SPPL2A

Summary

SPPL2A (signal peptide peptidase like 2A, HGNC:30227) is a protein-coding gene on chromosome 15q21.2, encoding Signal peptide peptidase-like 2A (Q8TCT8). 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, which are transmembrane proteins with two conserved catalytic motifs localized within the membrane-spanning regions, as well as a member of the signal peptide peptidase-like protease (SPPL) family. This protein is expressed in all major adult human tissues and localizes to late endosomal compartments and lysosomal membranes. A pseudogene of this gene also lies on chromosome 15.

Source: NCBI Gene 84888 — RefSeq curated summary.

At a glance

• Gene–disease (curated): immunodeficiency 86 (Moderate, GenCC)
• GWAS associations: 19
• Clinical variants (ClinVar): 395 total — 2 pathogenic
• Phenotypes (HPO): 5
• Druggable target: yes
• MANE Select transcript: NM_032802

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30227
Approved symbol	SPPL2A
Name	signal peptide peptidase like 2A
Location	15q21.2
Locus type	gene with protein product
Status	Approved
Aliases	IMP3, PSL2
Ensembl gene	ENSG00000138600
Ensembl biotype	protein_coding
OMIM	608238
Entrez	84888

Gene structure

Transcript identifiers

Ensembl transcripts: 24 — 12 protein_coding, 9 retained_intron, 3 nonsense_mediated_decay

ENST00000261854, ENST00000558146, ENST00000558414, ENST00000558934, ENST00000559293, ENST00000559527, ENST00000560288, ENST00000698130, ENST00000698131, ENST00000698132, ENST00000698133, ENST00000698134, ENST00000698135, ENST00000698136, ENST00000698137, ENST00000698138, ENST00000698139, ENST00000698140, ENST00000890968, ENST00000890969, ENST00000890970, ENST00000951698, ENST00000951699, ENST00000951700

RefSeq mRNA: 1 — MANE Select: NM_032802 NM_032802

CCDS: CCDS10138

Canonical transcript exons

ENST00000261854 — 15 exons

Exon	Start	End
ENSE00000931389	50748113	50748202
ENSE00000931390	50747495	50747628
ENSE00000931394	50732603	50732684
ENSE00000931396	50726321	50726377
ENSE00000931398	50722124	50722201
ENSE00000931399	50719940	50720100
ENSE00001101996	50702266	50707874
ENSE00002569745	50765468	50765706
ENSE00003480209	50749636	50749746
ENSE00003481063	50748688	50748870
ENSE00003496700	50736644	50736740
ENSE00003569332	50736101	50736202
ENSE00003596982	50725221	50725323
ENSE00003600645	50730965	50731039
ENSE00003646051	50739680	50739828

Expression profiles

Bgee: expression breadth ubiquitous, 262 present calls, max score 99.16.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 68.7103 / max 525.3354, expressed in 1825 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
149878	67.5747	1825
149881	0.8590	371
149879	0.2059	75
149880	0.0706	13

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ileal mucosa	UBERON:0000331	99.16	gold quality
secondary oocyte	CL:0000655	98.96	gold quality
tibialis anterior	UBERON:0001385	98.64	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	98.49	gold quality
vastus lateralis	UBERON:0001379	98.40	gold quality
quadriceps femoris	UBERON:0001377	98.36	gold quality
biceps brachii	UBERON:0001507	98.07	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	98.02	gold quality
skeletal muscle tissue	UBERON:0001134	97.95	gold quality
deltoid	UBERON:0001476	97.87	gold quality
cartilage tissue	UBERON:0002418	97.76	gold quality
rectum	UBERON:0001052	97.66	gold quality
colonic mucosa	UBERON:0000317	97.35	gold quality
duodenum	UBERON:0002114	97.33	gold quality
islet of Langerhans	UBERON:0000006	97.29	gold quality
mucosa of sigmoid colon	UBERON:0004993	97.19	gold quality
muscle tissue	UBERON:0002385	97.15	gold quality
oocyte	CL:0000023	97.09	gold quality
heart right ventricle	UBERON:0002080	96.69	gold quality
calcaneal tendon	UBERON:0003701	96.69	gold quality
skeletal muscle organ	UBERON:0014892	96.69	gold quality
left ventricle myocardium	UBERON:0006566	96.62	gold quality
epithelial cell of pancreas	CL:0000083	96.57	gold quality
gastrocnemius	UBERON:0001388	96.57	gold quality
jejunum	UBERON:0002115	96.53	gold quality
vermiform appendix	UBERON:0001154	96.52	gold quality
body of pancreas	UBERON:0001150	96.46	gold quality
pancreas	UBERON:0001264	96.40	gold quality
mucosa of stomach	UBERON:0001199	96.34	gold quality
muscle of leg	UBERON:0001383	96.30	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-CURD-88	yes	4.44
E-MTAB-7381	no	953.31
E-ENAD-27	no	3.41
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): TP63

miRNA regulators (miRDB)

