GSAP

Summary

GSAP (gamma-secretase activating protein, HGNC:28042) is a protein-coding gene on chromosome 7q11.23, encoding Gamma-secretase-activating protein (A4D1B5). Regulator of gamma-secretase activity, which specifically activates the production of amyloid-beta protein (amyloid-beta protein 40 and amyloid-beta protein 42), without affecting the cleavage of other gamma-secretase targets such has Notch.

Accumulation of neurotoxic amyloid-beta is a major hallmark of Alzheimer disease (AD; MIM 104300). Formation of amyloid-beta is catalyzed by gamma-secretase (see PSEN1; MIM 104311), a protease with numerous substrates. PION, or GSAP, selectively increases amyloid-beta production through a mechanism involving its interaction with both gamma-secretase and its substrate, the amyloid-beta precursor protein (APP; MIM 104760) C-terminal fragment (APP-CTF) (He et al., 2010 [PubMed 20811458]).

Source: NCBI Gene 54103 — RefSeq curated summary.

At a glance

• GWAS associations: 7
• Clinical variants (ClinVar): 149 total
• GTEx eGene: eQTL in 45 tissues, sQTL in 21 (q < 0.05)
• ChEMBL bioactivity: 1 clinical-phase molecule tested; no curated mechanism-of-action drug
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.20 (unconstrained)
• MANE Select transcript: NM_017439
• Notable: 149 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28042
Approved symbol	GSAP
Name	gamma-secretase activating protein
Location	7q11.23
Locus type	gene with protein product
Status	Approved
Aliases	LOC54103
Ensembl gene	ENSG00000186088
Ensembl biotype	protein_coding
OMIM	613552
Entrez	54103

Gene structure

Transcript identifiers

Ensembl transcripts: 49 — 22 protein_coding, 17 nonsense_mediated_decay, 6 retained_intron, 4 protein_coding_CDS_not_defined

MANE Select: ENST00000257626

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 3, TSL 2: 4, TSL 3: 2, TSL 4: 2, TSL 5: 2

ENST00000257626, ENST00000334003, ENST00000415112, ENST00000426477, ENST00000430584, ENST00000434084, ENST00000440473, ENST00000441833, ENST00000449779, ENST00000474686, ENST00000482866, ENST00000489920, ENST00000491796, ENST00000880888, ENST00000943097, ENST00000974577, ENST00000974578, ENST00000974579, ENST00000974580, ENST00000974581, ENST00000974582, ENST00000974583, ENST00000974584, ENST00000974585, ENST00001016950, ENST00001016951, ENST00001016952, ENST00001016953, ENST00001016954, ENST00001016956, ENST00001016957, ENST00001108518, ENST00001108519, ENST00001108520, ENST00001108521, ENST00001108522, ENST00001108523, ENST00001113795, ENST00001117802, ENST00001117803, ENST00001117804, ENST00001117805, ENST00001117806, ENST00001117807, ENST00001127356, ENST00001127357, ENST00001127358, ENST00001128254, ENST00001135122

RefSeq mRNA: 7 — MANE Select: NM_017439 NM_001350896, NM_001350897, NM_001350898, NM_001350899, NM_001350900, NM_001350901, NM_017439

CCDS: CCDS34672

Canonical transcript exons

ENST00000257626 — 31 exons

Exon	Start	End
ENSE00001519751	77416213	77416349
ENSE00002146379	77330239	77330367
ENSE00003463013	77352944	77353026
ENSE00003464758	77353572	77353641
ENSE00003466933	77375058	77375101
ENSE00003473646	77360824	77360901
ENSE00003484003	77404559	77404615
ENSE00003485822	77387360	77387448
ENSE00003489812	77329333	77329391
ENSE00003495531	77396982	77397035
ENSE00003498848	77355555	77355647
ENSE00003499003	77320725	77320819
ENSE00003508758	77362583	77362660
ENSE00003525963	77349351	77349404
ENSE00003535668	77355213	77355430
ENSE00003539354	77374070	77374155
ENSE00003540359	77381305	77381354
ENSE00003550934	77326212	77326273
ENSE00003551131	77314370	77314489
ENSE00003573352	77376848	77376907
ENSE00003589443	77328606	77328637
ENSE00003590382	77311841	77311940
ENSE00003600572	77397346	77397415
ENSE00003604774	77382574	77382643
ENSE00003609174	77310751	77311449
ENSE00003629541	77313488	77313549
ENSE00003629595	77377286	77377390
ENSE00003645845	77321333	77321403
ENSE00003664100	77406029	77406105
ENSE00003670885	77323647	77323742
ENSE00003680988	77312101	77312202

Expression profiles

Bgee: expression breadth ubiquitous, 279 present calls, max score 96.09.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 8.3214 / max 237.7892, expressed in 1010 samples.

