SPPL2B

Summary

SPPL2B (signal peptide peptidase like 2B, HGNC:30627) is a protein-coding gene on chromosome 19p13.3, encoding Signal peptide peptidase-like 2B (Q8TCT7). Intramembrane-cleaving aspartic protease (I-CLiP) that cleaves type II membrane signal peptides in the hydrophobic plane of the membrane.

This gene encodes a member of the GXGD family of aspartic proteases. The GXGD proteases are transmembrane proteins with two conserved catalytic motifs localized within the membrane-spanning regions. This enzyme localizes to endosomes, lysosomes, and the plasma membrane. It cleaves the transmembrane domain of tumor necrosis factor alpha to release the intracellular domain, which triggers cytokine expression in the innate and adaptive immunity pathways. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 56928 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 25 total
• Druggable target: yes
• MANE Select transcript: NM_152988

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30627
Approved symbol	SPPL2B
Name	signal peptide peptidase like 2B
Location	19p13.3
Locus type	gene with protein product
Status	Approved
Aliases	IMP4, PSL1, KIAA1532
Ensembl gene	ENSG00000005206
Ensembl biotype	protein_coding
OMIM	608239
Entrez	56928

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 17 protein_coding, 4 retained_intron, 3 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

ENST00000585725, ENST00000586111, ENST00000586332, ENST00000587851, ENST00000589515, ENST00000593243, ENST00000610743, ENST00000612623, ENST00000613503, ENST00000614784, ENST00000614794, ENST00000618220, ENST00000621568, ENST00000622308, ENST00000894061, ENST00000894062, ENST00000894063, ENST00000894064, ENST00000894065, ENST00000894066, ENST00000894067, ENST00000894068, ENST00000894069, ENST00000957274, ENST00000957275, ENST00000957276

RefSeq mRNA: 2 — MANE Select: NM_152988 NM_001077238, NM_152988

CCDS: CCDS74252, CCDS74253

Canonical transcript exons

ENST00000613503 — 15 exons

Exon	Start	End
ENSE00003660174	2334602	2334721
ENSE00003706527	2352946	2355095
ENSE00003718751	2351434	2351594
ENSE00003722670	2340076	2340172
ENSE00003724298	2343965	2344039
ENSE00003728911	2339069	2339208
ENSE00003730643	2339824	2339966
ENSE00003731215	2328684	2328775
ENSE00003731485	2345253	2345330
ENSE00003733094	2337443	2337625
ENSE00003735866	2340898	2341014
ENSE00003739019	2344362	2344424
ENSE00003742937	2343211	2343292
ENSE00003751702	2338752	2338841
ENSE00003752424	2344553	2344652

Expression profiles

Bgee: expression breadth ubiquitous, 229 present calls, max score 98.91.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 508.3604 / max 4235.6408, expressed in 1828 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
173068	481.1759	1828
173086	26.6703	1805
173085	0.5142	260

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right uterine tube	UBERON:0001302	98.91	gold quality
adenohypophysis	UBERON:0002196	97.81	gold quality
left testis	UBERON:0004533	97.76	gold quality
right testis	UBERON:0004534	97.71	gold quality
right hemisphere of cerebellum	UBERON:0014890	97.71	gold quality
small intestine Peyer’s patch	UBERON:0003454	97.69	gold quality
metanephros cortex	UBERON:0010533	97.34	gold quality
transverse colon	UBERON:0001157	97.28	gold quality
cerebellar hemisphere	UBERON:0002245	97.23	gold quality
right lobe of thyroid gland	UBERON:0001119	97.14	gold quality
body of pancreas	UBERON:0001150	97.01	gold quality
left lobe of thyroid gland	UBERON:0001120	96.98	gold quality
mucosa of transverse colon	UBERON:0004991	96.95	gold quality
cerebellar cortex	UBERON:0002129	96.91	gold quality
body of stomach	UBERON:0001161	96.59	gold quality
pituitary gland	UBERON:0000007	95.90	gold quality
mucosa of stomach	UBERON:0001199	95.78	gold quality
left uterine tube	UBERON:0001303	95.69	gold quality
right ovary	UBERON:0002118	95.53	gold quality
minor salivary gland	UBERON:0001830	95.45	gold quality
left ovary	UBERON:0002119	95.38	gold quality
tibial nerve	UBERON:0001323	95.29	gold quality
granulocyte	CL:0000094	95.26	gold quality
skin of abdomen	UBERON:0001416	95.25	gold quality
muscle layer of sigmoid colon	UBERON:0035805	95.23	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	95.19	gold quality
small intestine	UBERON:0002108	95.16	gold quality
endocervix	UBERON:0000458	95.12	gold quality
skin of leg	UBERON:0001511	95.09	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	95.03	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.83