34 targeting SPPL2A, 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-548C-3P	99.99	74.01	7587
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-219A-5P	99.91	73.36	735
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-4493	99.90	66.48	977
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-605-3P	99.88	69.22	1833
HSA-MIR-4782-3P	99.88	73.31	735
HSA-MIR-6766-3P	99.88	73.38	732
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-6126	99.62	68.09	996
HSA-MIR-425-5P	99.59	67.67	900
HSA-MIR-3942-3P	99.57	69.03	2854
HSA-MIR-302B-5P	99.50	69.49	1857
HSA-MIR-302D-5P	99.50	69.34	1863
HSA-MIR-4672	99.50	71.58	2893
HSA-MIR-5582-5P	99.27	71.42	1879
HSA-MIR-642A-3P	99.23	67.67	1258
HSA-MIR-642B-3P	99.23	67.67	1258
HSA-MIR-8066	99.05	68.66	1532
HSA-MIR-138-2-3P	98.91	68.33	1643

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)
• ADAM10 and SPPL2a were identified as two proteases implicated in FasL processing and release of the FasL intracellular domain, which has been shown to be important for retrograde FasL signaling (PMID:17557115)
• SPPL2a and SPPL2b mediate the intramembrane cleavage, whereas neither SPP nor SPPL3 is capable of processing the Bri2 N-terminal fragment. (PMID:17965014)
• Data show that endogenous SPPL2a - in agreement with overexpression studies - is localised in membranes of lysosomes/late endosomes. (PMID:21896273)
• Regulated intramembrane proteolysis of the frontotemporal lobar degeneration risk factor, TMEM106B, by signal peptide peptidase-like 2a (SPPL2a). (PMID:24872421)
• In human B cells, SPPL2a is indispensable for turnover of CD74 N-terminal fragment. A human 15q21.2 microdeletion leads to loss of SPPL2a transcript and protein. (PMID:25035924)
• Study propose that elements within the transmembrane segment and the luminal juxtamembrane domain facilitate intramembrane proteolysis of CD74 by SPPL2a. (PMID:26987812)
• inherited SPPL2a deficiency in humans underlies mycobacterial disease by decreasing the numbers of dendritic cells and impairing IFN-gamma production by mycobacterium-specific memory TH1* cells (PMID:30127434)
• SPPL2a/b negatively regulates LOX-1 signaling and atherosclerosis. (PMID:30819724)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Sppl2a	ENSMUSG00000027366
rattus_norvegicus	Sppl2a	ENSRNOG00000011652

Paralogs (4): SPPL2B (ENSG00000005206), HM13 (ENSG00000101294), SPPL3 (ENSG00000157837), SPPL2C (ENSG00000185294)

Protein

Protein identifiers

Signal peptide peptidase-like 2A — Q8TCT8 (reviewed: Q8TCT8)

Alternative names: Intramembrane protease 3, Presenilin-like protein 2

All UniProt accessions (8): Q8TCT8, A0A8V8TLF6, A0A8V8TLI3, A0A8V8TLY7, A0A8V8TLZ2, A0A8V8TN76, H0YNA2, H0YNA7

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 FASLG, 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. Also responsible for the intramembrane cleavage of Fas antigen ligand FASLG, which promotes the release of the intracellular FasL domain (FasL ICD). Essential for degradation of the invariant chain CD74 that plays a central role in the function of antigen-presenting cells in the immune system. Plays a role in the regulation of innate and adaptive immunity. Catalyzes the intramembrane cleavage of the simian foamy virus envelope glycoprotein gp130 independently of prior ectodomain shedding by furin or furin-like proprotein convertase (PC)-mediated cleavage proteolysis.

Subunit / interactions. Interacts with ITM2B.

Subcellular location. Late endosome membrane. Lysosome membrane. Membrane.

Tissue specificity. Ubiquitous.

Post-translational modifications. Glycosylated.

Disease relevance. Immunodeficiency 86 (IMD86) [MIM:619549] An autosomal recessive disorder characterized by susceptibility to mycobacterial disease after exposure to BCG vaccine. Affected individuals usually develop localized mycobacterial lymphadenopathy. The disease is caused by variants affecting the gene represented in this entry.

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. The C-terminal tail is necessary for lysosomal transport.

Similarity. Belongs to the peptidase A22B family.

RefSeq proteins (1): NP_116191* (*=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

Enzyme classification (BRENDA):

• EC 3.4.23.B24 — (BRENDA: organisms, substrates, inhibitors, Km, kcat entries)

UniProt features (40 total): topological domain 10, transmembrane region 9, glycosylation site 7, sequence conflict 5, short sequence motif 2, active site 2, signal peptide 1, chain 1, domain 1, sequence variant 1, mutagenesis site 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
9K92	ELECTRON MICROSCOPY	3.3
9K93	ELECTRON MICROSCOPY	3.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8TCT8-F1	79.28	0.37

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): 351; 412

Glycosylation sites (7): 58, 66, 74, 116, 126, 149, 155

Mutagenesis-validated functional residues (1):