Highest expression (Bgee): granulocyte, uterine tube, monocyte, mononuclear cell, leukocyte.

Genetic regulation across tissues (GTEx eQTL / sQTL)

GSAP is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 45 tissues and its splicing (sQTL) in 21 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 66 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Cells Cultured fibroblasts	eqtl	2.5e-57	+0.57	7:77409628:C:T
Muscle Skeletal	eqtl	1.1e-45	+0.50	7:77416561:T:A
Whole Blood	eqtl	1.7e-39	-0.31	7:77364260:C:T
Liver	eqtl	1.7e-36	+0.87	7:77397143:G:A
Brain Frontal Cortex BA9	eqtl	8.0e-32	+0.69	7:77416489:G:C
Artery Tibial	eqtl	6.3e-29	+0.43	7:77418465:C:A
Brain Cortex	eqtl	4.3e-26	+0.64	7:77416489:G:C
Skin Not Sun Exposed Suprapubic	eqtl	2.2e-25	+0.33	7:77416489:G:C
Thyroid	eqtl	1.6e-24	+0.25	7:77416489:G:C
Brain Cerebellum	eqtl	1.8e-24	+0.55	7:77416561:T:A
Lung	sqtl	4.0e-23	+0.48	7:77307768:T:C
Artery Aorta	eqtl	4.8e-21	+0.36	7:77416489:G:C
Brain Nucleus accumbens basal ganglia	eqtl	3.3e-19	+0.50	7:77416561:T:A
Whole Blood	sqtl	3.7e-19	+0.52	7:77366149:G:A
Brain Cerebellar Hemisphere	eqtl	4.1e-19	+0.45	7:77416561:T:A
Adipose Subcutaneous	sqtl	2.5e-18	+0.62	7:77311972:A:G
Skin Sun Exposed Lower leg	sqtl	6.4e-18	+0.64	7:77307768:T:C
Brain Anterior cingulate cortex BA24	eqtl	1.6e-17	+0.61	7:77416489:G:C
Heart Atrial Appendage	eqtl	4.0e-16	+0.32	7:77416561:T:A
Skin Sun Exposed Lower leg	eqtl	1.1e-15	+0.25	7:77416489:G:C

FANTOM5 promoters

3 alternative TSS:

Promoter ID	TPM avg	Samples expressed
84462	8.2472	1007
84454	0.0579	20
84453	0.0162	8

