct binding to CDH1 or CDH2. Interaction with CDH1 stabilizes the complex and stimulates cell-cell aggregation. Interaction with CDH2 is essential for trafficking of CDH2 from the endoplasmic reticulum to the plasma membrane. Interacts with CTNND2, CTNNB1, CTNND1, JUP, HERPUD1, FLNA, FLNB, MTCH1, PKP4 and PARL. Interacts through its N-terminus with GFAP (isoform 2). Interacts with DOCK3; this interaction mediates the membrane association of DOCK3. Interacts with isoform 1 and isoform 3 of UBQLN1.

Subcellular location. Endoplasmic reticulum. Endoplasmic reticulum membrane. Golgi apparatus membrane. Cytoplasmic granule. Cell membrane. Cell projection. Growth cone. Early endosome. Early endosome membrane. Neuron projection. Axon. Synapse.

Tissue specificity. Detected in azurophile granules in neutrophils and in platelet cytoplasmic granules (at protein level). Expressed in a wide range of tissues including various regions of the brain, liver, spleen and lymph nodes.

Post-translational modifications. Heterogeneous proteolytic processing generates N-terminal (NTF) and C-terminal (CTF) fragments of approximately 35 and 20 kDa, respectively. During apoptosis, the C-terminal fragment (CTF) is further cleaved by caspase-3 to produce the fragment, PS1-CTF12. After endoproteolysis, the C-terminal fragment (CTF) is phosphorylated on serine residues by PKA and/or PKC. Phosphorylation on Ser-346 inhibits endoproteolysis.

Disease relevance. 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. The disease is caused by variants affecting the gene represented in this entry. Frontotemporal dementia 1 (FTD1) [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. The disease is caused by variants affecting the gene represented in this entry. 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. The disease is caused by variants affecting the gene represented in this entry. 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. The disease is caused by variants affecting the gene represented in this entry. Pick disease of the brain (PIDB) [MIM:172700] A rare form of dementia pathologically defined by severe atrophy, neuronal loss and gliosis. It is characterized by the occurrence of tau-positive inclusions, swollen neurons (Pick cells) and argentophilic neuronal inclusions known as Pick bodies that disproportionally affect the frontal and temporal cortical regions. Clinical features include aphasia, apraxia, confusion, anomia, memory loss and personality deterioration. The gene represented in this entry may be involved in disease pathogenesis.

Domain organisation. The PAL motif is required for normal active site conformation. Substrates, such as NOTCH1 and APP peptides, are bound between PSEN1 transmembrane domains and via the first lumenal loop and the cytoplasmic loop between the sixth and seventh transmembrane domains. Substrate binding causes a conformation change and formation of an intermolecular antiparallel beta-sheet between PSEN1 and its substrates.

Miscellaneous. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Similarity. Belongs to the peptidase A22A family.

Isoforms (7)

UniProt ID	Names	Canonical?
P49768-1	1, I-467	yes
P49768-2	2, I-463
P49768-3	3, I-374
P49768-4	4, Minilin
P49768-5	5
P49768-6	6
P49768-7	7

RefSeq proteins (2): NP_000012, NP_015557 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001108	Peptidase_A22A	Family
IPR002031	Pept_A22A_PS1	Family
IPR006639	Preselin/SPP	Family
IPR042524	Presenilin_C	Homologous_superfamily

Pfam: PF01080

UniProt features (285 total): sequence variant 132, mutagenesis site 76, helix 15, topological domain 10, strand 10, transmembrane region 9, region of interest 8, splice variant 6, modified residue 5, site 4, chain 3, compositionally biased region 2, active site 2, sequence conflict 1, turn 1, short sequence motif 1

Structure

Experimental structures (PDB)

27 structures.

PDB	Method	Resolution (Å)
8KCS	ELECTRON MICROSCOPY	2.4
6IYC	ELECTRON MICROSCOPY	2.6
7D8X	ELECTRON MICROSCOPY	2.6
8K8E	ELECTRON MICROSCOPY	2.6
8KCT	ELECTRON MICROSCOPY	2.6
6IDF	ELECTRON MICROSCOPY	2.7
8KCU	ELECTRON MICROSCOPY	2.7
8KCO	ELECTRON MICROSCOPY	2.8
7Y5T	ELECTRON MICROSCOPY	2.9
8X52	ELECTRON MICROSCOPY	2.9
8X54	ELECTRON MICROSCOPY	2.9
9K95	ELECTRON MICROSCOPY	2.9
6LR4	ELECTRON MICROSCOPY	3
8KCP	ELECTRON MICROSCOPY	3
8X53	ELECTRON MICROSCOPY	3
6LQG	ELECTRON MICROSCOPY	3.1
7C9I	ELECTRON MICROSCOPY	3.1
8OQY	ELECTRON MICROSCOPY	3.3
5A63	ELECTRON MICROSCOPY	3.4
8IM7	ELECTRON MICROSCOPY	3.4
8OQZ	ELECTRON MICROSCOPY	3.4
5FN4	ELECTRON MICROSCOPY	4
5FN3	ELECTRON MICROSCOPY	4.1
5FN2	ELECTRON MICROSCOPY	4.2
5FN5	ELECTRON MICROSCOPY	4.3
4UIS	ELECTRON MICROSCOPY	4.4
2KR6	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P49768-F1	72.27	0.35

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (6): 257; 385; 291–292 (cleavage; alternate); 292–293 (cleavage; alternate); 298–299 (cleavage); 345–346 (cleavage; by caspase)

Post-translational modifications (5): 43, 51, 310, 346, 367

Mutagenesis-validated functional residues (76):

Position	Phenotype
66–72	no effect on interaction with gfap.
76–77	no effect on interaction with gfap.
82–83	loss of interaction with gfap.
82	loss of interaction with gfap.
84–85	loss of interaction with gfap.
99	nearly abolishes protease activity with app. increased amyloid-beta 42/amyloid-beta 40 ratio in vitro.
105	nearly abolishes protease activity with app. increased amyloid-beta 42/amyloid-beta 40 ratio in vitro.
108	nearly abolishes protease activity with app.
112	formation of an artifactual disulfide bond with a substrate protein.
113	severe decrease of protease activity with app. increased amyloid-beta 42/amyloid-beta 40 ratio in vitro.
117	nearly abolishes protease activity with app. increased amyloid-beta 42/amyloid-beta 40 ratio in vitro.
123	nearly abolishes protease activity with app. increased amyloid-beta 42/amyloid-beta 40 ratio in vitro.
131	severe decrease of protease activity with app.
136	decreased protease activity with app.
143	increased amyloid-beta 42/amyloid-beta 40 ratio in vitro.
150	nearly abolishes protease activity with app.
165	decreased protease activity with app. increased amyloid-beta 42/amyloid-beta 40 ratio in vitro.
168	nearly abolishes protease activity with app.
176	nearly abolishes protease activity with app.
184	nearly abolishes protease activity with app. increased amyloid-beta 42/amyloid-beta 40 ratio in vitro.
202	nearly abolishes protease activity with app.
212	nearly abolishes protease activity with app.
214	nearly abolishes protease activity with app. increased amyloid-beta 42/amyloid-beta 40 ratio in vitro.
219	decreased protease activity with app. increased amyloid-beta 42/amyloid-beta 40 ratio in vitro.
223	abolishes protease activity with app.

Function

Pathways and Gene Ontology

Reactome pathways

14 pathways

ID	Pathway
R-HSA-1251985	Nuclear signaling by ERBB4
R-HSA-1474228	Degradation of the extracellular matrix
R-HSA-193692	Regulated proteolysis of p75NTR
R-HSA-205043	NRIF signals cell death from the nucleus
R-HSA-2122948	Activated NOTCH1 Transmits Signal to the Nucleus
R-HSA-2644606	Constitutive Signaling by NOTCH1 PEST Domain Mutants
R-HSA-2894862	Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants
R-HSA-2979096	NOTCH2 Activation and Transmission of Signal to the Nucleus
R-HSA-3928665	EPH-ephrin mediated repulsion of cells
R-HSA-6798695	Neutrophil degranulation
R-HSA-9013507	NOTCH3 Activation and Transmission of Signal to the Nucleus
R-HSA-9013700	NOTCH4 Activation and Transmission of Signal to the Nucleus
R-HSA-9017802	Noncanonical activation of NOTCH3
R-HSA-9839383	TGFBR3 PTM regulation

MSigDB gene sets: 903 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_DENDRITE_DEVELOPMENT, GOBP_MEMORY, GOBP_HINDBRAIN_DEVELOPMENT, GOBP_HEMATOPOIETIC_PROGENITOR_CELL_DIFFERENTIATION, REACTOME_SIGNALING_BY_NOTCH, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_NEGATIVE_REGULATION_OF_NEURON_APOPTOTIC_PROCESS, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, GOBP_NUCLEOSIDE_DIPHOSPHATE_METABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_PROTEOLYSIS, GOBP_METENCEPHALON_DEVELOPMENT