Position	Phenotype
412	loss of intramembrane-cleaving activity toward faslg, 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: 313 (showing top): GOBP_RIBOSOME_BIOGENESIS, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GOBP_RESPONSE_TO_PEPTIDE, GOCC_VACUOLAR_MEMBRANE, MODULE_151, SHEPARD_CRASH_AND_BURN_MUTANT_UP, GOBP_MATURATION_OF_SSU_RRNA, ATGTTAA_MIR302C, GTGCCTT_MIR506, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_RIBOSOMAL_SMALL_SUBUNIT_BIOGENESIS, MODULE_301, SCHAEFFER_PROSTATE_DEVELOPMENT_6HR_UP, GOCC_GOLGI_ASSOCIATED_VESICLE, GOBP_MEMBRANE_PROTEIN_INTRACELLULAR_DOMAIN_PROTEOLYSIS

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): lysosomal membrane (GO:0005765), late endosome (GO:0005770), plasma membrane (GO:0005886), membrane (GO:0016020), Golgi-associated vesicle membrane (GO:0030660), late endosome membrane (GO:0031902), extracellular exosome (GO:0070062), lumenal side of endoplasmic reticulum membrane (GO:0098553), cytoplasmic side of endoplasmic reticulum membrane (GO:0098554), lysosome (GO:0005764), endosome (GO:0005768), endomembrane system (GO:0012505), cytoplasmic vesicle membrane (GO:0030659), bounding membrane of organelle (GO:0098588)

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
membrane protein proteolysis	2
cellular anatomical structure	2
endoplasmic reticulum membrane	2
cytoplasmic vesicle	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
lysosome	1
lytic vacuole membrane	1
endosome	1
membrane	1
cell periphery	1
Golgi-associated vesicle	1
cytoplasmic vesicle membrane	1
bounding membrane of organelle	1
late endosome	1
endosome membrane	1
extracellular vesicle	1
lumenal side of membrane	1
cytoplasmic side of membrane	1
lytic vacuole	1
endomembrane system	1
vacuole	1
plasma membrane	1
vesicle membrane	1
organelle membrane	1

Protein interactions and networks

STRING

654 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SPPL2A	ITM2B	Q9Y287	586
SPPL2A	AP4E1	Q9UPM8	535
SPPL2A	CD74	P04233	529
SPPL2A	SCIMP	Q6UWF3	482
SPPL2A	RIN3	Q8TB24	456
SPPL2A	ADAM10	O14672	455
SPPL2A	MRPS24	P82668	444
SPPL2A	IRF8	Q02556	438
SPPL2A	IFNGR2	P38484	436
SPPL2A	IL12RB1	P42701	433
SPPL2A	ZDHHC6	Q9H6R6	433
SPPL2A	IL23R	Q5VWK5	426
SPPL2A	SELL	P14151	417
SPPL2A	SORL1	Q92673	414
SPPL2A	SELP	P16109	410
SPPL2A	KIAA1191	Q96A73	410

IntAct

17 interactions, top by confidence:

A	B	Type	Score
SGTA	SPPL2A	psi-mi:“MI:0915”(physical association)	0.780
SPPL2A	SGTA	psi-mi:“MI:0915”(physical association)	0.780
SPPL2A	WFS1	psi-mi:“MI:0915”(physical association)	0.560
SPPL2A	NFKB1	psi-mi:“MI:0915”(physical association)	0.370
LGALS8	SLC22A23	psi-mi:“MI:0914”(association)	0.350
	NPC1	psi-mi:“MI:0914”(association)	0.350
KIR2DL4	GPR89A	psi-mi:“MI:0914”(association)	0.350
SPPL2A	TFRC	psi-mi:“MI:0403”(colocalization)	0.270
SPPL2A	SGTA	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (22): SPPL2A (Two-hybrid), SPPL2A (Affinity Capture-MS), SPPL2A (Two-hybrid), SPPL2A (Affinity Capture-MS), SPPL2A (Affinity Capture-RNA), SPPL2A (Two-hybrid), SPPL2A (Affinity Capture-RNA), SPPL2A (Affinity Capture-MS), SPPL2A (Affinity Capture-MS), SPPL2A (Proximity Label-MS), SPPL2A (Affinity Capture-MS), SPPL2A (Affinity Capture-MS), SPPL2A (Co-fractionation), SPPL2A (Co-fractionation), SPPL2A (Co-fractionation)

ESM2 similar proteins: A0A075B734, A1L272, A2IBY8, A8W649, A9Y006, D4A7H1, E7EXX2, F7B113, O14520, O35454, O54794, O62735, O94956, P34080, P35525, P41181, P47862, P47863, P47864, P51789, P51797, P56402, P56403, P79099, Q06495, Q06496, Q08DE6, Q4R691, Q5PQL3, Q62052, Q866S3, Q8BLV3, Q8BXB6, Q8BZ00, Q8IVB4, Q8K078, Q8MIQ9, Q8R2N1, Q8TCT8, Q921R8

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, P93026

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	222
Likely benign	128
Benign	19

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
1299467	NM_032802.4(SPPL2A):c.733+1G>A	Pathogenic
1299468	NM_032802.4(SPPL2A):c.1328-1G>A	Pathogenic

SpliceAI

2078 predictions. Top by Δscore:

