APH1A

Summary

APH1A (aph-1A gamma-secretase subunit, HGNC:29509) is a protein-coding gene on chromosome 1q21.2, encoding Gamma-secretase subunit APH-1A (Q96BI3). Non-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).

This gene encodes a component of the gamma secretase complex that cleaves integral membrane proteins such as Notch receptors and beta-amyloid precursor protein. The gamma secretase complex contains this gene product, or the paralogous anterior pharynx defective 1 homolog B (APH1B), along with the presenilin, nicastrin, and presenilin enhancer-2 proteins. The precise function of this seven-transmembrane-domain protein is unknown though it is suspected of facilitating the association of nicastrin and presenilin in the gamma secretase complex as well as interacting with substrates of the gamma secretase complex prior to their proteolytic processing. Polymorphisms in a promoter region of this gene have been associated with an increased risk for developing sporadic Alzheimer’s disease. Alternative splicing results in multiple protein-coding and non-protein-coding transcript variants.

Source: NCBI Gene 51107 — RefSeq curated summary.

At a glance

• GWAS associations: 14
• Clinical variants (ClinVar): 35 total
• Druggable target: yes — 8 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001077628

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29509
Approved symbol	APH1A
Name	aph-1A gamma-secretase subunit
Location	1q21.2
Locus type	gene with protein product
Status	Approved
Aliases	APH-1A, CGI-78
Ensembl gene	ENSG00000117362
Ensembl biotype	protein_coding
OMIM	607629
Entrez	51107

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 6 protein_coding, 3 protein_coding_CDS_not_defined, 2 retained_intron

ENST00000236017, ENST00000360244, ENST00000369109, ENST00000414276, ENST00000461320, ENST00000476538, ENST00000486308, ENST00000486720, ENST00000493092, ENST00000877470, ENST00000877471

RefSeq mRNA: 4 — MANE Select: NM_001077628 NM_001077628, NM_001243771, NM_001243772, NM_016022

CCDS: CCDS41390, CCDS41391, CCDS58025

Canonical transcript exons

ENST00000369109 — 7 exons

Exon	Start	End
ENSE00000787754	150267957	150268127
ENSE00001611175	150267075	150267202
ENSE00001630115	150266533	150266656
ENSE00001894980	150265404	150266194
ENSE00001931224	150268698	150269016
ENSE00003563035	150267356	150267478
ENSE00003564189	150267716	150267789

Expression profiles

Bgee: expression breadth ubiquitous, 283 present calls, max score 97.77.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 57.1600 / max 271.7582, expressed in 1824 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
14308	53.7551	1824
14307	1.6615	1150
14312	0.6412	240
14306	0.5188	256
14311	0.3316	166
14310	0.2518	143

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
skin of leg	UBERON:0001511	97.77	gold quality
skin of abdomen	UBERON:0001416	97.71	gold quality
granulocyte	CL:0000094	97.59	gold quality
mucosa of transverse colon	UBERON:0004991	97.58	gold quality
right adrenal gland cortex	UBERON:0035827	97.55	gold quality
rectum	UBERON:0001052	97.51	gold quality
right lung	UBERON:0002167	97.40	gold quality
right adrenal gland	UBERON:0001233	97.34	gold quality
gall bladder	UBERON:0002110	97.33	gold quality
oocyte	CL:0000023	97.32	gold quality
left adrenal gland cortex	UBERON:0035825	97.28	gold quality
upper lobe of left lung	UBERON:0008952	97.27	gold quality
minor salivary gland	UBERON:0001830	97.25	gold quality
left adrenal gland	UBERON:0001234	97.22	gold quality
monocyte	CL:0000576	97.18	gold quality
leukocyte	CL:0000738	97.18	gold quality
left lobe of thyroid gland	UBERON:0001120	97.14	gold quality
mononuclear cell	CL:0000842	97.13	gold quality
metanephros cortex	UBERON:0010533	97.08	gold quality
left ovary	UBERON:0002119	97.06	gold quality
right lobe of thyroid gland	UBERON:0001119	97.03	gold quality
right lobe of liver	UBERON:0001114	97.02	gold quality
body of stomach	UBERON:0001161	97.01	gold quality
transverse colon	UBERON:0001157	96.97	gold quality
adrenal cortex	UBERON:0001235	96.93	gold quality
body of pancreas	UBERON:0001150	96.91	gold quality
ganglionic eminence	UBERON:0004023	96.87	gold quality
upper lobe of lung	UBERON:0008948	96.87	gold quality
esophagus mucosa	UBERON:0002469	96.86	gold quality
secondary oocyte	CL:0000655	96.84	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	10.13