Top tissues by expression

showing 100 of 297 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	96.09	gold quality
right uterine tube	UBERON:0001302	95.99	gold quality
monocyte	CL:0000576	95.45	gold quality
mononuclear cell	CL:0000842	95.45	gold quality
leukocyte	CL:0000738	95.08	gold quality
spleen	UBERON:0002106	94.20	gold quality
right lung	UBERON:0002167	93.16	gold quality
epithelium of nasopharynx	UBERON:0001951	92.80	gold quality
visceral pleura	UBERON:0002401	92.71	gold quality
right lobe of thyroid gland	UBERON:0001119	91.89	gold quality
secondary oocyte	CL:0000655	91.87	gold quality
upper lobe of left lung	UBERON:0008952	91.74	gold quality
left lobe of thyroid gland	UBERON:0001120	91.71	gold quality
upper lobe of lung	UBERON:0008948	91.54	gold quality
thyroid gland	UBERON:0002046	91.28	gold quality
lung	UBERON:0002048	91.05	gold quality
upper leg skin	UBERON:0004262	90.95	gold quality
pleura	UBERON:0000977	90.72	gold quality
pituitary gland	UBERON:0000007	90.22	gold quality
vermiform appendix	UBERON:0001154	90.22	gold quality
right lobe of liver	UBERON:0001114	89.99	gold quality
germinal epithelium of ovary	UBERON:0001304	89.96	gold quality
gall bladder	UBERON:0002110	89.93	gold quality
adenohypophysis	UBERON:0002196	89.84	gold quality
parietal pleura	UBERON:0002400	89.63	gold quality
small intestine Peyer’s patch	UBERON:0003454	89.63	gold quality
mucosa of stomach	UBERON:0001199	89.62	gold quality
lower lobe of lung	UBERON:0008949	89.59	gold quality
lymph node	UBERON:0000029	89.28	gold quality
bronchial epithelial cell	CL:0002328	88.90	gold quality
palpebral conjunctiva	UBERON:0001812	88.63	gold quality
bone marrow cell	CL:0002092	88.60	gold quality
blood	UBERON:0000178	88.57	gold quality
skin of hip	UBERON:0001554	88.46	gold quality
tibial nerve	UBERON:0001323	88.16	gold quality
minor salivary gland	UBERON:0001830	88.10	gold quality
lower esophagus	UBERON:0013473	88.10	gold quality
body of stomach	UBERON:0001161	88.09	gold quality
lower esophagus muscularis layer	UBERON:0035833	88.09	gold quality
muscle layer of sigmoid colon	UBERON:0035805	88.00	gold quality
body of pancreas	UBERON:0001150	87.90	gold quality
right adrenal gland cortex	UBERON:0035827	87.81	gold quality
right adrenal gland	UBERON:0001233	87.61	gold quality
liver	UBERON:0002107	87.58	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	87.43	gold quality
left adrenal gland	UBERON:0001234	87.31	gold quality
bone marrow	UBERON:0002371	87.30	gold quality
left adrenal gland cortex	UBERON:0035825	87.28	gold quality
small intestine	UBERON:0002108	87.21	gold quality
tonsil	UBERON:0002372	87.21	gold quality
stomach	UBERON:0000945	86.92	gold quality
bone element	UBERON:0001474	86.89	gold quality
metanephros cortex	UBERON:0010533	86.78	gold quality
eye	UBERON:0000970	86.60	gold quality
trabecular bone tissue	UBERON:0002483	86.44	gold quality
apex of heart	UBERON:0002098	86.20	gold quality
sigmoid colon	UBERON:0001159	86.15	gold quality
adrenal cortex	UBERON:0001235	86.09	gold quality
superficial temporal artery	UBERON:0001614	86.07	gold quality
epithelium of bronchus	UBERON:0002031	85.91	gold quality
adrenal gland	UBERON:0002369	85.91	gold quality
fundus of stomach	UBERON:0001160	85.80	gold quality
mouth mucosa	UBERON:0003729	85.71	gold quality
seminal vesicle	UBERON:0000998	85.54	gold quality
hair follicle	UBERON:0002073	85.47	gold quality
bronchus	UBERON:0002185	85.45	gold quality
caput epididymis	UBERON:0004358	85.45	gold quality
subcutaneous adipose tissue	UBERON:0002190	85.36	gold quality
pancreas	UBERON:0001264	85.17	gold quality
saliva-secreting gland	UBERON:0001044	85.11	gold quality
omental fat pad	UBERON:0010414	85.11	gold quality
skin of abdomen	UBERON:0001416	85.10	gold quality
peritoneum	UBERON:0002358	85.08	gold quality
adipose tissue of abdominal region	UBERON:0007808	85.05	gold quality
esophagus	UBERON:0001043	85.01	gold quality
primary visual cortex	UBERON:0002436	84.99	gold quality
caecum	UBERON:0001153	84.88	gold quality
left uterine tube	UBERON:0001303	84.80	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.70	gold quality
lower esophagus mucosa	UBERON:0035834	84.70	gold quality
nasal cavity mucosa	UBERON:0001826	84.60	gold quality
skin of leg	UBERON:0001511	84.57	gold quality
adipose tissue	UBERON:0001013	84.55	gold quality
sural nerve	UBERON:0015488	84.48	gold quality
intestine	UBERON:0000160	84.44	gold quality
rectum	UBERON:0001052	84.41	gold quality
transverse colon	UBERON:0001157	84.37	gold quality
connective tissue	UBERON:0002384	84.37	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	84.18	gold quality
calcaneal tendon	UBERON:0003701	83.95	gold quality
oocyte	CL:0000023	83.74	gold quality
tibia	UBERON:0000979	83.73	gold quality
colon	UBERON:0001155	83.71	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	83.67	gold quality
middle temporal gyrus	UBERON:0002771	83.66	gold quality
large intestine	UBERON:0000059	83.55	gold quality
zone of skin	UBERON:0000014	83.46	gold quality
Brodmann (1909) area 23	UBERON:0013554	83.40	gold quality
prostate gland	UBERON:0002367	83.09	gold quality
right frontal lobe	UBERON:0002810	82.92	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