Variant	Effect	Δscore
15:50720063:C:CT	acceptor_gain	1.0000
15:50722123:CCAA:C	donor_gain	1.0000
15:50726373:CCATT:C	acceptor_gain	1.0000
15:50726374:CATTC:C	acceptor_gain	1.0000
15:50726378:C:CC	acceptor_gain	1.0000
15:50731035:CATGA:C	acceptor_gain	1.0000
15:50731037:TGA:T	acceptor_gain	1.0000
15:50731040:C:CC	acceptor_gain	1.0000
15:50736095:TCATA:T	donor_loss	1.0000
15:50736096:CATA:C	donor_loss	1.0000
15:50736097:ATAC:A	donor_loss	1.0000
15:50736098:TACCT:T	donor_loss	1.0000
15:50736100:C:CG	donor_loss	1.0000
15:50736100:CCTGT:C	donor_gain	1.0000
15:50736198:CAATC:C	acceptor_gain	1.0000
15:50736199:AATC:A	acceptor_gain	1.0000
15:50736200:ATC:A	acceptor_gain	1.0000
15:50736201:TC:T	acceptor_gain	1.0000
15:50736201:TCCTA:T	acceptor_loss	1.0000
15:50736202:CC:C	acceptor_gain	1.0000
15:50736202:CCT:C	acceptor_loss	1.0000
15:50736203:C:CC	acceptor_gain	1.0000
15:50736204:T:A	acceptor_loss	1.0000
15:50736642:A:AC	donor_gain	1.0000
15:50736643:C:CC	donor_gain	1.0000
15:50736643:CGTG:C	donor_gain	1.0000
15:50736737:TAAA:T	acceptor_gain	1.0000
15:50736741:C:CC	acceptor_gain	1.0000
15:50739775:T:TA	donor_gain	1.0000
15:50747493:A:AC	donor_gain	1.0000

AlphaMissense

3411 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:50725235:T:A	D412V	1.000
15:50725235:T:C	D412G	1.000
15:50725235:T:G	D412A	1.000
15:50725238:C:T	G411E	1.000
15:50731002:T:G	D351A	1.000
15:50720034:A:G	L465P	0.999
15:50720034:A:T	L465H	0.999
15:50722201:C:T	G417D	0.999
15:50725221:C:G	G417R	0.999
15:50725223:G:C	P416R	0.999
15:50725223:G:T	P416Q	0.999
15:50725234:G:C	D412E	0.999
15:50725234:G:T	D412E	0.999
15:50725236:C:G	D412H	0.999
15:50725238:C:A	G411V	0.999
15:50725239:C:G	G411R	0.999
15:50725239:C:T	G411R	0.999
15:50725245:C:G	G409R	0.999
15:50725319:G:T	P384Q	0.999
15:50726360:C:A	M369I	0.999
15:50726360:C:G	M369I	0.999
15:50726360:C:T	M369I	0.999
15:50731001:A:C	D351E	0.999
15:50731001:A:T	D351E	0.999
15:50731002:T:A	D351V	0.999
15:50731002:T:C	D351G	0.999
15:50732656:C:G	G321R	0.999
15:50732656:C:T	G321R	0.999
15:50736126:A:G	W303R	0.999
15:50736126:A:T	W303R	0.999

dbSNP variants (sampled 300 via entrez): RS1000051161 (15:50732450 C>G), RS1000081786 (15:50732956 G>A), RS1000099864 (15:50765527 G>A,T), RS1000165093 (15:50734206 C>T), RS1000204551 (15:50729377 T>C), RS1000264214 (15:50738331 T>C), RS1000319615 (15:50728948 G>A,C), RS1000328877 (15:50708115 C>T), RS1000346367 (15:50725963 C>A,G), RS1000350966 (15:50752273 T>A), RS1000390257 (15:50735645 C>T), RS1000480467 (15:50702277 A>C), RS1000530782 (15:50743783 A>G), RS1000543524 (15:50728322 T>C), RS1000631434 (15:50737425 A>G)

Disease associations

OMIM: gene MIM:608238 | disease phenotypes: MIM:619549

GenCC curated gene-disease

Disease	Classification	Inheritance
immunodeficiency 86	Moderate	Autosomal recessive

Mondo (1): immunodeficiency 86 (MONDO:0030448)

Orphanet (0):

HPO phenotypes

5 total (5 of 5 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0003203	Decreased neutrophil oxidative burst
HP:0003496	Increased circulating IgM level
HP:0004315	Decreased circulating IgG concentration
HP:0020086	BCGitis

GWAS associations

19 associations (top):

Study	Trait	p-value
GCST002147_22	Fibrinogen	7.000000e-10
GCST002245_30	Alzheimer’s disease (late onset)	3.000000e-07
GCST003194_19	Fibrinogen levels	2.000000e-12
GCST004121_11	Fibrinogen levels	3.000000e-10
GCST004122_27	Fibrinogen levels	2.000000e-10
GCST004620_90	Sum basophil neutrophil counts	4.000000e-10
GCST004629_142	Neutrophil count	2.000000e-10
GCST005982_8	Calcium levels	3.000000e-12
GCST005984_64	Glomerular filtration rate	9.000000e-09
GCST005985_42	Creatinine levels	3.000000e-09
GCST006030_13	Chloride levels	2.000000e-11
GCST006031_10	Potassium levels	5.000000e-24
GCST006269_1150	General cognitive ability	2.000000e-08
GCST007511_5	Alzheimer’s disease (late onset)	4.000000e-07
GCST010002_169	Refractive error	6.000000e-12
GCST90002388_148	Lymphocyte count	3.000000e-11
GCST90002398_283	Neutrophil count	3.000000e-22
GCST90002403_480	Red blood cell count	2.000000e-09
GCST90002407_590	White blood cell count	5.000000e-25