GO Biological Process (103): autophagosome assembly (GO:0000045), negative regulation of transcription by RNA polymerase II (GO:0000122), blood vessel development (GO:0001568), cell fate specification (GO:0001708), somitogenesis (GO:0001756), neuron migration (GO:0001764), positive regulation of receptor recycling (GO:0001921), heart looping (GO:0001947), positive regulation of L-glutamate import across plasma membrane (GO:0002038), hematopoietic progenitor cell differentiation (GO:0002244), astrocyte activation involved in immune response (GO:0002265), T cell activation involved in immune response (GO:0002286), neural retina development (GO:0003407), membrane protein ectodomain proteolysis (GO:0006509), mitochondrial transport (GO:0006839), DNA damage response (GO:0006974), response to oxidative stress (GO:0006979), Notch signaling pathway (GO:0007219), Notch receptor processing (GO:0007220), learning or memory (GO:0007611), memory (GO:0007613), post-embryonic development (GO:0009791), regulation of gene expression (GO:0010468), positive regulation of gene expression (GO:0010628), negative regulation of gene expression (GO:0010629), regulation of neuron projection development (GO:0010975), protein transport (GO:0015031), choline transport (GO:0015871), obsolete synaptic vesicle targeting (GO:0016080), protein processing (GO:0016485), cerebellum development (GO:0021549), cerebral cortex cell migration (GO:0021795), Cajal-Retzius cell differentiation (GO:0021870), dorsal/ventral neural tube patterning (GO:0021904), embryonic limb morphogenesis (GO:0030326), positive regulation of proteasomal ubiquitin-dependent protein catabolic process (GO:0032436), endoplasmic reticulum calcium ion homeostasis (GO:0032469), positive regulation of tumor necrosis factor production (GO:0032760), amyloid-beta formation (GO:0034205), intracellular signal transduction (GO:0035556)

GO Molecular Function (13): endopeptidase activity (GO:0004175), aspartic-type endopeptidase activity (GO:0004190), calcium channel activity (GO:0005262), beta-catenin binding (GO:0008013), PDZ domain binding (GO:0030165), aspartic endopeptidase activity, intramembrane cleaving (GO:0042500), cadherin binding (GO:0045296), ATPase binding (GO:0051117), molecular adaptor activity (GO:0060090), growth factor receptor binding (GO:0070851), protein binding (GO:0005515), peptidase activity (GO:0008233), hydrolase activity (GO:0016787)

GO Cellular Component (46): Golgi membrane (GO:0000139), kinetochore (GO:0000776), nucleus (GO:0005634), nuclear outer membrane (GO:0005640), nucleoplasm (GO:0005654), mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), smooth endoplasmic reticulum (GO:0005790), rough endoplasmic reticulum (GO:0005791), Golgi apparatus (GO:0005794), centrosome (GO:0005813), plasma membrane (GO:0005886), cell cortex (GO:0005938), synaptic vesicle (GO:0008021), cell surface (GO:0009986), membrane (GO:0016020), aggresome (GO:0016235), cell junction (GO:0030054), dendrite (GO:0030425), growth cone (GO:0030426), neuromuscular junction (GO:0031594), early endosome membrane (GO:0031901), nuclear membrane (GO:0031965), protein-containing complex (GO:0032991), ciliary rootlet (GO:0035253), azurophil granule membrane (GO:0035577), sarcolemma (GO:0042383), presynaptic membrane (GO:0042734), neuron projection (GO:0043005), neuronal cell body (GO:0043025), dendritic shaft (GO:0043198), membrane raft (GO:0045121), gamma-secretase complex (GO:0070765), postsynapse (GO:0098794), glutamatergic synapse (GO:0098978), cytoplasm (GO:0005737), lysosomal membrane (GO:0005765), endosome (GO:0005768)

Reactome top-level categories

Rollup of top-14 pathways:

Category	Pathways
Signaling by ERBB4	1
Extracellular matrix organization	1
p75 NTR receptor-mediated signalling	1
Cell death signalling via NRAGE, NRIF and NADE	1
Signaling by NOTCH1	1
Signaling by NOTCH1 PEST Domain Mutants in Cancer	1
Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer	1
Signaling by NOTCH2	1
EPH-Ephrin signaling	1
Innate Immune System	1
Signaling by NOTCH3	1
Signaling by NOTCH4	1
NOTCH3 Activation and Transmission of Signal to the Nucleus	1
Signaling by TGFBR3	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular membrane-bounded organelle	4
cellular anatomical structure	4
cytoplasm	4
anatomical structure development	2
immune response	2
binding	2
nuclear outer membrane-endoplasmic reticulum membrane network	2
endomembrane system	2
endoplasmic reticulum	2
cell periphery	2
Atg12 activating enzyme activity	1
protein-phosphatidylethanolamide deconjugating activity	1
Atg12 conjugating enzyme activity	1
Atg12 ligase activity	1
organelle assembly	1
Atg1/ULK1 kinase complex assembly	1
autophagosome organization	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
vasculature development	1
cell fate commitment	1
cellular developmental process	1
anterior/posterior pattern specification	1
segmentation	1
chordate embryonic development	1
anatomical structure formation involved in morphogenesis	1
somite development	1
cell migration	1
generation of neurons	1
receptor recycling	1
regulation of receptor recycling	1
positive regulation of macromolecule metabolic process	1
positive regulation of signaling	1
embryonic heart tube morphogenesis	1
determination of heart left/right asymmetry	1
regulation of L-glutamate import across plasma membrane	1
positive regulation of organic acid transport	1
positive regulation of transmembrane transport	1
positive regulation of amino acid transport	1

Protein interactions and networks

STRING

3230 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PSEN1	NCSTN	Q92542	999
PSEN1	APH1A	Q96BI3	999
PSEN1	PSENEN	Q9NZ42	999
PSEN1	APH1B	Q8WW43	998
PSEN1	APP	P05067	992
PSEN1	CTNND2	Q9UQB3	988
PSEN1	PSEN2	P49810	983
PSEN1	BACE1	P56817	962
PSEN1	CTNNB1	P35222	957
PSEN1	APOE	P02649	956
PSEN1	GRB2	P29354	935
PSEN1	MAPT	P10636	933
PSEN1	CDH17	Q12864	925
PSEN1	CDH2	P19022	923
PSEN1	KCNIP3	Q9Y2W7	885

IntAct

194 interactions, top by confidence:

A	B	Type	Score
TSPAN5	ADAM10	psi-mi:“MI:0914”(association)	0.800
PSEN1	NCSTN	psi-mi:“MI:0914”(association)	0.790
PSEN1	NCSTN	psi-mi:“MI:0915”(physical association)	0.790
CDH1	CTNND1	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
PSEN1	APP	psi-mi:“MI:0570”(protein cleavage)	0.700
PSEN1	APP	psi-mi:“MI:0915”(physical association)	0.700
PSEN1	APBA1	psi-mi:“MI:0915”(physical association)	0.700
PSEN1	APP	psi-mi:“MI:0914”(association)	0.700
PSEN1	APBA1	psi-mi:“MI:0407”(direct interaction)	0.700
TAX1BP3	ARVCF	psi-mi:“MI:0914”(association)	0.690
APH1A	PSEN1	psi-mi:“MI:0915”(physical association)	0.670
PSEN1	APH1A	psi-mi:“MI:0915”(physical association)	0.670
PSEN1	TMBIM6	psi-mi:“MI:0915”(physical association)	0.660
PSEN1	TMBIM6	psi-mi:“MI:0403”(colocalization)	0.660
PSEN1	TMBIM6	psi-mi:“MI:0407”(direct interaction)	0.660
PSEN1	TMBIM6	psi-mi:“MI:0914”(association)	0.660
PSENEN	PSEN1	psi-mi:“MI:0915”(physical association)	0.640

BioGRID (308): TGFBR1 (Affinity Capture-Western), PSEN1 (Affinity Capture-Western), TRAF6 (Affinity Capture-Western), TGFBR1 (Co-localization), UBC (Co-localization), PSEN1 (Co-localization), PSEN1 (Affinity Capture-Western), NCSTN (Co-fractionation), NCSTN (Affinity Capture-Western), PSEN1 (Affinity Capture-Western), PSEN1 (Affinity Capture-Western), PSEN1 (Affinity Capture-RNA), PSEN1 (Synthetic Lethality), PSEN1 (Affinity Capture-MS), PSEN1 (Affinity Capture-Western)

ESM2 similar proteins: A0A061ACU2, A8WWR3, F1QB30, F1RAX4, F4JKK0, O02194, O43085, O60103, O64668, O74949, P34535, P40318, P49768, P49769, P79802, P90859, P97887, Q28GL3, Q3UF64, Q4JIM4, Q500V2, Q5M7Z0, Q5PP23, Q5R780, Q5RAG4, Q5RBT7, Q5Z880, Q6NPT7, Q6NTV1, Q6NZ21, Q6RH31, Q75CC8, Q7KRW1, Q7TMV1, Q8GUU2, Q8GWG6, Q8HXW5, Q8IMZ9, Q8VYC8, Q8W4Q5

Diamond homologs: O02100, O12976, O12977, O88777, P49768, P49769, P49810, P52166, P79801, P79802, P97887, Q0MS45, Q4JIM4, Q5R780, Q5RCN9, Q61144, Q6RH31, Q8HXW5, Q90X07, Q90ZE4, Q9XT96, Q9XT97, O02194, Q54ET2, Q9SIK7, Q9W6T7, O64668, Q54DE8, Q01608

SIGNOR signaling

40 interactions.

