SPPL3

Summary

SPPL3 (signal peptide peptidase like 3, HGNC:30424) is a protein-coding gene on chromosome 12q24.31, encoding Signal peptide peptidase-like 3 (Q8TCT6). Intramembrane-cleaving aspartic protease (I-CLiP) that cleaves type II membrane protein substrates in or close to their luminal transmembrane domain boundaries.

Enables aspartic endopeptidase activity, intramembrane cleaving and protein homodimerization activity. Involved in T cell receptor signaling pathway; membrane protein proteolysis; and positive regulation of calcineurin-NFAT signaling cascade. Located in Golgi-associated vesicle membrane; endoplasmic reticulum; and plasma membrane.

Source: NCBI Gene 121665 — RefSeq curated summary.

At a glance

• GWAS associations: 38
• Clinical variants (ClinVar): 44 total
• MANE Select transcript: NM_139015

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30424
Approved symbol	SPPL3
Name	signal peptide peptidase like 3
Location	12q24.31
Locus type	gene with protein product
Status	Approved
Aliases	IMP2, PSL4, MGC90402, MGC126674, MGC126676, DKFZP586C1324
Ensembl gene	ENSG00000157837
Ensembl biotype	protein_coding
OMIM	608240
Entrez	121665

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 12 protein_coding, 3 retained_intron

ENST00000353487, ENST00000392495, ENST00000534966, ENST00000536996, ENST00000540091, ENST00000543181, ENST00000543608, ENST00000543854, ENST00000545209, ENST00000855477, ENST00000855478, ENST00000913320, ENST00000961959, ENST00000961960, ENST00000961961

RefSeq mRNA: 1 — MANE Select: NM_139015 NM_139015

CCDS: CCDS9208

Canonical transcript exons

ENST00000353487 — 11 exons

Exon	Start	End
ENSE00001126822	120768953	120769059
ENSE00001126827	120782655	120782767
ENSE00001126834	120783674	120783752
ENSE00001302552	120762510	120765070
ENSE00001398401	120903845	120904358
ENSE00003493948	120767394	120767593
ENSE00003495466	120768325	120768488
ENSE00003535576	120791469	120791557
ENSE00003570557	120810809	120810886
ENSE00003658298	120766263	120766372
ENSE00003788400	120784474	120784593

Expression profiles

Bgee: expression breadth ubiquitous, 256 present calls, max score 98.61.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 31.6367 / max 159.6841, expressed in 1815 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
133679	14.6666	1801
133677	10.8390	1785
133674	2.0541	998
133678	1.8575	1330
133680	1.7376	1182
133676	0.2964	146
133675	0.1855	63

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
upper arm skin	UBERON:0004263	98.61	gold quality
skin of leg	UBERON:0001511	96.58	gold quality
ileal mucosa	UBERON:0000331	96.41	gold quality
nipple	UBERON:0002030	96.40	gold quality
zone of skin	UBERON:0000014	96.27	gold quality
skin of abdomen	UBERON:0001416	96.27	gold quality
upper leg skin	UBERON:0004262	96.20	gold quality
skin of hip	UBERON:0001554	95.52	gold quality
cortical plate	UBERON:0005343	95.38	gold quality
secondary oocyte	CL:0000655	95.34	gold quality
esophagus mucosa	UBERON:0002469	95.14	gold quality
penis	UBERON:0000989	94.99	gold quality
left testis	UBERON:0004533	94.87	gold quality
pancreatic ductal cell	CL:0002079	94.72	gold quality
cerebellar vermis	UBERON:0004720	94.55	gold quality
mammalian vulva	UBERON:0000997	94.53	gold quality
postcentral gyrus	UBERON:0002581	94.53	gold quality
right testis	UBERON:0004534	94.46	gold quality
parietal lobe	UBERON:0001872	94.29	gold quality
vagina	UBERON:0000996	94.19	gold quality
smooth muscle tissue	UBERON:0001135	94.00	gold quality
trigeminal ganglion	UBERON:0001675	93.95	gold quality
inferior vagus X ganglion	UBERON:0005363	93.83	gold quality
testis	UBERON:0000473	93.80	gold quality
dorsal root ganglion	UBERON:0000044	93.71	gold quality
ganglionic eminence	UBERON:0004023	93.63	gold quality
ectocervix	UBERON:0012249	93.62	gold quality
medulla oblongata	UBERON:0001896	93.53	gold quality
superior vestibular nucleus	UBERON:0007227	93.44	gold quality
corpus callosum	UBERON:0002336	93.37	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.81