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 76 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM
Corpus callosum	tissue	26.0
Spleen	tissue	17.5
Lung	tissue	17.4
Olfactory bulb	tissue	15.6
Liver	tissue	15.3
Cerebral cortex	tissue	14.0
Retrosplenial cortex	tissue	14.0
Insular cortex	tissue	13.9
Retrosplenial and cingulate cortex	tissue	13.4
Occipital cortex	tissue	13.4
Prefrontal cortex	tissue	13.0
Ventral forebrain	tissue	13.0
Hippocampal formation	tissue	12.7
Entorhinal cortex	tissue	12.7
Motor cortex	tissue	12.6
Temporal cortex	tissue	12.6
Putamen	tissue	12.4
Substantia nigra	tissue	12.2
Tonsil	tissue	12.2
Lymph node	tissue	12.1
Amygdala	tissue	11.8
Spinal cord	tissue	11.8
Somatosensory cortex	tissue	11.8
Periaqueductal gray	tissue	11.7
Septum	tissue	11.5
Parathyroid gland	tissue	11.1
Midbrain	tissue	11.1
Medulla oblongata	tissue	11.0
Cerebellum	tissue	10.6
Basal ganglia	tissue	10.5
Thalamus	tissue	10.5
Hypothalamus	tissue	10.2
Appendix	tissue	10.2
Retina	tissue	10.1
Superior colliculi	tissue	9.6
Pons	tissue	9.2
Bone marrow	tissue	8.3
Thyroid gland	tissue	7.8
Gallbladder	tissue	7.4
Stomach 1	tissue	7.3
Pituitary gland	tissue	6.9
Fallopian tube	tissue	6.0
Choroid plexus	tissue	5.9
Kidney	tissue	5.9
Urinary bladder	tissue	5.6
Thymus	tissue	5.6
Breast	tissue	5.5
Pancreas	tissue	5.1
Prostate	tissue	5.1
Adrenal gland	tissue	5.0
Adipose tissue	tissue	4.9
Seminal vesicle	tissue	4.8
Heart muscle	tissue	4.6
Hippocampus	tissue	4.6
Salivary gland	tissue	4.4
Rectum	tissue	4.4
Postcentral gyrus	tissue	4.3
Skin 1	tissue	4.2
Small intestine	tissue	4.2
Locus coeruleus	tissue	4.2

Brain sub-regions (HPA Brain Atlas): detected in 189; highest nTPM — White matter (26.0), Dorsal hippocampus (12.3), Dorsal spinal cord (11.8), Ventral spinal cord (11.2), Subiculum (10.8).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting GSAP by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 39 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-6885-3P	99.75	70.36	3187
HSA-MIR-8084	99.73	69.57	1760
HSA-MIR-6505-5P	99.73	69.25	1595
HSA-MIR-4422	99.72	72.07	2908
HSA-MIR-4255	99.72	67.70	1541
HSA-MIR-4677-5P	99.70	70.09	1940
HSA-MIR-379-3P	99.69	69.60	1524
HSA-MIR-411-3P	99.69	69.63	1524
HSA-MIR-10393-5P	99.65	68.01	1368
HSA-MIR-4328	99.57	71.06	4094
HSA-MIR-7844-5P	99.55	68.56	1428
HSA-MIR-5571-5P	99.49	66.99	1764
HSA-MIR-29A-5P	99.08	68.59	1813
HSA-MIR-4717-3P	99.06	66.34	1072
HSA-MIR-452-3P	99.01	66.25	1241
HSA-MIR-942-3P	98.81	69.04	876
HSA-MIR-519A-2-5P	98.78	71.74	1401
HSA-MIR-520B-5P	98.78	71.74	1401
HSA-MIR-1178-3P	98.57	67.09	890
HSA-MIR-3136-5P	98.53	67.68	793
HSA-MIR-4439	98.53	67.53	793
HSA-MIR-532-5P	98.43	67.53	760
HSA-MIR-4684-5P	98.29	67.99	1650
HSA-MIR-892B	98.00	67.11	821
HSA-MIR-4778-5P	97.96	68.06	1634
HSA-MIR-15A-3P	97.47	65.08	527

Functional genomics

gnomAD constraint: pLI 7.58e-07, LOEUF 1.2, missense Z -0.33 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000257626 — one region, missense o/e 1.01.