A	Effect	B	Mechanism
NCSTN	up-regulates	PSEN1	binding
DAPT	down-regulates	PSEN1	“chemical inhibition”
TMED10	up-regulates	PSEN1	binding
GSK3B	“down-regulates activity”	PSEN1	phosphorylation
“4-[2-[(1R)-1-(N-(4-chlorophenyl)sulfonyl-2,5-difluoroanilino)ethyl]-5-fluorophenyl]butanoic acid”	down-regulates	PSEN1	“chemical inhibition”
MAPK9	up-regulates	PSEN1	phosphorylation
PSEN1	“form complex”	gamma-secretase	binding
PSEN1	up-regulates	gamma-secretase	cleavage
GSK3B/Axin/APC	“down-regulates activity”	PSEN1	phosphorylation
PSEN1	down-regulates	CTNNB1	binding
PRKCA	“up-regulates activity”	PSEN1	phosphorylation
PRKCB	“up-regulates activity”	PSEN1	phosphorylation
PRKCG	“up-regulates activity”	PSEN1	phosphorylation
PRKCZ	“up-regulates activity”	PSEN1	phosphorylation
PSEN1	up-regulates	NOTCH	cleavage
FBXW7	“down-regulates quantity by destabilization”	PSEN1	binding
“Cullin 1-RBX1-Skp1”	“down-regulates quantity by destabilization”	PSEN1	polyubiquitination
TRAF6	“up-regulates quantity by stabilization”	PSEN1	ubiquitination
PSEN1	up-regulates	NOTCH1	cleavage
CDK5	up-regulates	PSEN1	phosphorylation
APH1A	up-regulates	PSEN1	binding
APH1B	up-regulates	PSEN1	binding
PSENEN	up-regulates	PSEN1	cleavage

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 145 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
NRIF signals cell death from the nucleus	5	34.3×	2e-05
Activated NOTCH1 Transmits Signal to the Nucleus	9	30.9×	5e-09
NOTCH3 Activation and Transmission of Signal to the Nucleus	6	27.4×	7e-06
NOTCH2 Activation and Transmission of Signal to the Nucleus	6	25.3×	1e-05
Nuclear signaling by ERBB4	6	20.0×	4e-05
Constitutive Signaling by NOTCH1 PEST Domain Mutants	7	13.2×	5e-05
Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants	7	13.2×	5e-05
EPH-ephrin mediated repulsion of cells	6	12.7×	3e-04

GO biological processes:

GO term	Partners	Fold	FDR
membrane protein ectodomain proteolysis	8	40.2×	5e-09
regulation of long-term neuronal synaptic plasticity	5	38.4×	3e-05
cellular response to amyloid-beta	5	15.2×	2e-03
neuron apoptotic process	8	11.5×	8e-05
Notch signaling pathway	9	9.9×	6e-05
protein processing	7	9.2×	1e-03
protein localization to plasma membrane	9	7.6×	4e-04
neuron projection development	7	6.6×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

620 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	80
Likely pathogenic	45
Uncertain significance	209
Likely benign	84
Benign	23

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1027511	NM_000021.4(PSEN1):c.300dup (p.Lys101Ter)	Pathogenic
1045636	NM_000021.4(PSEN1):c.667C>A (p.Gln223Lys)	Pathogenic
1178342	NM_000021.4(PSEN1):c.1247T>C (p.Ile416Thr)	Pathogenic
1184946	NM_000021.4(PSEN1):c.625G>C (p.Gly209Arg)	Pathogenic
1298589	NM_000021.4(PSEN1):c.520_522del (p.Leu174del)	Pathogenic
1450587	NM_000021.4(PSEN1):c.1129A>T (p.Arg377Trp)	Pathogenic
1453682	NM_000021.4(PSEN1):c.750G>T (p.Leu250Phe)	Pathogenic
1458372	NM_000021.4(PSEN1):c.838G>A (p.Glu280Lys)	Pathogenic
1459049	NC_000014.8:g.(?73673074)(73673200_?)del	Pathogenic
18123	NM_000021.4(PSEN1):c.436A>C (p.Met146Leu)	Pathogenic
18124	NM_000021.4(PSEN1):c.488A>G (p.His163Arg)	Pathogenic
18125	NM_000021.4(PSEN1):c.737C>A (p.Ala246Glu)	Pathogenic
18126	NM_000021.4(PSEN1):c.856C>G (p.Leu286Val)	Pathogenic
18127	NM_000021.4(PSEN1):c.1229G>A (p.Cys410Tyr)	Pathogenic
18128	NM_000021.4(PSEN1):c.415A>G (p.Met139Val)	Pathogenic
18129	NM_000021.4(PSEN1):c.436A>G (p.Met146Val)	Pathogenic
18130	NM_000021.4(PSEN1):c.487C>T (p.His163Tyr)	Pathogenic
18131	NM_000021.4(PSEN1):c.839A>C (p.Glu280Ala)	Pathogenic
18132	NM_000021.4(PSEN1):c.839A>G (p.Glu280Gly)	Pathogenic
18135	NM_000021.4(PSEN1):c.360A>T (p.Glu120Asp)	Pathogenic
18137	NM_000021.4(PSEN1):c.438G>A (p.Met146Ile)	Pathogenic
18138	NM_000021.4(PSEN1):c.749T>C (p.Leu250Ser)	Pathogenic
18139	NM_000021.4(PSEN1):c.833G>C (p.Arg278Thr)	Pathogenic
18141	NM_000021.4(PSEN1):c.1300_1301delinsTG (p.Ala434Cys)	Pathogenic
18142	NM_000021.4(PSEN1):c.275G>C (p.Cys92Ser)	Pathogenic
18143	NM_000021.4(PSEN1):c.617G>C (p.Gly206Ala)	Pathogenic
18146	NM_000021.4(PSEN1):c.497T>C (p.Leu166Pro)	Pathogenic
18147	NM_000021.4(PSEN1):c.520C>A (p.Leu174Met)	Pathogenic
18148	NM_000021.4(PSEN1):c.811C>G (p.Leu271Val)	Pathogenic
18149	NM_000021.4(PSEN1):c.548G>T (p.Gly183Val)	Pathogenic

SpliceAI

2953 predictions. Top by Δscore:

Variant	Effect	Δscore
14:73136578:GC:G	donor_gain	1.0000
14:73136613:G:GT	donor_gain	1.0000
14:73136614:A:T	donor_gain	1.0000
14:73147965:A:AG	acceptor_gain	1.0000
14:73147966:G:GA	acceptor_gain	1.0000
14:73147966:GA:G	acceptor_gain	1.0000
14:73148095:G:GG	donor_gain	1.0000
14:73166892:A:T	donor_gain	1.0000
14:73170788:T:TA	acceptor_gain	1.0000
14:73170793:A:AG	acceptor_gain	1.0000
14:73170794:T:G	acceptor_gain	1.0000
14:73170794:TAGA:T	acceptor_loss	1.0000
14:73170794:TAGAA:T	acceptor_gain	1.0000
14:73170795:A:AG	acceptor_gain	1.0000
14:73170795:AGAAT:A	acceptor_gain	1.0000
14:73170796:G:GT	acceptor_gain	1.0000
14:73170796:GA:G	acceptor_gain	1.0000
14:73170796:GAA:G	acceptor_gain	1.0000
14:73170796:GAAT:G	acceptor_gain	1.0000
14:73170796:GAATG:G	acceptor_gain	1.0000
14:73170911:G:GT	donor_gain	1.0000
14:73170991:G:GA	donor_gain	1.0000
14:73171008:T:TG	donor_gain	1.0000
14:73171012:G:GG	donor_gain	1.0000
14:73171045:GCT:G	donor_gain	1.0000
14:73171046:CT:C	donor_gain	1.0000
14:73171048:G:GG	donor_gain	1.0000
14:73173563:TAGA:T	acceptor_loss	1.0000
14:73173564:A:G	acceptor_loss	1.0000
14:73173565:G:GA	acceptor_gain	1.0000