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

150 targeting SPPL3, 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-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-7152-3P	99.97	67.47	849
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-381-3P	99.93	71.87	2854
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-300	99.92	71.76	2856
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-7-1-3P	99.91	71.53	4384

Literature-anchored findings (GeneRIF, showing 13)

• 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)
• SPPL3 cleaves a SPP substrate, but a more distantly related homologue SPPL2b does not, providing strong evidence that the malaria SPP and human SPPL3 have conserved active sites, while the active sites SPPL2b is distinct (PMID:16873890)
• human SPPL3 is the first GxGD-type aspartyl protease shown to be capable of acting like a sheddase, similar to members of the rhomboid family, which belong to the class of intramembrane-cleaving serine proteases. (PMID:23132852)
• Authors demonstrate that SPPL3 alters the pattern of cellular N-glycosylation by triggering the proteolytic release of active site-containing ectodomains of glycosidases and glycosyltransferases. (PMID:25354954)
• SPPL3 cleaves Golgi type II membrane proteins leading to their secretion. SPPL3 substrates include Golgi glycosyltransferases MGAT5, B4GALT1, and B3GNT1. By facilitating disengagement of these glycosyltransferases from their membrane anchors, SPPL3 causes their premature secretion and consequently orchestrates the extent of N-glycosylation on human and murine cells. (PMID:25354954)
• SPPL3 enhances the signal-induced association of stromal interaction molecule 1 (PMID:25384971)
• SPPL3 substrates identified on a proteome-wide scale in human and murine cells include numerous glycan-modifying enzymes residing in the Golgi network and implicated in distinct glycosylation pathways, including N-glycosylation, mucin-type O-glycosylation, O-mannosylation and glycosaminoglycan biosynthesis. (PMID:25827571)
• Secretome analysis identifies novel signal Peptide peptidase-like 3 substrates and reveals a role of Sppl3 in multiple Golgi glycosylation pathways (PMID:25827571)
• Data suggest that activation of the metalloproteinase ADAM10 by signal peptide peptidase-like 3 (SPPL3) triggered by mutant BRAF(V600E) was a critical transformation event. (PMID:28292959)
• The SPPL3-Defined Glycosphingolipid Repertoire Orchestrates HLA Class I-Mediated Immune Responses. (PMID:33271119)
• SPPL3-dependent downregulation of the synthesis of (neo)lacto-series glycosphingolipid is required for the staining of cell surface CD59. (PMID:34303967)
• N-terminome analyses underscore the prevalence of SPPL3-mediated intramembrane proteolysis among Golgi-resident enzymes and its role in Golgi enzyme secretion. (PMID:35279766)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	sppl3	ENSDARG00000025220
mus_musculus	Sppl3	ENSMUSG00000029550
rattus_norvegicus	Sppl3	ENSRNOG00000001178
drosophila_melanogaster	SppL	FBGN0039381

Paralogs (4): SPPL2B (ENSG00000005206), HM13 (ENSG00000101294), SPPL2A (ENSG00000138600), SPPL2C (ENSG00000185294)

Protein

Protein identifiers

Signal peptide peptidase-like 3 — Q8TCT6 (reviewed: Q8TCT6)

Alternative names: Intramembrane protease 2, Presenilin homologous protein 1, Presenilin-like protein 4