Literature-anchored findings (GeneRIF, showing 8)

• A gamma-secretase activating protein (GSAP) that selectively increases amyloid-beta production via interactions with both gamma-secretase and its substrate, the amyloid precursor protein carboxy-terminal fragment. (PMID:20811458)
• Aberrant regulation of gamma-secretase activating protein expression plays a key role in acceleration of gamma-cleavage of beta-secretase-cleaved C-terminal fragment of amyloid precursor protein and accumulation of Abeta in AD brains (PMID:21718343)
• Protocols for recombinant bacterial expression and purification of potentially important protein GSAP are not successful in generating soluble forms of GSAP that contain well-ordered and homogeneous tertiary structure. (PMID:22681044)
• gamma-secretase activating protein (GSAP) and imatinib have roles in the regulation of gamma-secretase activity and amyloid-beta generation (PMID:23209290)
• Its promoter variant contributes to Alzheimer’s disease liability. (PMID:25037285)
• GSAP cleavage via caspase-3 is regulated and depend upon the availability of 5-Lipoxygenase in Alzheimer’s disease. (PMID:26076991)
• These data demonstrate that GSAP proteins are differentially dysregulated in severe Alzheimer Disease, but only the full-length form was associated with cognitive test scores in Alzheimer Disease. (PMID:28743126)
• GSAP regulates lipid homeostasis and mitochondrial function associated with Alzheimer’s disease. (PMID:34156424)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	gsap	ENSDARG00000045481
mus_musculus	Gsap	ENSMUSG00000039934
rattus_norvegicus	Gsap	ENSRNOG00000028801
drosophila_melanogaster	pigeon	FBGN0010309

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
PTPN12	protein-coding	5782
CCDC146-AS1	ncRNA	105375359
CCDC146	protein-coding	57639
FGL2	protein-coding	10875

Protein

Protein identifiers

Gamma-secretase-activating protein — A4D1B5 (reviewed: A4D1B5)

Alternative names: Protein pigeon homolog

All UniProt accessions (3): A4D1B5, B7ZL33, H7C0Q7

UniProt curated annotations — full annotation on UniProt →

Function. Regulator of gamma-secretase activity, which specifically activates the production of amyloid-beta protein (amyloid-beta protein 40 and amyloid-beta protein 42), without affecting the cleavage of other gamma-secretase targets such has Notch. The gamma-secretase complex is an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (amyloid-beta precursor protein). Specifically promotes the gamma-cleavage of APP CTF-alpha (also named APP-CTF) by the gamma-secretase complex to generate amyloid-beta, while it reduces the epsilon-cleavage of APP CTF-alpha, leading to a low production of AICD.

Subunit / interactions. Interacts with APP; specifically interacts with the CTF-alpha product of APP. Interacts with the gamma-secretase complex.

Subcellular location. Golgi apparatus. trans-Golgi network.

Tissue specificity. Widely expressed.

Post-translational modifications. The protein is first synthesized as a holoprotein form of 98 kDa and rapidly processed into the gamma-secretase-activating protein 16 kDa C-terminal form, which constitutes the predominant form.

Miscellaneous. The gamma-secretase regulator activity is specifically inhibited by imatinib (also known as STI571 or Gleevec), an anticancer drug that selectively decreases amyloid-beta protein production. Imatinib binds PION/GSAP and acts by preventing PION/GSAP interaction with the gamma-secretase substrate, CTF-alpha. Its role as an activator of amyloid-beta protein production makes it a promising therapeutic target for the treatment of Alzheimer disease.

Similarity. Belongs to the GSAP family.