AlphaMissense

3056 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:73170963:T:A	L85H	1.000
14:73170963:T:C	L85P	1.000
14:73170972:C:A	P88H	1.000
14:73170972:C:G	P88R	1.000
14:73170985:C:G	C92W	1.000
14:73192720:G:A	G209R	1.000
14:73192720:G:C	G209R	1.000
14:73192721:G:A	G209E	1.000
14:73192772:T:C	L226P	1.000
14:73192783:A:C	S230R	1.000
14:73192785:T:A	S230R	1.000
14:73192785:T:G	S230R	1.000
14:73192834:T:A	W247R	1.000
14:73192834:T:C	W247R	1.000
14:73192864:G:C	D257H	1.000
14:73198031:A:C	D257A	1.000
14:73198031:A:T	D257V	1.000
14:73198032:T:A	D257E	1.000
14:73198032:T:G	D257E	1.000
14:73198040:C:A	A260D	1.000
14:73198043:T:A	V261D	1.000
14:73198057:G:C	G266R	1.000
14:73198058:G:A	G266D	1.000
14:73198064:T:A	L268H	1.000
14:73198064:T:C	L268P	1.000
14:73198067:G:C	R269P	1.000
14:73198073:T:A	L271Q	1.000
14:73198073:T:C	L271P	1.000
14:73198076:T:A	V272D	1.000
14:73198085:C:A	A275D	1.000

dbSNP variants (sampled 300 via entrez): RS1000008 (14:73191183 G>A), RS1000031277 (14:73147916 A>G,T), RS1000033403 (14:73191961 A>G), RS1000102659 (14:73146268 G>C), RS1000136143 (14:73193498 C>T), RS1000165333 (14:73141690 C>T), RS1000186379 (14:73165788 T>G), RS1000190715 (14:73185795 T>C), RS1000289888 (14:73217120 T>G), RS1000309702 (14:73179201 C>G,T), RS1000319797 (14:73172235 C>T), RS1000359534 (14:73197970 C>A,T), RS1000385711 (14:73187442 C>G,T), RS1000404278 (14:73215227 C>T), RS1000434550 (14:73171707 G>A)

Disease associations

OMIM: gene MIM:104311 | disease phenotypes: MIM:172700, MIM:607822, MIM:613737, MIM:613694, MIM:187300, MIM:606889

GenCC curated gene-disease

Disease	Classification	Inheritance
Alzheimer disease 3	Strong	Autosomal dominant
Pick disease	Strong	Autosomal dominant
semantic dementia	Strong	Autosomal dominant
early-onset autosomal dominant Alzheimer disease	Supportive	Autosomal dominant
familial isolated dilated cardiomyopathy	Supportive	Autosomal dominant
behavioral variant of frontotemporal dementia	Supportive	Autosomal dominant
dilated cardiomyopathy 1U	Limited	Autosomal dominant
acne inversa, familial, 3	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
dilated cardiomyopathy 1U	Disputed	AD

Mondo (16): Pick disease (MONDO:0008243), Alzheimer disease 3 (MONDO:0011913), acne inversa, familial, 3 (MONDO:0013398), frontotemporal dementia (MONDO:0017276), Alzheimer disease (MONDO:0004975), dilated cardiomyopathy 1U (MONDO:0013371), telangiectasia, hereditary hemorrhagic, type 1 (MONDO:0008535), early-onset autosomal dominant Alzheimer disease (MONDO:0015140), congenital nervous system disorder (MONDO:0002320), dilated cardiomyopathy (MONDO:0005021), heart failure (MONDO:0005252), dementia (MONDO:0001627), Alzheimer disease 4 (MONDO:0011743), semantic dementia (MONDO:0010857), (MONDO:0015470)

Orphanet (6): Early-onset autosomal dominant Alzheimer disease (Orphanet:1020), Frontotemporal dementia (Orphanet:282), Familial isolated dilated cardiomyopathy (Orphanet:154), Hereditary hemorrhagic telangiectasia (Orphanet:774), Dilated cardiomyopathy (Orphanet:217604), NON RARE IN EUROPE: Alzheimer disease (Orphanet:238616)

HPO phenotypes

125 total (30 of 125 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000407	Sensorineural hearing impairment
HP:0000474	Thickened nuchal skin fold
HP:0000504	Abnormality of vision
HP:0000657	Oculomotor apraxia
HP:0000708	Atypical behavior
HP:0000709	Psychosis
HP:0000710	Hyperorality
HP:0000711	Restlessness
HP:0000713	Agitation
HP:0000716	Depression
HP:0000718	Aggressive behavior
HP:0000719	Inappropriate behavior
HP:0000723	Restrictive behavior
HP:0000726	Dementia
HP:0000727	Frontal lobe dementia
HP:0000733	Motor stereotypy
HP:0000734	Disinhibition
HP:0000737	Irritability
HP:0000738	Hallucinations
HP:0000739	Anxiety
HP:0000741	Apathy
HP:0000745	Abnormal diminished volition
HP:0000748	Inappropriate laughter
HP:0000751	Personality changes
HP:0000757	Lack of insight
HP:0000969	Edema
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST010002_156	Refractive error	7.000000e-25
GCST010243_152	Apolipoprotein B levels	1.000000e-08
GCST90002404_398	Red cell distribution width	4.000000e-15
GCST90002406_425	Reticulocyte fraction of red cells	4.000000e-10

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004615	apolipoprotein B measurement
EFO:0009188	Red cell distribution width

MeSH disease descriptors (9)

Descriptor	Name	Tree numbers
D000544	Alzheimer Disease	C10.228.140.380.100; C10.574.945.249; F03.615.400.100
D002311	Cardiomyopathy, Dilated	C14.280.195.160; C14.280.238.070; C16.320.488.750
D003704	Dementia	C10.228.140.380; F03.615.400
D057180	Frontotemporal Dementia	C10.228.140.380.266.299; C10.574.950.300.299; C18.452.845.800.300.299; F03.615.400.380.299
D006333	Heart Failure	C14.280.434
D020774	Pick Disease of the Brain	C10.228.140.380.266.299.500; F03.615.400.380.299.500
C536596	Alzheimer disease type 4 (supp.)
C536598	Alzheimer disease, familial, type 3 (supp.)
C566296	Cardiomyopathy, Dilated, 1u (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2094135 (PROTEIN COMPLEX), CHEMBL2473 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

8 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 8,401 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1770916	NIROGACESTAT	4	756
CHEMBL190083	TARENFLURBIL	3	4,903
CHEMBL520733	SEMAGACESTAT	3	701
CHEMBL1090771	AVAGACESTAT	2	479
CHEMBL4297422	RG-4733	2	668
CHEMBL463981	BEGACESTAT	2	218
CHEMBL2151205	E-2212	1	19
CHEMBL4205422	MK-0752	1	657

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — A22: Presenilin

Most potent curated ligand interactions (9 total), top 9:

Ligand	Action	Affinity	Parameter
avagacestat	Inhibition	9.5	pIC50
ELND006	Inhibition	9.47	pIC50
SCH-900229	Inhibition	9.0	pIC50
RO4929097	Inhibition	8.4	pIC50
PF-06648671	Allosteric modulator	8.01	pIC50
begacestat	Inhibition	7.83	pEC50
semagacestat	Inhibition	7.82	pIC50
AZ4800	Inhibition	7.59	pIC50
CHF-5074	Binding	4.4	pEC50

Binding affinities (BindingDB)