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): HIF1A, YY1

miRNA regulators (miRDB)

67 targeting APH1A, 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-12118	100.00	65.88	1270
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-548AC	99.84	70.77	4351
HSA-MIR-548H-3P	99.84	70.80	4349
HSA-MIR-548Z	99.84	70.80	4349
HSA-MIR-8080	99.82	67.52	1342
HSA-MIR-204-5P	99.79	71.62	2439
HSA-MIR-211-5P	99.79	71.65	2440

Literature-anchored findings (GeneRIF, showing 30)

• 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)
• APH-1 binds to presenilins and nicastrin and may play a role in maturation of presenilin-nicastrin complexes (PMID:12471034)
• Expression of APH-1A increases amyloid beta peptide levels and gamma-secretase activity. (PMID:12763021)
• APH-1 and the gamma-secretase complex bind to the transmembrane domain region of nicastrin (PMID:12917438)
• Six different polymorphisms have been determined but the polymorphisms in APH-1a/b coding regions are not linked to higher risk for Alzheimer disease in an Italian population. (PMID:12972157)
• APH-1 can be processed by several endoproteolytic events and generates a stable C-terminal fragment that associates with nicastrin (PMID:14593096)
• conserved transmembrane Gly122, Gly126, and Gly130 in the fourth transmembrane region of APH-1a are part of the membrane helix-helix interaction GXXXG motif and are essential for the stable association of APH-1aL with presenilin, nicastrin, and PEN-2 (PMID:14627705)
• Only the combined overexpression of presenilin 1 and nicastrin together with APH-1a G122D facilitated the formation of a fully active gamma-secretase complex (PMID:15210705)
• both APH-1a splice forms and APH-1b are expressed in peripheral and neuronal cells. APH-1aS, APH-1aL, and APH-1b form separate, proteolytically active gamma-secretase complexes containing either one of the two presenilins. (PMID:15286082)
• presenilin 1 (PS1)-derived fragments, mature nicastrin, APH-1, and PEN-2, associate with cholesterol-rich detergent insoluble membrane (DIM) domains of non-neuronal cells and neurons (PMID:15322084)
• knock down of APH-1a, but not APH-1b, resulted in impaired maturation of nicastrin and reduced expression of presenilin 1, presenilin 2, and PEN-2 proteins (PMID:15629423)
• These results collectively indicate that the three forms of APH-1 can replace each other in presenilin (PS) complexes and that the transmembrane GxxxG region is essential for the stability of the APH-1 protein as well as the assembly of PS complexes. (PMID:16757808)
• Over-expression of APH-1 and inhibition of proteasomal APH-1 degradation facilitated gamma-secretase cleavage of APP to generate Abeta. Thus,degradation of APH-1 protein is mediated by the ubiquitin-proteasome pathway. (PMID:17059559)
• analysis of model of the gamma-secretase complex subunit architecture and demonstration of the close proximity of the C-terminal fragment of presenilin with APH-1 (PMID:18801744)
• S-palmitoylation plays a role in stability and raft localization of nicastrin and APH-1, but does not directly modulate gamma-secretase processing of APP and other substrates. (PMID:19028695)