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 9)

• SPP, SPPL2a, -2b, -2c, and -3 probably cleave type II-oriented substrate peptides as shown by consensus analysis (PMID:15385547)
• SPPL2b is targeted through the secretory pathway to endosomes/lysosomes, whereas SPP and SPPL3 are restricted to the ER. (PMID:15998642)
• Results demonstrate that SPPL2b utilizes multiple intramembrane cleavages to liberate the intracellular domain of tumor necrosis factor alpha into the cytosol. (PMID:16829951)
• SPPL2a and SPPL2b mediate the intramembrane cleavage, whereas neither SPP nor SPPL3 is capable of processing the Bri2 N-terminal fragment. (PMID:17965014)
• Alzheimer disease-like mutant SPPL2b slowed intramembrane proteolysis of tumor necrosis factor alpha and caused a relative increase of longer intracellular cleavage products. (PMID:18768471)
• The alpha-helical content of the transmembrane domain of the British dementia protein-2 (Bri2) determines its processing by signal peptide peptidase-like 2b (SPPL2b). (PMID:22194595)
• TfR1 N-terminal fragment is a substrate for intramembrane proteolysis by SPPL2b. (PMID:23384347)
• SPPL2a/b negatively regulates LOX-1 signaling and atherosclerosis. (PMID:30819724)
• Signal peptide peptidase-like 2b modulates the amyloidogenic pathway and exhibits an Abeta-dependent expression in Alzheimer’s disease. (PMID:38367747)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	sppl2	ENSDARG00000030448
mus_musculus	Sppl2b	ENSMUSG00000035206
rattus_norvegicus	Sppl2b	ENSRNOG00000057881

Paralogs (4): HM13 (ENSG00000101294), SPPL2A (ENSG00000138600), SPPL3 (ENSG00000157837), SPPL2C (ENSG00000185294)

Protein

Protein identifiers

Signal peptide peptidase-like 2B — Q8TCT7 (reviewed: Q8TCT7)

Alternative names: Intramembrane protease 4, Presenilin homologous protein 4, Presenilin-like protein 1

All UniProt accessions (5): Q8TCT7, A0A087WT77, A0A087WWL4, A0A087WZ50, A0A087WZ93

UniProt curated annotations — full annotation on UniProt →

Function. Intramembrane-cleaving aspartic protease (I-CLiP) that cleaves type II membrane signal peptides in the hydrophobic plane of the membrane. Functions in ITM2B and TNF processing. Catalyzes the intramembrane cleavage of the anchored fragment of shed TNF (TNF), which promotes the release of the intracellular domain (ICD) for signaling to the nucleus. May play a role in the regulation of innate and adaptive immunity. Catalyzes the intramembrane cleavage of the simian foamy virus processed leader peptide gp18 of the envelope glycoprotein gp130 dependently of prior ectodomain shedding by furin or furin-like proprotein convertase (PC)-mediated cleavage proteolysis.

Subunit / interactions. Monomer. Homodimer. Interacts with ITM2B. Interacts with TNF. Interacts with the simian foamy virus envelope glycoprotein gp130 and its processed leader peptide gp18LP; preferentially interacts with the leader peptide gp18LP.

Subcellular location. Cell membrane. Golgi apparatus membrane. Lysosome membrane. Endosome membrane. Membrane.

Tissue specificity. Expressed predominantly in adrenal cortex and mammary gland.

Post-translational modifications. Glycosylated.

Domain organisation. The PAL motif is required for normal active site conformation. The catalytic domains embedded in the membrane are in the opposite orientation to that of the presenilin protein family; therefore, it is predicted to cleave type II-oriented substrate peptides like the prototypic protease SPP.