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0004833	neutrophil count
EFO:0005090	basophil count
EFO:0004838	calcium measurement
EFO:0009283	potassium measurement
EFO:0004337	intelligence
EFO:1001870	late-onset Alzheimers disease
EFO:0004587	lymphocyte count
EFO:0004305	erythrocyte count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4105833 (SINGLE PROTEIN)

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

ChEMBL bioactivities

36 potent at pChembl≥5 of 36 total, top 36 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.52	IC50	0.3	nM	CHEMBL5204104
9.30	IC50	0.5	nM	CHEMBL5203663
9.22	IC50	0.6	nM	CHEMBL5182068
9.00	IC50	1	nM	CHEMBL5171841
9.00	IC50	1	nM	CHEMBL5197736
9.00	IC50	1	nM	CHEMBL5199989
8.40	IC50	4	nM	CHEMBL4759048
8.30	IC50	5	nM	CHEMBL4059711
8.22	IC50	6	nM	CHEMBL255473
8.15	IC50	7	nM	CHEMBL4762492
8.05	IC50	9	nM	CHEMBL4759048
8.00	IC50	10	nM	CHEMBL392068
7.89	IC50	13	nM	CHEMBL4753654
7.82	IC50	15	nM	CHEMBL4792187
7.60	IC50	25	nM	CHEMBL4759943
7.46	IC50	35	nM	CHEMBL4077007
7.36	IC50	44	nM	CHEMBL4076827
7.16	IC50	70	nM	CHEMBL4064631
7.12	IC50	76	nM	CHEMBL4100749
7.11	IC50	77	nM	CHEMBL4069936
7.06	IC50	88	nM	CHEMBL4740837
6.80	IC50	160	nM	CHEMBL4069936
6.70	IC50	200	nM	CHEMBL4762370
6.65	IC50	225	nM	CHEMBL4077336
6.46	IC50	350	nM	CHEMBL4747630
6.21	IC50	620	nM	CHEMBL4789381
6.08	IC50	840	nM	CHEMBL4785324
6.07	IC50	860	nM	CHEMBL4743609
6.06	IC50	870	nM	CHEMBL4074838
6.05	IC50	900	nM	CHEMBL4753079
6.04	IC50	910	nM	CHEMBL4798232
5.99	IC50	1020	nM	CHEMBL4105093
5.86	IC50	1390	nM	CHEMBL4075787
5.82	IC50	1500	nM	CHEMBL4741014
5.54	IC50	2850	nM	CHEMBL4086098
5.37	IC50	4300	nM	CHEMBL4762488