Isoforms (4)

UniProt ID	Names	Canonical?
A4D1B5-1	1	yes
A4D1B5-2	2
A4D1B5-3	3
A4D1B5-4	4

RefSeq proteins (7): NP_001337825, NP_001337826, NP_001337827, NP_001337828, NP_001337829, NP_001337830, NP_059135* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR026172	GSAP_fam	Family
IPR028010	GSAP_C_dom	Domain

Pfam: PF14959

UniProt features (10 total): splice variant 4, sequence variant 4, chain 2

Structure

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-A4D1B5-F1	80.78	0.28

Human Protein Atlas

Protein class: Predicted intracellular proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): vesicles

Antibody reliability (HPA): IF approved

Function

Pathways and Gene Ontology

Reactome pathways

0 curated (TAS) of 0; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

MSigDB gene sets: 261 (showing top): BROWNE_HCMV_INFECTION_30MIN_DN, BROWNE_HCMV_INFECTION_6HR_DN, BASSO_B_LYMPHOCYTE_NETWORK, GOBP_POSITIVE_REGULATION_OF_AMIDE_METABOLIC_PROCESS, GOBP_REGULATION_OF_AMYLOID_PRECURSOR_PROTEIN_CATABOLIC_PROCESS, GOCC_TRANS_GOLGI_NETWORK, DEURIG_T_CELL_PROLYMPHOCYTIC_LEUKEMIA_DN, GOBP_AMIDE_METABOLIC_PROCESS, RIGGI_EWING_SARCOMA_PROGENITOR_DN, VANHARANTA_UTERINE_FIBROID_DN, GOBP_REGULATION_OF_AMIDE_METABOLIC_PROCESS, GOBP_AMYLOID_PRECURSOR_PROTEIN_METABOLIC_PROCESS, chr7q11, GNF2_PTPRC, HAN_SATB1_TARGETS_DN

GO Biological Process (2): regulation of proteolysis (GO:0030162), positive regulation of amyloid-beta formation (GO:1902004)

GO Molecular Function (2): amyloid-beta binding (GO:0001540), protein binding (GO:0005515)

GO Cellular Component (2): trans-Golgi network (GO:0005802), Golgi apparatus (GO:0005794)

GO top-level categories

11 GO namespaces:

Category	Terms
proteolysis	1
regulation of protein metabolic process	1
amyloid-beta formation	1
regulation of amyloid-beta formation	1
positive regulation of amyloid precursor protein catabolic process	1
peptide binding	1
binding	1
Golgi apparatus subcompartment	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 4 of 6 annotations. The rest are phylogenetic / computational / electronic (IEA).

4 experimentally-supported GO terms:

GO term	NS	Evidence
positive regulation of amyloid-beta formation	BP	direct assay
regulation of proteolysis	BP	direct assay
trans-Golgi network	CC	direct assay
amyloid-beta binding	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 376 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GSAP	APP	P05067	728
GSAP	PSEN1	P49768	712
GSAP	TMED10	P49755	587
GSAP	NCSTN	Q92542	566
GSAP	APH1A	Q96BI3	549
GSAP	PSENEN	Q9NZ42	549
GSAP	RHBDL2	Q9NX52	491
GSAP	MRPL15	Q9P015	476
GSAP	BACE1	P56817	475
GSAP	RITA1	Q96K30	390
GSAP	SNN	O75324	379
GSAP	APH1B	Q8WW43	375
GSAP	GPR22	Q99680	367
GSAP	A0A0J9YYB4	A0A0J9YYB4	363
GSAP	RBP1	P09455	343

IntAct

Human interaction partners of GSAP in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

1 partners by confidence:

Partner	Interaction type	MIscore	Records
APP	physical association	0.400	3

BioGRID (8 interactions; top human partners by supporting records): APP (Affinity Capture-Western; 4 records), NASP (Cross-Linking-MS (XL-MS)), NCSTN (Affinity Capture-Western), PSEN1 (Affinity Capture-Western), PSENEN (Affinity Capture-Western)

Disease & clinical

Genetic variants

Variant evidence for GSAP: 149 ClinVar records (0 pathogenic / likely pathogenic); 7 GWAS associations.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	98
Likely benign	14
Benign	2

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 38 predictions of 2,968):

Position(s)	Effect	Δscore	Sites
7:77312208	acceptor_gain	1.0000
7:77320723–77320724	donor_loss	1.0000	5
7:77320824	acceptor_gain	1.0000
7:77326210–77326211	donor_loss	1.0000	5
7:77326274–77326275	acceptor_loss	1.0000	4
7:77353042	acceptor_gain	1.0000
7:77382572–77382573	donor_loss	1.0000	5
7:77387449–77387450	acceptor_loss	1.0000	6
7:77396980–77396981	donor_loss	1.0000	5
7:77397036–77397037	acceptor_loss	1.0000	5