107 measured of 128 human assays (128 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CHEMBL2396959	IC50	0.22 nM
CHEMBL2396964	IC50	0.3 nM
CHEMBL570980	IC50	0.52 nM
CHEMBL570752	IC50	0.75 nM
CHEMBL585542	IC50	1 nM
CHEMBL585911	IC50	1 nM
CHEMBL2396963	IC50	1 nM
CHEMBL2396965	IC50	1.1 nM
CHEMBL571429	IC50	2 nM
CHEMBL392075	IC50	2.6 nM
CHEMBL582818	IC50	4 nM
5-Chloro-thiophene-2-sulfonic acid [5-((E)-3-morpholin-4-yl-propenyl)-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-13-yl]-amide	IC50	5 nM
5-Chloro-thiophene-2-sulfonic acid [5-(2-morpholin-4-yl-ethoxy)-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-13-yl]-amide	IC50	5 nM
N-[13-(5-Chloro-thiophene-2-sulfonylamino)-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-5-yl]-2-(4-phenyl-piperazin-1-yl)-acetamide	IC50	5 nM
N-[13-(5-Chloro-thiophene-2-sulfonylamino)-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-5-yl]-2-piperidin-1-yl-acetamide	IC50	6 nM
N-[13-(5-Chloro-thiophene-2-sulfonylamino)-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-5-yl]-2-pyrrolidin-1-yl-acetamide	IC50	7 nM
N-[13-(5-Chloro-thiophene-2-sulfonylamino)-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-5-yl]-2-morpholin-4-yl-acetamide	IC50	7 nM
CHEMBL1837060	IC50	7 nM
CHEMBL571663	IC50	8 nM
CHEMBL583663	IC50	9 nM
CHEMBL2396972	IC50	9.4 nM
CHEMBL1837048	IC50	10 nM
CHEMBL4525398	IC50	11 nM
Pyridine-2-carboxylic acid [13-(5-chloro-thiophene-2-sulfonylamino)-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-5-yl]-amide	IC50	12 nM
5-Chloro-thiophene-2-sulfonic acid [5-((E)-3-imidazol-1-yl-propenyl)-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-13-yl]-amide	IC50	15 nM
(13-Benzenesulfonylamino-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-5-yl)-carbamic acid 4-chloro-benzyl ester	IC50	16 nM
CHEMBL2396953	IC50	18 nM
CHEMBL582822	IC50	20 nM
5-Chloro-thiophene-2-sulfonic acid {5-[(E)-3-(4-phenyl-piperazin-1-yl)-propenyl]-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-13-yl}-amide	IC50	21 nM
CHEMBL1837045	IC50	21 nM
[13-(5-Chloro-thiophene-2-sulfonylamino)-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-5-yl]-carbamic acid benzyl ester	IC50	23 nM
CHEMBL256616	IC50	23 nM
CHEMBL571401	IC50	26 nM
5-Chloro-thiophene-2-sulfonic acid (5-fluoro-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-13-yl)-amide	IC50	29 nM
5-Chloro-thiophene-2-sulfonic acid (4-fluoro-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-13-yl)-amide	IC50	34 nM
5-Chloro-thiophene-2-sulfonic acid {5-[(E)-3-(4-methyl-piperazin-1-yl)-propenyl]-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-13-yl}-amide	IC50	39 nM
N-[13-(5-Chloro-thiophene-2-sulfonylamino)-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-5-yl]-2-diethylamino-acetamide	IC50	41 nM
CHEMBL4799315	IC50	42 nM
CHEMBL2396960	IC50	45 nM
CHEMBL2396971	IC50	47 nM
Thiophene-2-sulfonic acid tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-13-ylamide	IC50	50 nM
5-chloro-thiophene-2-sulfonic acid tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-13-ylamide	IC50	62 nM
CHEMBL403372	IC50	62 nM
CHEMBL585913	IC50	66 nM
N-[13-(5-Chloro-thiophene-2-sulfonylamino)-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-5-yl]-2-(4-methyl-piperazin-1-yl)-acetamide	IC50	69 nM
N-(5-Fluoro-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-13-yl)-benzenesulfonamide	IC50	70 nM
5-Chloro-thiophene-2-sulfonic acid [5-(2-piperidin-1-yl-ethoxy)-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-13-yl]-amide	IC50	73 nM
(13-Benzenesulfonylamino-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-5-yl)-carbamic acid benzyl ester	IC50	74 nM
Pyridine-2-carboxylic acid (13-benzenesulfonylamino-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-5-yl)-amide	IC50	75 nM
CHEMBL402285	IC50	81 nM

ChEMBL bioactivities

3365 potent at pChembl≥5 of 3627 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.99	EC50	0.0103	nM	CHEMBL4456488
10.94	EC50	0.0114	nM	CHEMBL4443026
10.93	EC50	0.0117	nM	CHEMBL4525398
10.89	EC50	0.013	nM	CHEMBL4547187
10.86	EC50	0.0139	nM	CHEMBL4535601
10.82	IC50	0.015	nM	CHEMBL392113
10.70	IC50	0.02	nM	CHEMBL235659
10.62	IC50	0.024	nM	CHEMBL235869
10.52	IC50	0.03	nM	CHEMBL468083
10.43	IC50	0.037	nM	CHEMBL235869
10.40	IC50	0.04	nM	CHEMBL209888
10.38	IC50	0.042	nM	CHEMBL235659
10.30	IC50	0.05	nM	CHEMBL393761
10.22	IC50	0.06	nM	CHEMBL377691
10.22	IC50	0.06	nM	CHEMBL401521
10.22	IC50	0.06	nM	CHEMBL252671
10.22	IC50	0.06	nM	CHEMBL523832
10.22	IC50	0.06	nM	CHEMBL495009
10.22	IC50	0.06	nM	CHEMBL512282
10.22	IC50	0.06	nM	CHEMBL467457
10.15	IC50	0.07	nM	CHEMBL511572
10.12	IC50	0.075	nM	CHEMBL392113
10.10	IC50	0.08	nM	CHEMBL379089
10.10	IC50	0.08	nM	CHEMBL392068
10.10	IC50	0.08	nM	CHEMBL237875
10.10	IC50	0.08	nM	CHEMBL495185
10.09	IC50	0.082	nM	CHEMBL392068
10.05	IC50	0.09	nM	CHEMBL393542
10.00	IC50	0.1	nM	CHEMBL2396772
10.00	IC50	0.1	nM	CHEMBL237850
9.96	IC50	0.11	nM	CHEMBL236597
9.94	EC50	0.114	nM	CHEMBL392068
9.92	EC50	0.119	nM	CHEMBL392068
9.92	IC50	0.12	nM	CHEMBL523883
9.89	IC50	0.13	nM	AVAGACESTAT
9.87	EC50	0.135	nM	CHEMBL392068
9.85	IC50	0.14	nM	CHEMBL2396771
9.85	IC50	0.14	nM	CHEMBL2096800
9.85	IC50	0.14	nM	CHEMBL237666
9.82	IC50	0.15	nM	CHEMBL372085
9.82	IC50	0.15	nM	CHEMBL511928
9.77	IC50	0.17	nM	CHEMBL494588
9.77	IC50	0.17	nM	CHEMBL583904
9.77	IC50	0.17	nM	CHEMBL572032
9.75	IC50	0.178	nM	CHEMBL2059813
9.75	IC50	0.178	nM	CHEMBL5202466
9.74	IC50	0.18	nM	CHEMBL2396770
9.72	IC50	0.19	nM	CHEMBL2164125
9.72	IC50	0.19	nM	CHEMBL210587
9.70	IC50	0.2	nM	CHEMBL392246