Similarity. Belongs to the peptidase A22B family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q8TCT7-1	1	yes
Q8TCT7-2	2
Q8TCT7-4	4

RefSeq proteins (2): NP_001070706, NP_694533* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003137	PA_domain	Domain
IPR006639	Preselin/SPP	Family
IPR007369	Peptidase_A22B_SPP	Family
IPR046450	PA_dom_sf	Homologous_superfamily

Pfam: PF02225, PF04258

UniProt features (35 total): topological domain 10, transmembrane region 9, splice variant 3, compositionally biased region 2, active site 2, glycosylation site 2, signal peptide 1, chain 1, domain 1, region of interest 1, short sequence motif 1, sequence variant 1, mutagenesis site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8TCT7-F1	76.62	0.32

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 (2): 359; 421

Glycosylation sites (2): 97, 129

Mutagenesis-validated functional residues (1):

Position	Phenotype
421	loss of intramembrane-cleaving activity toward itm2b, tnf and the simian foamy virus envelope glycoprotein gp130.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-5357905	Regulation of TNFR1 signaling
R-HSA-162582	Signal Transduction
R-HSA-73887	Death Receptor Signaling
R-HSA-75893	TNF signaling

MSigDB gene sets: 284 (showing top): GSE45365_NK_CELL_VS_BCELL_DN, TGGTGCT_MIR29A_MIR29B_MIR29C, SHEPARD_BMYB_MORPHOLINO_UP, GOBP_RIBOSOME_BIOGENESIS, GOBP_RESPONSE_TO_PEPTIDE, GOCC_VACUOLAR_MEMBRANE, SHEPARD_CRASH_AND_BURN_MUTANT_UP, GOBP_MATURATION_OF_SSU_RRNA, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, TERAMOTO_OPN_TARGETS_CLUSTER_4, WEI_MYCN_TARGETS_WITH_E_BOX, BROWNE_HCMV_INFECTION_48HR_DN, GOBP_REGULATION_OF_IMMUNE_RESPONSE, MARTINEZ_RB1_TARGETS_DN, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM4

GO Biological Process (6): membrane protein ectodomain proteolysis (GO:0006509), regulation of tumor necrosis factor-mediated signaling pathway (GO:0010803), membrane protein intracellular domain proteolysis (GO:0031293), membrane protein proteolysis (GO:0033619), regulation of immune response (GO:0050776), proteolysis (GO:0006508)

GO Molecular Function (5): aspartic endopeptidase activity, intramembrane cleaving (GO:0042500), protein homodimerization activity (GO:0042803), protein binding (GO:0005515), peptidase activity (GO:0008233), hydrolase activity (GO:0016787)

GO Cellular Component (14): Golgi membrane (GO:0000139), nucleoplasm (GO:0005654), lysosomal membrane (GO:0005765), centrosome (GO:0005813), plasma membrane (GO:0005886), endosome membrane (GO:0010008), actin cytoskeleton (GO:0015629), membrane (GO:0016020), Golgi-associated vesicle membrane (GO:0030660), lumenal side of endoplasmic reticulum membrane (GO:0098553), cytoplasmic side of endoplasmic reticulum membrane (GO:0098554), lysosome (GO:0005764), endosome (GO:0005768), Golgi apparatus (GO:0005794)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
TNF signaling	1
Signal Transduction	1
Death Receptor Signaling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
bounding membrane of organelle	3
membrane protein proteolysis	2
cellular anatomical structure	2
cytoplasmic vesicle membrane	2
endoplasmic reticulum membrane	2
endomembrane system	2
regulation of cytokine-mediated signaling pathway	1
tumor necrosis factor-mediated signaling pathway	1
proteolysis	1
regulation of immune system process	1
immune response	1
regulation of response to stimulus	1
protein metabolic process	1
aspartic-type endopeptidase activity	1
identical protein binding	1
protein dimerization activity	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
catalytic activity	1
Golgi apparatus	1
nuclear lumen	1
lysosome	1
lytic vacuole membrane	1
centriole	1
microtubule organizing center	1
membrane	1
cell periphery	1
endosome	1
cytoskeleton	1
Golgi-associated vesicle	1
lumenal side of membrane	1
cytoplasmic side of membrane	1
lytic vacuole	1
cytoplasmic vesicle	1
cytoplasm	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