• that there is an association between the -980C/G polymorphism in the APH-1a promoter region and the development of sporadic Alzheimer’s disease (PMID:19368855)
• the conserved transmembrane histidine residues contribute to APH1 function and can affect presenilin catalytic activity (PMID:19369254)
• Aph-1 associates directly with full-length and C-terminal fragments of gamma-secretase substrates (PMID:20145246)
• Co-overexpression of presenilin-1 or APH-1 abrogated gamma-secretase inhibition probably through prevention of the incorporation of CRB2 into the gamma-secretase complex (PMID:20299451)
• Endogenous Aph-1a and its proteolytic fragment have unique properties for cleavage control that may have implications for gamma-secretase regulation and intracellular distribution. (PMID:20674680)
• Coexpression of wild-type or S-palmitoylation-deficient APH1aL and nicastrin leads to marked stabilization of transgenic presenilin 1 in the brains of double-transgenic mice. (PMID:21123562)
• The -980C/G polymorphism in APH-1A promoter confers risk of Alzheimer’s disease (PMID:21443683)
• We demonstrate that extending the transmembrane domain of the amyloid precursor protein-derived C99 substrate in proximity to the cytosolic face strongly influences gamma-secretase cleavage specificity. (PMID:23253155)
• A loss of PS/gamma-secretase function to cleave Abeta42(43) may initiate Alzheimer’s disease. (PMID:23291095)
• analysis of how the conformation of presenilin, Pen-2, Aph-1, and nicastrin affect the function and mechanism of gamma-secretase (PMID:25918421)
• No statistically significant difference was detected either in APOE or APH-1a polymorphisms, not suggesting a strong susceptibility to the development of Alzheimer disease. (PMID:26738354)
• Data show that presenilin 1 (PS1)-containing gamma-secretase complexes were targeted to the plasma membrane, whereas presenilin 2 (PS2)-containing ones were addressed to the trans-Golgi network, to recycling endosomes. (PMID:27059953)
• Data show that presenilin 1 (PS1)/anterior-pharynx-defective protein 1 (Aph1b), presenilin 2 (PS2)/Aph1aL, PS2/Aph1aS and PS2/anterior pharynx defective 1 homolog B (Aph1b) gamma-secretase produced amyloid beta peptide (Abeta) with a higher Abeta42+Abeta43-to-Abeta40 (Abeta42(43)/Abeta40) ratio than the other gamma-secretases. (PMID:27608597)
• Using purified PSEN1/Aph1A gamma-secretase and the APPC99-3XFLAG substrate, authors show that substrate shortening progressively destabilizes the consecutive enzyme-substrate complexes that characterize the sequential gamma-secretase processing of APP; present a unifying model for how PSEN or APP mutations enhance amyloidogenic Abeta production, suggests that environmental factors may increase Alzheimer’s Disease risk. (PMID:28753424)
• Specific Mutations in Aph1 Cause gamma-Secretase Activation. (PMID:35008932)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
mus_musculus	Aph1a	ENSMUSG00000015750
rattus_norvegicus	Aph1a	ENSRNOG00000023816
drosophila_melanogaster	aph-1	FBGN0031458
caenorhabditis_elegans	aph-1	WBGENE00000147