AlphaMissense

1,002 missense substitutions predicted likely pathogenic (of 5,654 scored), across 331 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
F153	8	0.923	0.990
H356	8	0.839	0.951
F9	8	0.838	0.968
F86	8	0.831	0.965
D600	8	0.784	0.920
W214	7	0.964	0.995
W767	7	0.945	0.985
W523	7	0.929	0.984
W211	7	0.925	0.991
F698	7	0.922	0.985
E466	7	0.898	0.951
N98	7	0.878	0.982
F806	7	0.871	0.975
F339	7	0.862	0.964
F238	7	0.850	0.962
E132	7	0.849	0.926
E52	7	0.835	0.922
F322	7	0.827	0.965
F371	7	0.826	0.940
F839	7	0.823	0.967

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

2 prognostic cancer types:

Cancer	Prognostic	p-value
Glioblastoma Multiforme (validation)	unfavorable	4.25e-05
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	0.000373

Disease associations

OMIM: gene MIM:613552 | disease phenotypes:

GWAS associations

7 associations:

Study	Trait	p-value
GCST005038_102	Allergic disease (asthma, hay fever or eczema)	2e-13
GCST010043_107	Asthma	1e-8
GCST010042_82	Asthma	3e-8
GCST003628_4	Clozapine-induced agranulocytosis/granulocytopenia in treatment-resistant schizophrenia	2e-6
GCST010577_18	Crohn’s disease	3e-6
GCST005024_72	Pursuit maintenance gain	4e-6
GCST007216_9	Crohn’s disease	7e-6

EFO canonical traits (from GWAS)

1 canonical traits:

EFO ID	Trait name
EFO:0008433	pursuit maintenance gain measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3638343 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 781 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

1 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL1770916	NIROGACESTAT	4	781

PharmGKB: 1 entry (CPIC guideline: no)

Binding affinities (BindingDB)

2 measured of 2 human assays (3 total across all organisms); most potent 2 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
N-[13-[(5-chlorothiophen-2-yl)sulfonylamino]-5-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trienyl]-2-(4-fluorophenoxy)acetamide	IC50	1 nM	US-9023767: γ-Secretase substrates and methods of use
2-[[2-(3,5-difluorophenyl)acetyl]amino]-N-(1-methyl-2-oxo-5-phenyl-3H-1,4-benzodiazepin-3-yl)propanamide	IC50	1.2 nM	US-9023767: γ-Secretase substrates and methods of use

ChEMBL bioactivities

3 potent at pChembl≥5 of 3 total, top 3 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.00	IC50	1	nM	CHEMBL3703681
8.92	IC50	1.2	nM	CHEMBL3703680
8.21	IC50	6.2	nM	NIROGACESTAT

PubChem BioAssay actives

1 with measured affinity, of 1 total; 1 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
Nirogacestat	1924179: Inhibition of human gamma secretase by western blot assay	ic50	0.0062	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, affects expression, decreases methylation, increases expression, affects cotreatment	6
(+)-JQ1 compound	increases expression, decreases expression	3
bisphenol A	affects expression, affects cotreatment, decreases methylation	2
Vorinostat	affects cotreatment, decreases expression	2
Cisplatin	affects cotreatment, increases expression	2
Estradiol	affects cotreatment, decreases expression	2
Tetrachlorodibenzodioxin	decreases expression	2
Tretinoin	decreases expression, increases expression	2
Cyclosporine	increases expression, decreases expression	2
aristolochic acid I	decreases expression	1
dicrotophos	decreases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
trichostatin A	decreases expression, increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
cobaltous chloride	decreases expression	1
butyraldehyde	decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
diallyl trisulfide	increases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
MRK 003	decreases expression	1
jinfukang	affects cotreatment, increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	decreases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Leflunomide	decreases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	increases abundance, increases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3705978	Binding	HTRF Biochemical Assay: Among the advantages of this Abeta 42 HTRF gamma-secretase assay is the construction of the biotinylated, recombinant CT6-I45F substrate, which has provided a highly active substrate allowing for increased sensitivit	Œ=-Secretase substrates and methods of use

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for GSAP across ~30M SureChEMBL compounds — explore on Sugi Predict.