PubChem BioAssay actives

36 with measured affinity, of 36 total; 34 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
(2R)-2-methyl-N’-[1-methyl-3-(2-methylpropanoylamino)pyrazol-5-yl]-N-[(6S)-5-oxo-2,3,6,11-tetrahydro-1H-pyrazolo[1,2-b][2,3]benzodiazepin-6-yl]butanediamide	1880734: Inhibition of human SPPL2A expressed in human U2OS cells assessed as nuclear mask transferring to EGFP channel using EGFP-labeled TNFalpha (aa1-76) NTF as substrate and measured after 24 hrs by Hoechst staining based translocation assay	ic50	0.0003	uM
4-methyl-2-(2-methylpropanoylamino)-N-[(2R)-3,3,3-trifluoro-2-[[(6S)-5-oxo-2,3,6,11-tetrahydro-1H-pyrazolo[1,2-b][2,3]benzodiazepin-6-yl]carbamoyl]propyl]-1,3-thiazole-5-carboxamide	1880734: Inhibition of human SPPL2A expressed in human U2OS cells assessed as nuclear mask transferring to EGFP channel using EGFP-labeled TNFalpha (aa1-76) NTF as substrate and measured after 24 hrs by Hoechst staining based translocation assay	ic50	0.0005	uM
(2S)-2-cyclobutyl-N’-[1-methyl-3-(2-methylpropanoylamino)pyrazol-5-yl]-N-[(6S)-5-oxo-2,3,6,11-tetrahydro-1H-pyrazolo[1,2-b][2,3]benzodiazepin-6-yl]butanediamide	1880734: Inhibition of human SPPL2A expressed in human U2OS cells assessed as nuclear mask transferring to EGFP channel using EGFP-labeled TNFalpha (aa1-76) NTF as substrate and measured after 24 hrs by Hoechst staining based translocation assay	ic50	0.0006	uM
4-methyl-N-[(2R)-2-methyl-3-oxo-3-[[(6S)-5-oxo-2,3,6,11-tetrahydro-1H-pyrazolo[1,2-b][2,3]benzodiazepin-6-yl]amino]propyl]-2-(2-methylpropanoylamino)-1,3-thiazole-5-carboxamide	1880734: Inhibition of human SPPL2A expressed in human U2OS cells assessed as nuclear mask transferring to EGFP channel using EGFP-labeled TNFalpha (aa1-76) NTF as substrate and measured after 24 hrs by Hoechst staining based translocation assay	ic50	0.0010	uM
(2R)-N’-[3-(2,2-difluoroethylcarbamoyl)-1-methylpyrazol-5-yl]-2-methyl-N-[(6S)-5-oxo-2,3,6,11-tetrahydro-1H-pyrazolo[1,2-b][2,3]benzodiazepin-6-yl]butanediamide	1880734: Inhibition of human SPPL2A expressed in human U2OS cells assessed as nuclear mask transferring to EGFP channel using EGFP-labeled TNFalpha (aa1-76) NTF as substrate and measured after 24 hrs by Hoechst staining based translocation assay	ic50	0.0010	uM
(2R)-N’-[4-chloro-2-(2-methylpropanoylamino)-1,3-thiazol-5-yl]-2-methyl-N-[(6S)-5-oxo-2,3,6,11-tetrahydro-1H-pyrazolo[1,2-b][2,3]benzodiazepin-6-yl]butanediamide	1880734: Inhibition of human SPPL2A expressed in human U2OS cells assessed as nuclear mask transferring to EGFP channel using EGFP-labeled TNFalpha (aa1-76) NTF as substrate and measured after 24 hrs by Hoechst staining based translocation assay	ic50	0.0010	uM
N-[(2S,3S)-3-amino-2-hydroxy-3-[4-(trifluoromethoxy)phenyl]propyl]-4-tert-butyl-N-cyclobutylbenzenesulfonamide	1673490: Inhibition of SPPL2a 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	0.0040	uM
(2R)-N’-(3,5-difluorophenyl)-2-methyl-N-[(6S)-5-oxo-2,3,6,11-tetrahydro-1H-pyrazolo[1,2-b][2,3]benzodiazepin-6-yl]butanediamide	1479248: Inhibition of human SPPL2a expressed in HEK293 cells using GAL4-VP16 fusedTNFalpha (1 to 76)-NTF as substrate after 24 hrs by Bright-Glo luciferase reporter gene assay	ic50	0.0050	uM
benzyl N-[(2S)-4-methyl-1-[[(2S)-4-methyl-1-[[3-[[(2S)-4-methyl-2-[[(2S)-4-methyl-2-(phenylmethoxycarbonylamino)pentanoyl]amino]pentanoyl]amino]-2-oxopropyl]amino]-1-oxopentan-2-yl]amino]-1-oxopentan-2-yl]carbamate	1479248: Inhibition of human SPPL2a expressed in HEK293 cells using GAL4-VP16 fusedTNFalpha (1 to 76)-NTF as substrate after 24 hrs by Bright-Glo luciferase reporter gene assay	ic50	0.0060	uM
N-[(2S,3S)-3-amino-2-hydroxy-3-phenylpropyl]-3-tert-butyl-N-cyclobutylbenzenesulfonamide	1673485: Inhibition of human SPPL2a expressed in HEK293 cells cotransfected with Gal4 luciferase reporter plasmid and VP16-TNFalpha(1-76)-NTF incubated for 24 hrs by luciferase reporter gene assay based luminescence assay	ic50	0.0070	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	1479248: Inhibition of human SPPL2a expressed in HEK293 cells using GAL4-VP16 fusedTNFalpha (1 to 76)-NTF as substrate after 24 hrs by Bright-Glo luciferase reporter gene assay	ic50	0.0100	uM
N-[(2S,3S)-3-amino-2-hydroxy-3-phenylpropyl]-N-cyclobutyl-5,5,8,8-tetramethyl-6,7-dihydronaphthalene-2-sulfonamide	1673485: Inhibition of human SPPL2a expressed in HEK293 cells cotransfected with Gal4 luciferase reporter plasmid and VP16-TNFalpha(1-76)-NTF incubated for 24 hrs by luciferase reporter gene assay based luminescence assay	ic50	0.0130	uM