Paralogs (1): APH1B (ENSG00000138613)

Protein

Protein identifiers

Gamma-secretase subunit APH-1A — Q96BI3 (reviewed: Q96BI3)

Alternative names: Aph-1alpha, Presenilin-stabilization factor

All UniProt accessions (2): Q96BI3, Q5TB21

UniProt curated annotations — full annotation on UniProt →

Function. Non-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). Required for normal gamma-secretase assembly. The gamma-secretase complex 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.

Subunit / interactions. The functional gamma-secretase complex is composed of at least four polypeptides: a presenilin homodimer (PSEN1 or PSEN2), nicastrin (NCSTN), APH1 (APH1A or APH1B) and PSENEN/PEN2.

Subcellular location. Endoplasmic reticulum membrane. Golgi apparatus. Golgi stack membrane.

Tissue specificity. Widely expressed. Expressed in leukocytes, lung, placenta, small intestine, liver, kidney, spleen thymus, skeletal muscle, heart and brain. Isoform 1 and isoform 2 are nearly expressed at the same level.

Similarity. Belongs to the APH-1 family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q96BI3-1	1, L, Aph-alpha1	yes
Q96BI3-2	2, S, Aph-alpha2
Q96BI3-3	3

RefSeq proteins (4): NP_001071096, NP_001230700, NP_001230701, NP_057106 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR009294	Aph-1	Family

Pfam: PF06105

UniProt features (40 total): helix 10, topological domain 8, transmembrane region 7, turn 5, splice variant 3, strand 3, mutagenesis site 2, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

25 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
7Y5X	ELECTRON MICROSCOPY	3
8KCP	ELECTRON MICROSCOPY	3
8X53	ELECTRON MICROSCOPY	3
6LQG	ELECTRON MICROSCOPY	3.1
7C9I	ELECTRON MICROSCOPY	3.1
5A63	ELECTRON MICROSCOPY	3.4
7Y5Z	ELECTRON MICROSCOPY	3.4
8IM7	ELECTRON MICROSCOPY	3.4
5FN4	ELECTRON MICROSCOPY	4
5FN3	ELECTRON MICROSCOPY	4.1
5FN2	ELECTRON MICROSCOPY	4.2
5FN5	ELECTRON MICROSCOPY	4.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96BI3-F1	91.69	0.78

Functional residue map

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

Mutagenesis-validated functional residues (2):

Position	Phenotype
171	impaired gamma-secretease assembly and reduced proteolytic activity of the gamma-secretase complex.
197	impaired gamma-secretease assembly and reduced proteolytic activity of the gamma-secretase complex.

Function

Pathways and Gene Ontology

Reactome pathways

36 pathways

ID	Pathway
R-HSA-1251985	Nuclear signaling by ERBB4
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-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-977225	Amyloid fiber formation
R-HSA-9839383	TGFBR3 PTM regulation
R-HSA-1236394	Signaling by ERBB4
R-HSA-1266738	Developmental Biology
R-HSA-157118	Signaling by NOTCH
R-HSA-162582	Signal Transduction
R-HSA-1643685	Disease
R-HSA-193704	p75 NTR receptor-mediated signalling
R-HSA-1980143	Signaling by NOTCH1
R-HSA-1980145	Signaling by NOTCH2
R-HSA-204998	Cell death signalling via NRAGE, NRIF and NADE
R-HSA-2644602	Signaling by NOTCH1 PEST Domain Mutants in Cancer
R-HSA-2644603	Signaling by NOTCH1 in Cancer
R-HSA-2682334	EPH-Ephrin signaling
R-HSA-2894858	Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer
R-HSA-392499	Metabolism of proteins
R-HSA-422475	Axon guidance
R-HSA-5663202	Diseases of signal transduction by growth factor receptors and second messengers
R-HSA-73887	Death Receptor Signaling

MSigDB gene sets: 205 (showing top): E2F_Q4, REACTOME_SIGNALING_BY_NOTCH, RRAGTTGT_UNKNOWN, GOBP_METANEPHROS_DEVELOPMENT, CCAWYNNGAAR_UNKNOWN, E2F4DP1_01, GAANYNYGACNY_UNKNOWN, SP3_Q3, GOBP_NOTCH_RECEPTOR_PROCESSING, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, MONNIER_POSTRADIATION_TUMOR_ESCAPE_UP, PATIL_LIVER_CANCER, E2F1DP1_01, GOBP_PROTEIN_MATURATION, E2F1DP2_01

GO Biological Process (11): metanephros development (GO:0001656), membrane protein ectodomain proteolysis (GO:0006509), Notch signaling pathway (GO:0007219), Notch receptor processing (GO:0007220), protein processing (GO:0016485), membrane protein intracellular domain proteolysis (GO:0031293), amyloid-beta formation (GO:0034205), amyloid precursor protein metabolic process (GO:0042982), amyloid precursor protein catabolic process (GO:0042987), proteolysis (GO:0006508), positive regulation of catalytic activity (GO:0043085)

GO Molecular Function (4): enzyme binding (GO:0019899), protein-macromolecule adaptor activity (GO:0030674), endopeptidase activator activity (GO:0061133), protein binding (GO:0005515)