PubChem BioAssay actives

3103 with measured affinity, of 5000 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
N-benzyl-2-methyl-N’-(5-methyl-6-oxo-7H-benzo[d][1]benzazepin-7-yl)propanediamide	301810: Inhibition of human gamma secretase assessed as amyloid-beta40 peptide production in HEK293 cells by ELISA	ic50	<0.0001	uM
2-methyl-N-(5-methyl-6-oxo-7H-benzo[d][1]benzazepin-7-yl)-N’-(3,3,3-trifluoropropyl)propanediamide	301809: Inhibition of human gamma secretase in HEK293 cells by reporter gene assay	ic50	<0.0001	uM
2-methyl-N-(5-methyl-6-oxo-7H-benzo[d][1]benzazepin-7-yl)-N’-(2,2,2-trifluoroethyl)propanediamide	301809: Inhibition of human gamma secretase in HEK293 cells by reporter gene assay	ic50	<0.0001	uM
N-[(1R,5S)-3-(5-fluoro-6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-4-(3-fluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine	1586853: Inhibition of gamma-secretase (unknown origin) assessed as decrease in amyloid beta-42 secretion by cell based AlphaLisa assay	ec50	<0.0001	uM
4-(3-fluorophenyl)-N-[(1R,5S)-3-(2-methoxy-4-pyridinyl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine	1586853: Inhibition of gamma-secretase (unknown origin) assessed as decrease in amyloid beta-42 secretion by cell based AlphaLisa assay	ec50	<0.0001	uM
N-[(1R,5S)-3-(6-chloropyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-4-(3-fluoro-4-methylphenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine	1586853: Inhibition of gamma-secretase (unknown origin) assessed as decrease in amyloid beta-42 secretion by cell based AlphaLisa assay	ec50	<0.0001	uM
N-[(1R,5S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-4-[4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine	1586853: Inhibition of gamma-secretase (unknown origin) assessed as decrease in amyloid beta-42 secretion by cell based AlphaLisa assay	ec50	<0.0001	uM
N-[(1R,5S)-3-(2-chloro-4-pyridinyl)-3-azabicyclo[3.2.1]octan-8-yl]-4-(3,4-difluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine	1586853: Inhibition of gamma-secretase (unknown origin) assessed as decrease in amyloid beta-42 secretion by cell based AlphaLisa assay	ec50	<0.0001	uM
4-(3-fluoro-5-methylphenyl)-N-[(1R,5S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine	1586853: Inhibition of gamma-secretase (unknown origin) assessed as decrease in amyloid beta-42 secretion by cell based AlphaLisa assay	ec50	<0.0001	uM
5-N-(3,4-difluorophenyl)-5-N-ethyl-3-N-[(1R,5S)-3-(5-fluoro-6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-1-methyl-1,2,4-triazole-3,5-diamine	1586853: Inhibition of gamma-secretase (unknown origin) assessed as decrease in amyloid beta-42 secretion by cell based AlphaLisa assay	ec50	<0.0001	uM
5-N-(3,5-difluorophenyl)-5-N-ethyl-3-N-[(1R,5S)-3-(2-methoxy-4-pyridinyl)-3-azabicyclo[3.2.1]octan-8-yl]-1-methyl-1,2,4-triazole-3,5-diamine	1586853: Inhibition of gamma-secretase (unknown origin) assessed as decrease in amyloid beta-42 secretion by cell based AlphaLisa assay	ec50	<0.0001	uM
(1’R,4R,10’S)-5’-[1-(4-fluorophenyl)imidazol-4-yl]-2-(2,2,2-trifluoroethyl)spiro[1,2,5-thiadiazolidine-4,13’-tricyclo[8.2.1.03,8]trideca-3(8),4,6-triene] 1,1-dioxide	375649: Inhibition of gamma secretase in human SH-SY5Y cells by HTRF assay	ic50	<0.0001	uM
(4aS,6R,8aS)-6-(4-chlorophenyl)sulfonyl-1-cyclopropyl-6-(2,5-difluorophenyl)-4,4a,5,7,8,8a-hexahydro-3H-benzo[c][1,2,6]thiadiazine 2,2-dioxide	265340: Inhibition of gamma secretase	ic50	<0.0001	uM
[1-[[(7S)-5-methyl-6-oxo-7H-benzo[d][1]benzazepin-7-yl]amino]-1-oxopropan-2-yl] N-(2,2,3,3,3-pentafluoropropyl)carbamate	301809: Inhibition of human gamma secretase in HEK293 cells by reporter gene assay	ic50	<0.0001	uM
(2S)-2-[[(2S)-2-(3,5-difluorophenyl)-2-hydroxyacetyl]amino]-N-[(7S)-5-methyl-6-oxo-7H-benzo[d][1]benzazepin-7-yl]propanamide	1628293: Inhibition of gamma secretase in HEK293 cells expressing APP 695 assessed as reduction in amyloid beta levels after 5 hrs by Western blot analysis	ic50	0.0001	uM
methyl 2-methyl-2-[[(2R,3R)-3-methyl-2-[[(2R)-3-methyl-2-[[2-methyl-2-[[(2R)-3-methyl-2-[[(2R,3S)-2-[[2-methyl-2-[[(2R,3R)-3-methyl-2-[[(2R)-3-methyl-2-[[(2R)-3-methyl-2-[[2-methyl-2-[[2-[[(2R)-3-methyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]butanoyl]amino]acetyl]amino]propanoyl]amino]butanoyl]amino]butanoyl]amino]pentanoyl]amino]propanoyl]amino]-3-phenylmethoxybutanoyl]amino]butanoyl]amino]propanoyl]amino]butanoyl]amino]pentanoyl]amino]propanoate	241010: Inhibitory activity against Gamma-secretase in HeLa cells expressing APP-reporter	ic50	0.0001	uM
N-(cyclopropylmethyl)-2-methyl-N’-(5-methyl-6-oxo-7H-benzo[d][1]benzazepin-7-yl)propanediamide	301810: Inhibition of human gamma secretase assessed as amyloid-beta40 peptide production in HEK293 cells by ELISA	ic50	0.0001	uM
(1’R,4R,10’S)-5’-[5-(4-fluorophenyl)-1-methylpyrazol-3-yl]-2-(2,2,2-trifluoroethyl)spiro[1,2,5-thiadiazolidine-4,13’-tricyclo[8.2.1.03,8]trideca-3(8),4,6-triene] 1,1-dioxide	375649: Inhibition of gamma secretase in human SH-SY5Y cells by HTRF assay	ic50	0.0001	uM
(1’R,4R,10’S)-5’-[1-(2,4-difluorophenyl)imidazol-4-yl]-2-(2,2,2-trifluoroethyl)spiro[1,2,5-thiadiazolidine-4,13’-tricyclo[8.2.1.03,8]trideca-3(8),4,6-triene] 1,1-dioxide	375649: Inhibition of gamma secretase in human SH-SY5Y cells by HTRF assay	ic50	0.0001	uM
(1’R,4R,10’S)-5’-[1-(3,4-difluorophenyl)imidazol-4-yl]-2-(2,2,2-trifluoroethyl)spiro[1,2,5-thiadiazolidine-4,13’-tricyclo[8.2.1.03,8]trideca-3(8),4,6-triene] 1,1-dioxide	375649: Inhibition of gamma secretase in human SH-SY5Y cells by HTRF assay	ic50	0.0001	uM
(1’R,4R,10’S)-5’-[1-(4-chlorophenyl)imidazol-4-yl]-2-(2,2,2-trifluoroethyl)spiro[1,2,5-thiadiazolidine-4,13’-tricyclo[8.2.1.03,8]trideca-3(8),4,6-triene] 1,1-dioxide	375649: Inhibition of gamma secretase in human SH-SY5Y cells by HTRF assay	ic50	0.0001	uM
(1’R,4R,10’S)-5’-[1-(4-fluorophenyl)-1,2,4-triazol-3-yl]-2-(2,2,2-trifluoroethyl)spiro[1,2,5-thiadiazolidine-4,13’-tricyclo[8.2.1.03,8]trideca-3(8),4,6-triene] 1,1-dioxide	375649: Inhibition of gamma secretase in human SH-SY5Y cells by HTRF assay	ic50	0.0001	uM
(1’R,4R,10’S)-5’-[5-(2,4-difluorophenyl)-1-methylpyrazol-3-yl]-2-(2,2,2-trifluoroethyl)spiro[1,2,5-thiadiazolidine-4,13’-tricyclo[8.2.1.03,8]trideca-3(8),4,6-triene] 1,1-dioxide	375649: Inhibition of gamma secretase in human SH-SY5Y cells by HTRF assay	ic50	0.0001	uM
(1’R,4R,10’S)-5’-[5-(3,4-difluorophenyl)-1-methylpyrazol-3-yl]-2-(2,2,2-trifluoroethyl)spiro[1,2,5-thiadiazolidine-4,13’-tricyclo[8.2.1.03,8]trideca-3(8),4,6-triene] 1,1-dioxide	375649: Inhibition of gamma secretase in human SH-SY5Y cells by HTRF assay	ic50	0.0001	uM
(1’R,4R,10’S)-5’-[5-(4-chlorophenyl)-1-methylpyrazol-3-yl]-2-(2,2,2-trifluoroethyl)spiro[1,2,5-thiadiazolidine-4,13’-tricyclo[8.2.1.03,8]trideca-3(8),4,6-triene] 1,1-dioxide	375649: Inhibition of gamma secretase in human SH-SY5Y cells by HTRF assay	ic50	0.0001	uM
N-[4-(4-chlorophenyl)sulfonyl-4-(2,5-difluorophenyl)cyclohexyl]azetidine-1-sulfonamide	258050: Inhibition of human gamma-secretase in SHSY5Y neuroblastoma cells	ic50	0.0001	uM
[(2R)-2-[5-chloro-N-(4-chlorophenyl)sulfonyl-2-(hydroxymethyl)anilino]propyl] N-ethyl-N-(3-imidazol-1-ylpropyl)carbamate	314049: Inhibition of gamma secretase in human H4 cells assessed as reduction in amyloid beta40 level by ELISA	ic50	0.0001	uM
[(2R)-2-[5-chloro-N-(4-chlorophenyl)sulfonyl-2-(hydroxymethyl)anilino]propyl] N-(cyclopropylmethyl)-N-(3-imidazol-1-ylpropyl)carbamate	314049: Inhibition of gamma secretase in human H4 cells assessed as reduction in amyloid beta40 level by ELISA	ic50	0.0001	uM
(4aR,6R,8aS)-6-(4-chlorophenyl)sulfonyl-6-(2,5-difluorophenyl)-3-methyl-1,3,4,4a,5,7,8,8a-octahydrobenzo[c]thiazine 2,2-dioxide	265340: Inhibition of gamma secretase	ic50	0.0001	uM
(4aR,6R,8aS)-6-(4-chlorophenyl)sulfonyl-6-(2,5-difluorophenyl)-3-ethyl-1,3,4,4a,5,7,8,8a-octahydrobenzo[c]thiazine 2,2-dioxide	265340: Inhibition of gamma secretase	ic50	0.0001	uM
(2S)-2-[3-(3,5-difluorophenyl)propanoylamino]-N-[5-(6-hydroxy-6-methylheptan-2-yl)-1,3-thiazol-2-yl]pentanamide	301212: Inhibition of gamma secretase activity in human H4 cells transfected with APP695 mutant assessed as beta amyloid(1-40) production by whole cell assay	ic50	0.0001	uM
(2S)-2-[3-(3,5-difluorophenyl)propanoylamino]-N-[5-(6-methoxy-6-methylheptan-2-yl)-1,3-thiazol-2-yl]pentanamide	301212: Inhibition of gamma secretase activity in human H4 cells transfected with APP695 mutant assessed as beta amyloid(1-40) production by whole cell assay	ic50	0.0001	uM
(2S)-2-[3-(3,5-difluorophenyl)propanoylamino]-N-[5-[(2S)-6-methoxy-6-methylheptan-2-yl]-1,3-thiazol-2-yl]butanamide	301212: Inhibition of gamma secretase activity in human H4 cells transfected with APP695 mutant assessed as beta amyloid(1-40) production by whole cell assay	ic50	0.0001	uM
(2S)-2-hydroxy-N-[(2S)-1-[[5-[(2S)-6-methoxy-6-methylheptan-2-yl]-1,3-thiazol-2-yl]amino]-1-oxopentan-2-yl]-3,3-dimethylbutanamide	301212: Inhibition of gamma secretase activity in human H4 cells transfected with APP695 mutant assessed as beta amyloid(1-40) production by whole cell assay	ic50	0.0001	uM
(2S)-2-[3-(3,5-difluorophenyl)propanoylamino]-N-[5-(6-methoxy-6-methylheptan-2-yl)-1,3-thiazol-2-yl]butanamide	301212: Inhibition of gamma secretase activity in human H4 cells transfected with APP695 mutant assessed as beta amyloid(1-40) production by whole cell assay	ic50	0.0001	uM
(2R)-2-[(4-chlorophenyl)sulfonyl-[[2-fluoro-4-(1,2,4-oxadiazol-3-yl)phenyl]methyl]amino]-5,5,5-trifluoropentanamide	754316: Inhibition of gamma-secretase in human IMR32 cell membrane using APP as substrate after 2 hrs by ELISA	ic50	0.0001	uM
(4R)-4-cyclopropyl-8-fluoro-5-[[6-(trifluoromethyl)-3-pyridinyl]sulfonyl]-1,4-dihydropyrazolo[4,5-c]quinoline	755856: Inhibition of partially purified human gamma-secretase-mediated cleavage of MBP-APPc125Sw fusion protein measured after overnight incubation by ELISA	ic50	0.0001	uM
(4R)-4-cyclopropyl-8-fluoro-5-[4-(trifluoromethyl)phenyl]sulfonyl-1,4-dihydropyrazolo[4,5-c]quinoline	755856: Inhibition of partially purified human gamma-secretase-mediated cleavage of MBP-APPc125Sw fusion protein measured after overnight incubation by ELISA	ic50	0.0001	uM
(1’R,4R,10’S)-2-(2,2,2-trifluoroethyl)-5’-[(E)-3-[4-(trifluoromethyl)piperidin-1-yl]prop-1-enyl]spiro[1,2,5-thiadiazolidine-4,13’-tricyclo[8.2.1.03,8]trideca-3(8),4,6-triene] 1,1-dioxide	375649: Inhibition of gamma secretase in human SH-SY5Y cells by HTRF assay	ic50	0.0002	uM
2-[1-(4-chlorophenyl)sulfonyl-2-[2-fluoro-4-(1,2,4-oxadiazol-3-yl)phenyl]ethyl]-5,5,5-trifluoropentanamide	1866066: Inhibition of gamma-secretase (unknown origin) assessed as decrease in Abeta42 levels	ic50	0.0002	uM
2-[1-(4-chlorophenyl)sulfonyl-2-[4-(1,2,4-oxadiazol-3-yl)-2-bicyclo[1.1.1]pentanyl]ethyl]-5,5,5-trifluoropentanamide	1866066: Inhibition of gamma-secretase (unknown origin) assessed as decrease in Abeta42 levels	ic50	0.0002	uM
(2S)-3-(3,4-difluorophenyl)-2-methyl-N-[(3S)-1-methyl-2-oxo-5-(1-oxo-2H-isoquinolin-6-yl)-3H-1,4-benzodiazepin-3-yl]propanamide	71732: In vitro inhibition of gamma secretase.	ic50	0.0002	uM
(1’R,4R,10’S)-5’-[1-(2-fluorophenyl)imidazol-4-yl]-2-(2,2,2-trifluoroethyl)spiro[1,2,5-thiadiazolidine-4,13’-tricyclo[8.2.1.03,8]trideca-3(8),4,6-triene] 1,1-dioxide	375649: Inhibition of gamma secretase in human SH-SY5Y cells by HTRF assay	ic50	0.0002	uM
5’-[5-(2-fluorophenyl)-1-methylpyrazol-3-yl]-2-(2,2,2-trifluoroethyl)spiro[1,2,5-thiadiazolidine-4,13’-tricyclo[8.2.1.03,8]trideca-3(8),4,6-triene] 1,1-dioxide	375649: Inhibition of gamma secretase in human SH-SY5Y cells by HTRF assay	ic50	0.0002	uM
5-(4-chlorophenyl)sulfonyl-4-cyclopropyl-1,4-dihydropyrazolo[4,5-c]quinoline	448576: Inhibition of Gamma-secretase in human IMR-32 cells after 2 hrs by ELISA assay	ic50	0.0002	uM
5-(4-chlorophenyl)sulfonyl-4-(trifluoromethyl)-1,4-dihydropyrazolo[4,5-c]quinoline	448576: Inhibition of Gamma-secretase in human IMR-32 cells after 2 hrs by ELISA assay	ic50	0.0002	uM
(4aR,6R,8aS)-6-(4-chlorophenyl)sulfonyl-6-(2,5-difluorophenyl)-3-propyl-1,3,4,4a,5,7,8,8a-octahydrobenzo[c]thiazine 2,2-dioxide	265340: Inhibition of gamma secretase	ic50	0.0002	uM
(4aS,6R,8aS)-6-(4-chlorophenyl)sulfonyl-3-cyclopropyl-6-(2,5-difluorophenyl)-4,4a,5,7,8,8a-hexahydro-1H-benzo[c][1,2,6]thiadiazine 2,2-dioxide	265340: Inhibition of gamma secretase	ic50	0.0002	uM
(2S)-2-[3-(3,5-difluorophenyl)propanoylamino]-N-[5-(6-methoxy-6-methylheptan-2-yl)-1,3-thiazol-2-yl]propanamide	301212: Inhibition of gamma secretase activity in human H4 cells transfected with APP695 mutant assessed as beta amyloid(1-40) production by whole cell assay	ic50	0.0002	uM
(2S)-2-hydroxy-N-[(2S)-1-[[5-(6-hydroxy-6-methylheptan-2-yl)-1,3-thiazol-2-yl]amino]-1-oxopentan-2-yl]-3,3-dimethylbutanamide	301212: Inhibition of gamma secretase activity in human H4 cells transfected with APP695 mutant assessed as beta amyloid(1-40) production by whole cell assay	ic50	0.0002	uM