N-[(2S,3S)-3-amino-2-hydroxy-3-phenylpropyl]-3,4-dichloro-N-cycloheptylbenzenesulfonamide	1673485: Inhibition of human SPPL2a expressed in HEK293 cells cotransfected with Gal4 luciferase reporter plasmid and VP16-TNFalpha(1-76)-NTF incubated for 24 hrs by luciferase reporter gene assay based luminescence assay	ic50	0.0150	uM
N-[(2S,3S)-3-amino-2-hydroxy-3-phenylpropyl]-4-tert-butyl-N-cyclobutylbenzenesulfonamide	1673485: Inhibition of human SPPL2a expressed in HEK293 cells cotransfected with Gal4 luciferase reporter plasmid and VP16-TNFalpha(1-76)-NTF incubated for 24 hrs by luciferase reporter gene assay based luminescence assay	ic50	0.0250	uM
(2R)-2-methyl-N’-(2-methylphenyl)-N-[(6S)-5-oxo-2,3,6,11-tetrahydro-1H-pyrazolo[1,2-b][2,3]benzodiazepin-6-yl]butanediamide	1479248: Inhibition of human SPPL2a expressed in HEK293 cells using GAL4-VP16 fusedTNFalpha (1 to 76)-NTF as substrate after 24 hrs by Bright-Glo luciferase reporter gene assay	ic50	0.0350	uM
(2R)-N’-(5-fluoro-2-methyl-3-pyridinyl)-2-methyl-N-[(6S)-5-oxo-2,3,6,11-tetrahydro-1H-pyrazolo[1,2-b][2,3]benzodiazepin-6-yl]butanediamide	1479248: Inhibition of human SPPL2a expressed in HEK293 cells using GAL4-VP16 fusedTNFalpha (1 to 76)-NTF as substrate after 24 hrs by Bright-Glo luciferase reporter gene assay	ic50	0.0440	uM
(2R)-2-methyl-N’-(3-methylphenyl)-N-[(6S)-5-oxo-2,3,6,11-tetrahydro-1H-pyrazolo[1,2-b][2,3]benzodiazepin-6-yl]butanediamide	1479248: Inhibition of human SPPL2a expressed in HEK293 cells using GAL4-VP16 fusedTNFalpha (1 to 76)-NTF as substrate after 24 hrs by Bright-Glo luciferase reporter gene assay	ic50	0.0700	uM
(2R)-N’-(5-fluoro-2-methyl-3-pyridinyl)-N-[(6S)-10-fluoro-5-oxo-2,3,6,11-tetrahydro-1H-pyrazolo[1,2-b][2,3]benzodiazepin-6-yl]-2-methylbutanediamide	1479248: Inhibition of human SPPL2a expressed in HEK293 cells using GAL4-VP16 fusedTNFalpha (1 to 76)-NTF as substrate after 24 hrs by Bright-Glo luciferase reporter gene assay	ic50	0.0760	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	1479248: Inhibition of human SPPL2a expressed in HEK293 cells using GAL4-VP16 fusedTNFalpha (1 to 76)-NTF as substrate after 24 hrs by Bright-Glo luciferase reporter gene assay	ic50	0.0770	uM
N-[(2S,3S)-3-amino-2-hydroxy-3-phenylpropyl]-3,4-dichloro-N-cyclobutylbenzenesulfonamide	1673485: Inhibition of human SPPL2a expressed in HEK293 cells cotransfected with Gal4 luciferase reporter plasmid and VP16-TNFalpha(1-76)-NTF incubated for 24 hrs by luciferase reporter gene assay based luminescence assay	ic50	0.0880	uM
N-[(2S,3S)-3-amino-2-hydroxy-3-phenylpropyl]-3,4-dichloro-N-(2-methylpropyl)benzenesulfonamide	1673485: Inhibition of human SPPL2a expressed in HEK293 cells cotransfected with Gal4 luciferase reporter plasmid and VP16-TNFalpha(1-76)-NTF incubated for 24 hrs by luciferase reporter gene assay based luminescence assay	ic50	0.2000	uM
(2S)-2-cyclopropyl-N-[(6S)-5,11-dioxo-1,2,3,6-tetrahydropyrazolo[1,2-b][2,3]benzodiazepin-6-yl]-N’-(5-fluoro-2-methyl-3-pyridinyl)butanediamide	1479248: Inhibition of human SPPL2a expressed in HEK293 cells using GAL4-VP16 fusedTNFalpha (1 to 76)-NTF as substrate after 24 hrs by Bright-Glo luciferase reporter gene assay	ic50	0.2250	uM
N-[(2S,3S)-3-amino-2-hydroxy-3-phenylpropyl]-3,4-dichloro-N-propan-2-yloxybenzenesulfonamide	1673485: Inhibition of human SPPL2a expressed in HEK293 cells cotransfected with Gal4 luciferase reporter plasmid and VP16-TNFalpha(1-76)-NTF incubated for 24 hrs by luciferase reporter gene assay based luminescence assay	ic50	0.3500	uM
N-[(2S,3S)-3-amino-2-hydroxy-3-phenylpropyl]-N-benzyl-3,4-dichlorobenzenesulfonamide	1673485: Inhibition of human SPPL2a expressed in HEK293 cells cotransfected with Gal4 luciferase reporter plasmid and VP16-TNFalpha(1-76)-NTF incubated for 24 hrs by luciferase reporter gene assay based luminescence assay	ic50	0.6200	uM
N-[(2S,3S)-3-amino-2-hydroxy-3-phenylpropyl]-N-cyclobutyl-1,3-benzothiazole-5-sulfonamide	1673485: Inhibition of human SPPL2a expressed in HEK293 cells cotransfected with Gal4 luciferase reporter plasmid and VP16-TNFalpha(1-76)-NTF incubated for 24 hrs by luciferase reporter gene assay based luminescence assay	ic50	0.8400	uM