GO Cellular Component (13): Golgi membrane (GO:0000139), early endosome (GO:0005769), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), Golgi apparatus (GO:0005794), plasma membrane (GO:0005886), synaptic vesicle (GO:0008021), endosome membrane (GO:0010008), membrane (GO:0016020), Golgi cisterna membrane (GO:0032580), presynaptic membrane (GO:0042734), gamma-secretase complex (GO:0070765), synaptic membrane (GO:0097060)

Reactome top-level categories

Rollup of top-17 pathways:

Category	Pathways
Signaling by ERBB4	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
Signaling by NOTCH3	1
Signaling by NOTCH4	1
NOTCH3 Activation and Transmission of Signal to the Nucleus	1
Metabolism of proteins	1
Signaling by TGFBR3	1
Signaling by Receptor Tyrosine Kinases	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein metabolic process	3
membrane protein proteolysis	2
protein binding	2
bounding membrane of organelle	2
endosome	2
cytoplasm	2
endomembrane system	2
intracellular membrane-bounded organelle	2
organelle membrane	2
presynapse	2
kidney development	1
cell surface receptor signaling pathway	1
proteolysis	1
protein maturation	1
amyloid precursor protein catabolic process	1
amyloid-beta metabolic process	1
amyloid precursor protein metabolic process	1
catalytic activity	1
positive regulation of molecular function	1
regulation of catalytic activity	1
molecular adaptor activity	1
endopeptidase activity	1
peptidase activator activity	1
endopeptidase regulator activity	1
binding	1
Golgi apparatus	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
membrane	1
cell periphery	1
exocytic vesicle	1
cytoplasmic vesicle membrane	1
cellular anatomical structure	1
Golgi cisterna	1
synaptic membrane	1
plasma membrane protein complex	1
catalytic complex	1
synapse	1
plasma membrane region	1

Protein interactions and networks

STRING

940 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
APH1A	NCSTN	Q92542	999
APH1A	PSEN1	P49768	999
APH1A	PSENEN	Q9NZ42	999
APH1A	PSEN2	P49810	998
APH1A	TMED10	P49755	964
APH1A	APP	P05067	890
APH1A	RHBDL2	Q9NX52	831
APH1A	TNF	P01375	820
APH1A	BACE1	P56817	793
APH1A	ADAM10	O14672	790
APH1A	GSAP	A4D1B5	757
APH1A	APH1B	Q8WW43	755
APH1A	NOTCH1	P46531	727
APH1A	MMEL1	Q495T6	724
APH1A	HM13	Q8TCT9	700

IntAct

110 interactions, top by confidence:

A	B	Type	Score
APH1A	NCSTN	psi-mi:“MI:0915”(physical association)	0.760
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:0914”(association)	0.660
LAT	APH1A	psi-mi:“MI:0915”(physical association)	0.560
TUSC5	APH1A	psi-mi:“MI:0915”(physical association)	0.560
MPP1	APH1A	psi-mi:“MI:0915”(physical association)	0.560
SCAND1	APH1A	psi-mi:“MI:0915”(physical association)	0.560
MFSD6	APH1A	psi-mi:“MI:0915”(physical association)	0.560
ANKRD46	APH1A	psi-mi:“MI:0915”(physical association)	0.560
APH1A	TMEM140	psi-mi:“MI:0915”(physical association)	0.560
TMEM218	APH1A	psi-mi:“MI:0915”(physical association)	0.560
ASGR1	APH1A	psi-mi:“MI:0915”(physical association)	0.560
APH1A	SLC39A9	psi-mi:“MI:0915”(physical association)	0.560
IGFBP5	APH1A	psi-mi:“MI:0915”(physical association)	0.560
APOD	APH1A	psi-mi:“MI:0915”(physical association)	0.560
APH1A	SLC38A7	psi-mi:“MI:0915”(physical association)	0.560
APH1A	SERP1	psi-mi:“MI:0915”(physical association)	0.560
APH1A	MRAP2	psi-mi:“MI:0915”(physical association)	0.560
SMAGP	APH1A	psi-mi:“MI:0915”(physical association)	0.560
APH1A	FXYD6	psi-mi:“MI:0915”(physical association)	0.560
APH1A	FIS1	psi-mi:“MI:0915”(physical association)	0.560
APH1A	FYN	psi-mi:“MI:0915”(physical association)	0.560
APH1A	CYTH1	psi-mi:“MI:0915”(physical association)	0.560
APP	APH1A	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (98): Psen2 (Affinity Capture-Western), Psen1 (Affinity Capture-Western), PSENEN (Affinity Capture-Western), NCSTN (Affinity Capture-Western), APH1A (Affinity Capture-RNA), APH1A (Affinity Capture-RNA), PSEN1 (Affinity Capture-Western), PSENEN (Affinity Capture-Western), NCSTN (Affinity Capture-Western), APH1A (Affinity Capture-Western), APH1A (Two-hybrid), NCSTN (Affinity Capture-Western), PSEN1 (Affinity Capture-Western), PSENEN (Affinity Capture-Western), APH1A (Affinity Capture-Western)