CTD chemical–gene interactions

62 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases reaction, increases expression, decreases expression, increases abundance, affects binding (+1 more)	4
sulindac sulfide	affects reaction, increases reaction, decreases activity, decreases response to substance, affects cleavage	3
Cannabidiol	decreases reaction, decreases response to substance, increases expression, affects response to substance, affects expression (+2 more)	3
Paraquat	increases expression, increases response to substance	2
Tobacco Smoke Pollution	increases response to substance, increases expression, affects cotreatment	2
Tretinoin	decreases reaction, increases expression, affects localization	2
FR900359	increases phosphorylation	1
oxyphylla A	decreases reaction, increases expression	1
pimagedine	affects cotreatment, decreases reaction, increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases methylation	1
deoxynivalenol	decreases expression	1
trichostatin A	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
ursodoxicoltaurine	affects cotreatment, decreases expression, decreases reaction, increases activity, increases expression	1
benzyloxycarbonylleucyl-leucyl-leucine aldehyde	affects response to substance, decreases expression, affects reaction	1
Go 6976	decreases reaction, increases expression	1
CGP 52608	affects binding, increases reaction	1
SB 203580	affects reaction, affects response to substance, decreases expression	1
deguelin	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression	1
N2-((2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl)-N1-((7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-L-alaninamide	decreases response to substance	1
enzalutamide	affects expression	1
(+)-JQ1 compound	decreases expression	1
Bortezomib	decreases expression	1
Oxaliplatin	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Acetaminophen	increases expression	1
Air Pollutants, Occupational	decreases expression	1
Amiodarone	increases expression	1