856 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SPPL2B	ITM2B	Q9Y287	620
SPPL2B	ADAM10	O14672	452
SPPL2B	SPRYD4	Q8WW59	427
SPPL2B	HM13	Q8TCT9	416
SPPL2B	SMCO3	A2RU48	404
SPPL2B	A0A0G2JP48	A0A0G2JP48	348
SPPL2B	CIAO2B	Q9Y3D0	347
SPPL2B	TMEM106A	Q96A25	345
SPPL2B	LRRCC1	Q9C099	339
SPPL2B	CD74	P04233	329
SPPL2B	TMEM106B	Q9NUM4	328
SPPL2B	ADAM17	P78536	324
SPPL2B	ITM2C	Q9NQX7	324
SPPL2B	SPPL3	Q8TCT6	317
SPPL2B	PLEKHM3	Q6ZWE6	314

IntAct

74 interactions, top by confidence:

A	B	Type	Score
NIPAL1	ESYT2	psi-mi:“MI:0914”(association)	0.640
MOXD1	GPAA1	psi-mi:“MI:0914”(association)	0.620
ADGRG5	KLRG2	psi-mi:“MI:0914”(association)	0.530
SPINK4	PLXNA2	psi-mi:“MI:0914”(association)	0.530
SPPL2B	UQCRQ	psi-mi:“MI:0914”(association)	0.530
FAM187B	HSPA5	psi-mi:“MI:0914”(association)	0.530
CD70	METTL15	psi-mi:“MI:0914”(association)	0.530
CLGN	NPC1	psi-mi:“MI:0914”(association)	0.530
CHRND	TPST2	psi-mi:“MI:0914”(association)	0.530
ENTPD7	PGK2	psi-mi:“MI:0914”(association)	0.530
NRN1	SLC1A1	psi-mi:“MI:0914”(association)	0.530
CD300E	SPPL2B	psi-mi:“MI:0914”(association)	0.530
GLMN	MGST3	psi-mi:“MI:0914”(association)	0.530
SIDT2	AP3D1	psi-mi:“MI:0914”(association)	0.530
		psi-mi:“MI:0914”(association)	0.350
UPK1A	TMEM223	psi-mi:“MI:0914”(association)	0.350
HTR3C	TMEM223	psi-mi:“MI:0914”(association)	0.350
ERGIC3	TMEM223	psi-mi:“MI:0914”(association)	0.350
CD70	GXYLT2	psi-mi:“MI:0914”(association)	0.350
CCNYL1	A2ML1	psi-mi:“MI:0914”(association)	0.350
SYNE4	GOLIM4	psi-mi:“MI:0914”(association)	0.350
MPPE1	ADAM10	psi-mi:“MI:0914”(association)	0.350
PTCH1	PLXNB2	psi-mi:“MI:0914”(association)	0.350
PTH1R	DEGS1	psi-mi:“MI:0914”(association)	0.350
HTR3A	GPAA1	psi-mi:“MI:0914”(association)	0.350
CHRND	EXTL3	psi-mi:“MI:0914”(association)	0.350

BioGRID (328): SPPL2B (Affinity Capture-MS), SPPL2B (Affinity Capture-MS), SPPL2B (Affinity Capture-MS), SPPL2B (Affinity Capture-MS), SPPL2B (Affinity Capture-MS), SPPL2B (Affinity Capture-MS), SPPL2B (Affinity Capture-MS), SPPL2B (Affinity Capture-MS), SPPL2B (Affinity Capture-MS), SLC30A5 (Affinity Capture-MS), PIGN (Affinity Capture-MS), KTN1 (Affinity Capture-MS), SLC30A6 (Affinity Capture-MS), SLC35G2 (Affinity Capture-MS), IGSF3 (Affinity Capture-MS)

ESM2 similar proteins: A0A5B9, A6NDV4, A6QLK4, B1AWJ5, E9PTA2, O75051, O94759, P01850, P01851, P01852, P01857, P01859, P01860, P01861, P01869, P01870, P01906, P01909, P03987, P06333, P0DSE2, P0DTU4, P11364, P15151, P15981, P20759, P20762, P32506, P54900, Q1WIM1, Q1WIM3, Q3TMX7, Q6P767, Q6ZRP7, Q7TQ33, Q812F8, Q8N126, Q8NFZ8, Q8R143, Q8R464