N-[(2S,3S)-3-amino-2-hydroxy-4-phenylbutyl]-3,4-dichloro-N-(2-methylpropyl)benzenesulfonamide	1673485: Inhibition of human SPPL2a expressed in HEK293 cells cotransfected with Gal4 luciferase reporter plasmid and VP16-TNFalpha(1-76)-NTF incubated for 24 hrs by luciferase reporter gene assay based luminescence assay	ic50	0.8600	uM
(2R)-N-[(6S)-5,11-dioxo-1,2,3,6-tetrahydropyrazolo[1,2-b][2,3]benzodiazepin-6-yl]-N’-(5-fluoro-2-methyl-3-pyridinyl)-2-methylbutanediamide	1479248: Inhibition of human SPPL2a expressed in HEK293 cells using GAL4-VP16 fusedTNFalpha (1 to 76)-NTF as substrate after 24 hrs by Bright-Glo luciferase reporter gene assay	ic50	0.8700	uM
N-[(2S,3S)-3-amino-2-hydroxy-3-phenylpropyl]-3,4-dichloro-N-(1-methylcyclobutyl)benzenesulfonamide	1673485: Inhibition of human SPPL2a expressed in HEK293 cells cotransfected with Gal4 luciferase reporter plasmid and VP16-TNFalpha(1-76)-NTF incubated for 24 hrs by luciferase reporter gene assay based luminescence assay	ic50	0.9000	uM
N-[(2S,3S)-3-amino-2-hydroxy-3-phenylpropyl]-3,4-dichloro-N-(2-hydroxy-2-methylpropyl)benzenesulfonamide	1673485: Inhibition of human SPPL2a expressed in HEK293 cells cotransfected with Gal4 luciferase reporter plasmid and VP16-TNFalpha(1-76)-NTF incubated for 24 hrs by luciferase reporter gene assay based luminescence assay	ic50	0.9100	uM
(2R)-2-methyl-N’-(2-methyl-3-pyridinyl)-N-[(6S)-5-oxo-2,3,6,11-tetrahydro-1H-pyrazolo[1,2-b][2,3]benzodiazepin-6-yl]butanediamide	1479248: Inhibition of human SPPL2a expressed in HEK293 cells using GAL4-VP16 fusedTNFalpha (1 to 76)-NTF as substrate after 24 hrs by Bright-Glo luciferase reporter gene assay	ic50	1.0200	uM
(2R)-2-methyl-N’-(4-methylphenyl)-N-[(6S)-5-oxo-2,3,6,11-tetrahydro-1H-pyrazolo[1,2-b][2,3]benzodiazepin-6-yl]butanediamide	1479248: Inhibition of human SPPL2a expressed in HEK293 cells using GAL4-VP16 fusedTNFalpha (1 to 76)-NTF as substrate after 24 hrs by Bright-Glo luciferase reporter gene assay	ic50	1.3900	uM
N-[(2S,3S)-3-amino-2-hydroxy-3-phenylpropyl]-3,4-dichloro-N-(oxetan-3-yl)benzenesulfonamide	1673485: Inhibition of human SPPL2a expressed in HEK293 cells cotransfected with Gal4 luciferase reporter plasmid and VP16-TNFalpha(1-76)-NTF incubated for 24 hrs by luciferase reporter gene assay based luminescence assay	ic50	1.5000	uM
(2R)-2-methyl-N-[(6S)-5-oxo-2,3,6,11-tetrahydro-1H-pyrazolo[1,2-b][2,3]benzodiazepin-6-yl]-N’-[2-(trifluoromethyl)phenyl]butanediamide	1479248: Inhibition of human SPPL2a expressed in HEK293 cells using GAL4-VP16 fusedTNFalpha (1 to 76)-NTF as substrate after 24 hrs by Bright-Glo luciferase reporter gene assay	ic50	2.8500	uM
benzyl N-[(2S,3S)-4-[(3,4-dichlorophenyl)sulfonyl-(2-methylpropyl)amino]-3-hydroxy-1-phenylbutan-2-yl]carbamate	1673485: Inhibition of human SPPL2a expressed in HEK293 cells cotransfected with Gal4 luciferase reporter plasmid and VP16-TNFalpha(1-76)-NTF incubated for 24 hrs by luciferase reporter gene assay based luminescence assay	ic50	4.3000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, decreases methylation	5
Phenylmercuric Acetate	affects cotreatment, increases expression	2
aristolochic acid I	decreases expression	1
moringin	decreases expression	1
dicrotophos	decreases expression	1
sodium arsenite	increases expression	1
benzo(e)pyrene	increases methylation	1
CGP 52608	affects binding, increases reaction	1
monomethylarsonous acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
ICG 001	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
jinfukang	decreases expression	1
NSC 689534	affects binding, increases expression	1
Temozolomide	increases expression	1
Sunitinib	increases expression	1
Arsenic Trioxide	increases expression	1
Air Pollutants	increases abundance, decreases expression	1
Benzo(a)pyrene	affects methylation	1
Cannabidiol	increases expression	1
Carbamazepine	affects expression	1
Copper	affects binding, increases expression	1
Doxorubicin	decreases expression	1
Formaldehyde	increases expression	1
Methapyrilene	increases methylation	1
Phenobarbital	affects expression	1
Rotenone	increases expression	1
Smoke	decreases expression	1
Tretinoin	increases expression	1
Cyclosporine	increases expression	1

ChEMBL screening assays

5 unique, capped per target: 5 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4048263	Binding	Inhibition of human SPPL2a expressed in HEK293 cells using GAL4-VP16 fusedTNFalpha (1 to 76)-NTF as substrate after 24 hrs by Bright-Glo luciferase reporter gene 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.