ESM2 similar proteins: A0JNC3, A9RA88, B0CMA4, B0YA61, F1RAX4, G5EBX4, O02100, O13909, O13989, O45876, O59802, O74520, O74949, P38837, P52166, Q0V9G6, Q20123, Q298S5, Q3B8H0, Q4WCL2, Q53FV1, Q55FS3, Q5EBF8, Q5F3W2, Q5R687, Q5RDM3, Q5U4Q2, Q5ZIU0, Q5ZMT9, Q66J27, Q6C741, Q6DF80, Q6FSD1, Q6NZZ4, Q6PQZ3, Q75EY7, Q80UA9, Q8AV61, Q8BVF7, Q8C7N7

Diamond homologs: O45876, Q5RDM3, Q8BVF7, Q8C7N7, Q8WW43, Q96BI3, Q9DCZ9, Q55FS3, Q8JHE9, Q8L9G7, Q9VQG2

SIGNOR signaling

9 interactions.

A	Effect	B	Mechanism
NCSTN	up-regulates	APH1A	binding
APH1A	“form complex”	gamma-secretase	binding
APH1A	up-regulates	NCSTN	binding
APH1A	up-regulates	PSEN1	binding
APH1A	up-regulates	PSEN2	binding
APH1A	up-regulates	PSENEN	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 59 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.

GO biological processes:

GO term	Partners	Fold	FDR
learning or memory	6	27.8×	7e-05
positive regulation of ERK1 and ERK2 cascade	8	13.1×	8e-05
negative regulation of gene expression	6	8.0×	8e-03
positive regulation of gene expression	9	6.7×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	21
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1391 predictions. Top by Δscore:

Variant	Effect	Δscore
1:150266532:CA:C	donor_gain	1.0000
1:150266654:TGT:T	acceptor_gain	1.0000
1:150266657:C:CC	acceptor_gain	1.0000
1:150267350:TCTTA:T	donor_loss	1.0000
1:150267351:CTTA:C	donor_loss	1.0000
1:150267352:TTAC:T	donor_loss	1.0000
1:150267353:TA:T	donor_loss	1.0000
1:150267423:C:CT	acceptor_gain	1.0000
1:150267430:T:TC	acceptor_gain	1.0000
1:150267461:C:CT	acceptor_gain	1.0000
1:150267462:G:T	acceptor_gain	1.0000
1:150267474:AGAAA:A	acceptor_gain	1.0000
1:150267475:GAAA:G	acceptor_gain	1.0000
1:150267476:AAA:A	acceptor_gain	1.0000
1:150267477:AA:A	acceptor_gain	1.0000
1:150267479:C:CC	acceptor_gain	1.0000
1:150267479:C:CG	acceptor_loss	1.0000
1:150267953:TTA:T	donor_loss	1.0000
1:150267954:TACTT:T	donor_loss	1.0000
1:150267955:A:AC	donor_gain	1.0000
1:150267956:C:CT	donor_gain	1.0000
1:150267959:A:AC	donor_gain	1.0000
1:150267959:AAG:A	donor_gain	1.0000
1:150267960:A:C	donor_gain	1.0000
1:150267990:T:TA	donor_gain	1.0000
1:150268126:CC:C	acceptor_gain	1.0000
1:150268127:CC:C	acceptor_gain	1.0000
1:150268779:A:T	donor_gain	1.0000
1:150266531:A:AC	donor_gain	0.9900
1:150266532:C:CC	donor_gain	0.9900