ChEMBL screening assays

557 unique, capped per target: 538 binding, 12 functional, 6 admet, 1 unclassified

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1037933	Binding	Inhibition of gamma secretase in human IMR32 cells assessed as inhibition of Abeta40 site cleavage by ELISA	N-Bridged bicyclic sulfonamides as inhibitors of gamma-secretase. — Bioorg Med Chem Lett
CHEMBL3611640	Unclassified	Selectivity ratio of IC50 for gamma-secretase-mediated cleavage of NotchdeltaE in in human HeLa cells expressing NotchdeltaE to IC50 for gamma-secretase in human SH-SY5Y cells expressing beta-APP C-terminal fragment SPA4CT	Discovery of novel triazolobenzazepinones as γ-secretase modulators with central Aβ42 lowering in rodents and rhesus monkeys. — Bioorg Med Chem Lett
CHEMBL4122735	ADMET	Modulation of gamma-secretase in human E6 cells expressing HeLaTetON-NotchdeltaE-NLuc/CLuc-RBP assessed as notch cleavage after 16 hrs by bioluminescence assay	Discovery of tetrahydroindazoles as a novel class of potent and in vivo efficacious gamma secretase modulators. — Bioorg Med Chem

Cellosaurus cell lines

134 cell lines: 59 induced pluripotent stem cell, 33 finite cell line, 32 transformed cell line, 10 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_1430	MSTO-211H	Cancer cell line	Male
CVCL_2Q61	AG09131	Transformed cell line	Male
CVCL_2Z42	GM00364	Finite cell line	Male
CVCL_4J89	AG07872	Finite cell line	Male
CVCL_4J90	AG07877	Transformed cell line	Male
CVCL_4K17	AG08063	Transformed cell line	Male
CVCL_4K18	AG08064	Finite cell line	Male
CVCL_4K19	AG08109	Transformed cell line	Female
CVCL_4K20	AG08110	Finite cell line	Female
CVCL_4K57	AG08445	Transformed cell line	Male

Clinical trials (associated diseases)

182 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT04520308	PHASE4	UNKNOWN	An Open-label, Single-arm Longitudinal Study With Dupilumab for Patients With Atopic Dermatitis
NCT05969054	PHASE4	UNKNOWN	Improvement Effect of Lacosamide and Levetiracetam on Cognitive in Alzheimer’s Disease Patients With Epilepsy
NCT00376051	PHASE4	COMPLETED	Serotonergic Function and Behavioural and Psychological Symptoms of Frontotemporal Dementia
NCT00545974	PHASE4	COMPLETED	Memantine (10mg BID) for the Frontal and Temporal Subtypes of Frontotemporal Dementia
NCT00950430	PHASE4	ENROLLING_BY_INVITATION	Imaging of Brain Amyloid Plaques in the Aging Population
NCT06093126	PHASE4	RECRUITING	Lemborexant for Insomnia in a Patient With Dementia: An N-of-1 Trial
NCT00594737	PHASE3	COMPLETED	Open Label Pilot Study of the Effects of Memantine on FDG-PET in Frontotemporal Dementia
NCT03682185	PHASE3	COMPLETED	The Healthy Patterns Sleep Study
NCT04374136	PHASE3	TERMINATED	A Phase 3 Study to Evaluate Efficacy and Safety of AL001 in Frontotemporal Dementia (INFRONT-3)
NCT02380573	PHASE2	COMPLETED	Effects of Methylene Blue in Healthy Aging, Mild Cognitive Impairment and Alzheimer’s Disease
NCT03806478	PHASE2	UNKNOWN	Study of APH-1105 in Patients With Mild to Moderate Alzheimer’s Disease
NCT07011706	PHASE2	ACTIVE_NOT_RECRUITING	ATI-045 Versus Placebo in Patients With Moderate-to-Severe Atopic Dermatitis
NCT07252440	PHASE2	RECRUITING	A Study to Evaluate the Efficacy and Safety of TTYP01 Tablets in Early Symptomatic Alzheimer’s Disease
NCT04937452	PHASE2	COMPLETED	Dopaminergic Therapy for Frontotemporal Dementia Patients
NCT00416169	PHASE2	COMPLETED	A Pilot Study to Explore the Safety and Tolerability of Galantamine HBr in the Treatment of Pick Complex/Frontotemporal Dementia
NCT01890343	PHASE2	COMPLETED	Imaging Characteristics of Florbetapir 18F in Patients With Frontotemporal Dementia, Alzheimer’s Disease and Normal Controls.
NCT01937013	PHASE2	COMPLETED	Impact of Emotional Mimicry and Oxytocin on Frontotemporal Dementia
NCT02676843	PHASE2	COMPLETED	Tau PET Imaging With 18F-AV-1451 in Subjects With MAPT Mutations
NCT02862210	PHASE2	COMPLETED	Low-Dose Lithium for the Treatment of Behavioral Symptoms in Frontotemporal Dementia
NCT03260920	PHASE2	UNKNOWN	Intranasal Oxytocin for Frontotemporal Dementia
NCT03987295	PHASE2	COMPLETED	A Phase 2 Study to Evaluate Safety of Long-term AL001 Dosing in Frontotemporal Dementia (FTD) Patients (INFRONT-2)
NCT04220021	PHASE2	ACTIVE_NOT_RECRUITING	Safety and Therapeutic Potential of the FDA-approved Drug Metformin for C9orf72 ALS/FTD
NCT04489017	PHASE2	COMPLETED	Palmitoylethanolamide Combined With Luteoline in Frontotemporal Dementia Patients. A Randomized Controlled Trial
NCT04993755	PHASE2	COMPLETED	A Phase 2a Study of TPN-101 in Patients With C9ORF72 ALS/FTD
NCT05742698	PHASE2	RECRUITING	Nabilone for Agitation in Frontotemporal Dementia
NCT06604520	PHASE2	RECRUITING	Vortioxetine for the Treatment of Mood and Cognitive Symptoms in Frontotemporal Dementia
NCT07154485	PHASE2	NOT_YET_RECRUITING	Investigator Initiated Study for the Safety and Efficacy in Frontotemporal Dementia
NCT03932916	PHASE1	COMPLETED	Safety and Pharmacokinetic of Donepezil Pamoate in Healthy Subjects
NCT06593626	PHASE1	COMPLETED	A Phase I Clinical Study on the Safety and Pharmacokinetics of [18F]Florbetazine Injection
NCT00077896	PHASE1	COMPLETED	Direct Current Brain Polarization in Frontotemporal Dementia
NCT00674960	PHASE1	UNKNOWN	Far Infrared Irradiation for the Management, Control and Treatment of Frontotemporal Dementia
NCT01386333	PHASE1	COMPLETED	Safety Study of Intranasal Oxytocin in Frontotemporal Dementia
NCT01623284	PHASE1	COMPLETED	PiB PET Scanning in Speech and Language Based Dementias
NCT03040713	PHASE1	COMPLETED	Flortaucipir PET Imaging in Subjects With FTD
NCT03636204	PHASE1	COMPLETED	A First in Human Study in Healthy Volunteers and in Participants With Frontotemporal Dementia With Granulin (GRN) Mutation
NCT05184569	PHASE1	RECRUITING	Veri-T: A Trial of Verdiperstat in Patients With svPPA Due to TDP-43 Pathology
NCT05315661	PHASE1	ACTIVE_NOT_RECRUITING	The Safety and The Efficacy Evaluation of ET-STEM in Patients With Frontotemporal Dementia
NCT06226064	PHASE1	COMPLETED	A Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of VES001 in Healthy Participants
NCT06705192	PHASE1	COMPLETED	Study in Asymptomatic GRN-FTD Patients to Investigate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of VES001
NCT05984784	PHASE1/PHASE2	TERMINATED	A Study to Evaluate the Safety, Pharmacokinetics, and Efficacy of IMG-007 in Adults With Atopic Dermatitis (AD)