Diamond homologs: A2A6C4, B9FJ61, O81062, P49049, Q3TD49, Q5F383, Q5PQL3, Q6ZGL9, Q8IUH8, Q8TCT6, Q8TCT7, Q8TCT8, Q9CUS9, Q9JJF9, Q9UTA3, P34248, Q0DWA9, Q0WMJ8, Q4V3B8, Q53P98, Q5N808, Q5Z413, Q7G7C7, Q8TCT9, Q8W469, Q9D8V0, Q9MA44, Q93Z32, O22925, O80977, P25152, Q02PA2, Q2HXL6, Q56ZQ3, Q6GQB9, Q8L7E3, Q9BZQ6, Q9HZQ8, Q9BSG0, Q9D9N8

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 86 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
Neurotransmitter receptors and postsynaptic signal transmission	7	13.0×	4e-05
Transmission across Chemical Synapses	7	9.9×	2e-04
Neuronal System	7	5.7×	5e-03

GO biological processes:

GO term	Partners	Fold	FDR
acetylcholine receptor signaling pathway	7	56.7×	8e-09
synaptic transmission, cholinergic	5	52.1×	5e-06
membrane depolarization	6	39.8×	2e-06
monoatomic ion transmembrane transport	10	27.0×	2e-09
monoatomic ion transport	5	10.1×	9e-03
chemical synaptic transmission	7	7.0×	5e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	3
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1431 predictions. Top by Δscore:

Variant	Effect	Δscore
19:2334596:CTGCA:C	acceptor_loss	1.0000
19:2334597:TGCAG:T	acceptor_loss	1.0000
19:2334598:GCAGG:G	acceptor_loss	1.0000
19:2334599:CAGGT:C	acceptor_loss	1.0000
19:2334600:AGGT:A	acceptor_gain	1.0000
19:2334601:G:A	acceptor_loss	1.0000
19:2334601:GGTG:G	acceptor_gain	1.0000
19:2334717:AGGCA:A	donor_gain	1.0000
19:2334718:GGCA:G	donor_gain	1.0000
19:2334718:GGCAG:G	donor_gain	1.0000
19:2334719:G:GT	donor_gain	1.0000
19:2334719:GCA:G	donor_gain	1.0000
19:2334720:CA:C	donor_gain	1.0000
19:2334721:AG:A	donor_loss	1.0000
19:2334722:G:GG	donor_gain	1.0000
19:2334722:G:T	donor_loss	1.0000
19:2334724:GAGT:G	donor_loss	1.0000
19:2334725:AGTA:A	donor_loss	1.0000
19:2337616:G:GT	donor_gain	1.0000
19:2337621:GGCTG:G	donor_gain	1.0000
19:2337622:GCTGG:G	donor_gain	1.0000
19:2338741:T:TA	acceptor_gain	1.0000
19:2338838:CACGG:C	donor_loss	1.0000
19:2338840:CGG:C	donor_loss	1.0000
19:2338842:G:GG	donor_gain	1.0000
19:2338842:GTAG:G	donor_loss	1.0000
19:2338843:T:A	donor_loss	1.0000
19:2339061:T:TA	acceptor_gain	1.0000
19:2339206:G:GT	donor_gain	1.0000
19:2339206:GAA:G	donor_gain	1.0000

AlphaMissense

3815 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:2344002:A:C	D359A	0.999
19:2334691:G:C	W52C	0.998
19:2334691:G:T	W52C	0.998
19:2340989:T:A	W311R	0.998
19:2340989:T:C	W311R	0.998
19:2343218:T:A	W322R	0.998
19:2343218:T:C	W322R	0.998
19:2344002:A:G	D359G	0.998
19:2344002:A:T	D359V	0.998
19:2344003:C:A	D359E	0.998
19:2344003:C:G	D359E	0.998
19:2344626:T:A	L417Q	0.998
19:2344628:G:C	G418R	0.998
19:2344635:G:A	G420E	0.998
19:2344638:A:C	D421A	0.998
19:2344638:A:G	D421G	0.998
19:2344638:A:T	D421V	0.998
19:2344639:C:A	D421E	0.998
19:2344639:C:G	D421E	0.998
19:2344650:C:A	P425Q	0.998
19:2351449:T:C	L457P	0.998
19:2337600:T:C	L115P	0.997
19:2344016:T:C	F364L	0.997
19:2344018:C:A	F364L	0.997
19:2344018:C:G	F364L	0.997
19:2344371:A:C	S375R	0.997
19:2344373:C:A	S375R	0.997
19:2344373:C:G	S375R	0.997
19:2344379:G:A	M377I	0.997
19:2344379:G:C	M377I	0.997