AlphaMissense

1680 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:150267460:C:T	G126D	0.997
1:150268767:C:T	G15D	0.997
1:150267448:C:T	G130D	0.996
1:150267449:C:G	G130R	0.996
1:150268117:A:G	W42R	0.996
1:150268117:A:T	W42R	0.996
1:150266627:G:C	S213R	0.995
1:150266627:G:T	S213R	0.995
1:150266629:T:G	S213R	0.995
1:150267095:G:C	H197D	0.995
1:150267147:A:C	F179L	0.995
1:150267147:A:T	F179L	0.995
1:150267149:A:G	F179L	0.995
1:150267164:A:G	W174R	0.995
1:150267164:A:T	W174R	0.995
1:150267450:A:C	S129R	0.995
1:150267450:A:T	S129R	0.995
1:150267452:T:G	S129R	0.995
1:150267461:C:G	G126R	0.995
1:150267462:G:C	F125L	0.995
1:150267462:G:T	F125L	0.995
1:150267464:A:G	F125L	0.995
1:150267472:C:T	G122D	0.995
1:150267772:A:G	L101S	0.995
1:150268699:C:G	G38R	0.995
1:150268699:C:T	G38R	0.995
1:150268768:C:G	G15R	0.995
1:150268788:C:T	G8D	0.995
1:150268789:C:G	G8R	0.995
1:150267096:A:C	S196R	0.994

dbSNP variants (sampled 300 via entrez): RS1000017680 (1:150268281 G>A,C), RS1002071391 (1:150265979 C>T), RS1002284344 (1:150265620 A>C,T), RS1002712264 (1:150270820 C>A,T), RS1004120862 (1:150269354 A>T), RS1004459059 (1:150266916 G>A), RS1005881610 (1:150265102 T>C), RS1006153616 (1:150270793 G>A), RS1006248369 (1:150270479 T>A), RS1007840473 (1:150270413 G>A), RS1008810831 (1:150268853 G>A), RS1009200425 (1:150266310 A>C), RS1009295416 (1:150266051 T>C), RS1011087703 (1:150270109 T>C), RS1012511096 (1:150269312 G>A,T)

Disease associations

OMIM: gene MIM:607629 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

14 associations (top):

Study	Trait	p-value
GCST002539_32	Schizophrenia	4.000000e-10
GCST003429_42	Morning vs. evening chronotype	2.000000e-10
GCST003453_5	Chronotype	1.000000e-09
GCST003454_4	Morning vs. evening chronotype	1.000000e-11
GCST008103_32	Bipolar disorder	5.000000e-08
GCST010002_366	Refractive error	3.000000e-15
GCST010696_11	Cortical thickness (min-P)	2.000000e-23
GCST010697_17	Cortical surface area (min-P)	9.000000e-09
GCST010698_23	Subcortical volume (min-P)	2.000000e-08
GCST010699_48	Brain morphology (min-P)	3.000000e-08
GCST010700_28	Cortical thickness (MOSTest)	8.000000e-38
GCST010701_113	Cortical surface area (MOSTest)	9.000000e-12
GCST010702_126	Subcortical volume (MOSTest)	4.000000e-09
GCST010703_244	Brain morphology (MOSTest)	9.000000e-12

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004346	neuroimaging measurement
EFO:0004840	cortical thickness

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2094135 (PROTEIN COMPLEX)

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)

Binding affinities (BindingDB)

45 measured of 60 human assays (60 total across all organisms); most potent 45 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
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
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
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
[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
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
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
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
4-Fluoro-N-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-13-yl-benzenesulfonamide	IC50	129 nM
5-Chloro-thiophene-2-sulfonic acid (5-chloro-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-13-yl)-amide	IC50	146 nM
5-Chloro-thiophene-2-sulfonic acid [5-((E)-3-piperidin-1-yl-propenyl)-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-13-yl]-amide	IC50	152 nM
(13-Benzenesulfonylamino-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-5-yl)-carbamic acid 2-chloro-benzyl ester	IC50	153 nM
5-Chloro-thiophene-2-sulfonic acid (4-chloro-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-13-yl)-amide	IC50	175 nM
N-Tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-13-yl-benzenesulfonamide	IC50	190 nM
5-Chloro-thiophene-2-sulfonic acid {5-[2-(3-hydroxy-pyrrolidin-1-yl)-ethoxy]-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-13-yl}-amide	IC50	209 nM
2-(Benzyl-methyl-amino)-N-[13-(5-chloro-thiophene-2-sulfonylamino)-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-5-yl]-acetamide	IC50	226 nM
5-Chloro-thiophene-2-sulfonic acid {5-[2-(2-methyl-piperidin-1-yl)-ethoxy]-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-13-yl}-amide	IC50	227 nM
2-Fluoro-N-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-13-yl-benzenesulfonamide	IC50	239 nM
5-Chloro-thiophene-2-sulfonic acid (5-hydroxy-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-13-yl)-amide	IC50	269 nM
3-Fluoro-N-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-13-yl-benzenesulfonamide	IC50	324 nM
5-Chloro-thiophene-2-sulfonic acid {5-[2-(2-methyl-pyrrolidin-1-yl)-ethoxy]-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-13-yl}-amide	IC50	335 nM
(13-Benzenesulfonylamino-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-5-yl)-carbamic acid 3-chloro-benzyl ester	IC50	412 nM
4-Chloro-N-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-13-yl-benzenesulfonamide	IC50	467 nM
5-Chloro-thiophene-2-sulfonic acid (5-methoxy-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-13-yl)-amide	IC50	490 nM
5-Methyl-hexanoic acid (13-benzenesulfonylamino-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-5-yl)-amide	IC50	535 nM
Butane-1-sulfonic acid tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-13-ylamide	IC50	610 nM
5-Chloro-thiophene-2-sulfonic acid {5-[2-(4-hydroxy-piperidin-1-yl)-ethoxy]-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-13-yl}-amide	IC50	623 nM
4-Methyl-N-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-13-yl-benzenesulfonamide	IC50	651 nM
Propane-1-sulfonic acid tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-13-ylamide	IC50	721 nM
2-Benzylamino-N-[13-(5-chloro-thiophene-2-sulfonylamino)-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-5-yl]-acetamide	IC50	3490 nM
N-(5-Amino-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-13-yl)-benzenesulfonamide	IC50	6000 nM

ChEMBL bioactivities

3227 potent at pChembl≥5 of 3433 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
9.92	EC50	0.119	nM	CHEMBL392068
9.92	IC50	0.12	nM	CHEMBL523883
9.89	IC50	0.13	nM	AVAGACESTAT
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
9.70	IC50	0.2	nM	CHEMBL571602
9.70	IC50	0.2	nM	CHEMBL133857

PubChem BioAssay actives

3041 with measured affinity, of 4776 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

21 total (human), top 21 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Smoke	decreases expression, increases abundance	2
7-(4-fluorophenyl)-N2-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta(d)pyrimidine-2,4-diamine	affects activity	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, increases expression	1
enzalutamide	affects expression	1
(+)-JQ1 compound	decreases expression	1
Sunitinib	increases expression	1
Zoledronic Acid	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	affects methylation	1
Cannabidiol	decreases expression	1
Catechin	affects cotreatment, increases expression	1
Doxorubicin	decreases expression	1
Hydrogen Peroxide	affects expression	1
Lead	increases expression	1
Testosterone	increases expression	1
Thiram	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Cadmium Chloride	decreases expression	1
Acrylamide	decreases expression	1

ChEMBL screening assays

478 unique, capped per target: 459 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

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1JQ	Abcam HeLa APH1A KO	Cancer cell line	Female

Clinical trials (associated diseases)

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