dbSNP variants (sampled 300 via entrez): RS1000021910 (19:2347149 T>C), RS1000074219 (19:2347043 C>T), RS1000150590 (19:2350982 C>T), RS1000225185 (19:2353305 G>A), RS1000231847 (19:2343040 G>A), RS1000265661 (19:2351158 C>G,T), RS1000363423 (19:2332472 C>T), RS1000369399 (19:2329144 C>T), RS1000375613 (19:2344178 TG>T), RS1000434047 (19:2340330 C>T), RS1000510333 (19:2332022 G>A), RS1000650612 (19:2332884 G>T), RS1000651095 (19:2336914 T>C), RS1000665432 (19:2343891 G>A,C,T), RS1000782586 (19:2327427 G>A)

Disease associations

OMIM: gene MIM:608239 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST002544_7	Parkinson’s disease	6.000000e-07
GCST009325_64	Parkinson’s disease or first degree relation to individual with Parkinson’s disease	4.000000e-10

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4105912 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.57	IC50	270	nM	CHEMBL4759048
6.37	IC50	430	nM	CHEMBL4069936

PubChem BioAssay actives

2 with measured affinity, of 2 total; 2 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-[(2S,3S)-3-amino-2-hydroxy-3-[4-(trifluoromethoxy)phenyl]propyl]-4-tert-butyl-N-cyclobutylbenzenesulfonamide	1673494: Inhibition of SPPL2b in human U2OS cells cotransfected with EGFP-labeled TNFalpha (1 to 76 residues)-NTF incubated for 24 hrs by Hoechst staining based Cellomics ArrayScan analysis	ic50	0.2700	uM
(2S)-2-cyclopropyl-N-[(6S)-5,11-dioxospiro[3,6-dihydro-1H-pyrazolo[1,2-b][2,3]benzodiazepine-2,1’-cyclopropane]-6-yl]-N’-(5-fluoro-2-methyl-3-pyridinyl)butanediamide	1479252: Inhibition of human SPPL2b expressed in human U2OS cells using EGFP-labeled TNFalpha (1 to 76 residues) NTF as substrate after 24 hrs by Hoechst staining based high content imaging assay	ic50	0.4300	uM

CTD chemical–gene interactions

22 total (human), top 22 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Arsenic	affects cotreatment, decreases expression, increases abundance, increases expression, affects methylation	3
sodium arsenite	affects cotreatment, decreases expression, increases abundance, increases expression	2
aristolochic acid I	increases expression	1
FR900359	increases phosphorylation	1
bisphenol A	affects cotreatment, increases methylation	1
beta-lapachone	decreases expression	1
butyraldehyde	decreases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
pentanal	decreases expression	1
perfluorooctane sulfonic acid	increases expression	1
MT19c compound	decreases expression	1
Fulvestrant	increases methylation, affects cotreatment	1
Doxorubicin	decreases expression	1
Formaldehyde	decreases expression	1
Manganese	affects cotreatment, decreases expression, increases abundance	1
Smoke	decreases expression	1
Thimerosal	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Valproic Acid	increases methylation	1
Vitamin E	increases expression	1
Acrylamide	decreases expression	1
Magnetite Nanoparticles	decreases methylation	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
CHEMBL4048267	Binding	Inhibition of human SPPL2b expressed in human U2OS cells using EGFP-labeled TNFalpha (1 to 76 residues) NTF as substrate after 24 hrs by Hoechst staining based high content imaging assay	Discovery of the First Potent, Selective, and Orally Bioavailable Signal Peptide Peptidase-Like 2a (SPPL2a) Inhibitor Displaying Pronounced Immunomodulatory Effects In Vivo. — J Med Chem

Clinical trials (associated diseases)

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