All UniProt accessions (6): Q8TCT6, F5H2A2, F5H4L1, F5H4Y6, F5H6I1, F5H7J2

UniProt curated annotations — full annotation on UniProt →

Function. Intramembrane-cleaving aspartic protease (I-CLiP) that cleaves type II membrane protein substrates in or close to their luminal transmembrane domain boundaries. Acts like a sheddase by mediating the proteolytic release and secretion of active site-containing ectodomains of glycan-modifiying glycosidase and glycosyltransferase enzymes such as MGAT5, B4GAT1 and B4GALT1. Catalyzes the intramembrane cleavage of the envelope glycoprotein gp130 and/or the leader peptide gp18LP of the simian foamy virus independent of prior ectodomain shedding by furin or furin-like proprotein convertase (PC)-mediated cleavage proteolysis. May also have the ability to serve as a shedding protease for subsequent intramembrane proteolysis by SPPL2A and SPPL2B of the envelope glycoprotein gp130. Plays a role in the regulation of cellular glycosylation processes. Required to link T-cell antigen receptor (TCR) and calcineurin-NFAT signaling cascades in lymphocytes by promoting the association of STIM1 and ORAI1 during store-operated calcium entry (SOCE) in a protease-independent manner.

Subunit / interactions. Monomer. Homodimer. Interacts with STIM1 (via the transmembrane region and the SOAR/CAD domain); the interaction promotes the binding of STIM1 to ORAI1. Interacts with the simian foamy virus envelope glycoprotein gp130 and its processed leader peptide gp18LP; preferentially interacts with the envelope glycoprotein gp130.

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

Tissue specificity. Widely expressed. Expressed in the brain.

Post-translational modifications. Not glycosylated.

Activity regulation. Its proteolytic activity is blocked by a signal peptide peptidase (SPP) inhibitor, (ZLL)2-ketone (ZLL) or a gamma-secretase inhibitor, LY411,575. However, is not inhibited by ZLL and LY411,575 for activity on simian foamy virus envelope glycoprotein gp130.

Domain organisation. The first transmembrane domain may act as a type I signal anchor. The catalytic loops is exposed toward the lumen. 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.

Similarity. Belongs to the peptidase A22B family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8TCT6-2	2	yes
Q8TCT6-3	3

RefSeq proteins (1): NP_620584* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006639	Preselin/SPP	Family
IPR007369	Peptidase_A22B_SPP	Family

Pfam: PF04258

UniProt features (28 total): topological domain 10, transmembrane region 9, active site 2, mutagenesis site 2, sequence conflict 2, chain 1, short sequence motif 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8TCT6-F1	78.39	0.33

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): 200; 271

Mutagenesis-validated functional residues (2):

Position	Phenotype
200	does not affect complex glycosylation pattern of cellular glycoproteins; when associated with a-271.
271	loss of intramembrane-cleaving activity toward the simian foamy virus envelope glycoprotein gp130. does not affect compl

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 184 (showing top): GOBP_REGULATION_OF_CALCIUM_MEDIATED_SIGNALING, GOBP_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, CAGCTG_AP4_Q5, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_POSITIVE_REGULATION_OF_CALCIUM_MEDIATED_SIGNALING, SCHAEFFER_PROSTATE_DEVELOPMENT_6HR_DN, GOCC_GOLGI_ASSOCIATED_VESICLE, GOBP_T_CELL_RECEPTOR_SIGNALING_PATHWAY, GOBP_POSITIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, GOBP_MEMBRANE_PROTEIN_ECTODOMAIN_PROTEOLYSIS, USF_02, GOBP_MEMBRANE_PROTEIN_PROTEOLYSIS, GTGACTT_MIR224, GOCC_CYTOPLASMIC_SIDE_OF_MEMBRANE

GO Biological Process (6): obsolete signal peptide processing (GO:0006465), positive regulation of cytosolic calcium ion concentration (GO:0007204), membrane protein proteolysis (GO:0033619), T cell receptor signaling pathway (GO:0050852), positive regulation of calcineurin-NFAT signaling cascade (GO:0070886), 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 (11): rough endoplasmic reticulum (GO:0005791), Golgi apparatus (GO:0005794), plasma membrane (GO:0005886), membrane (GO:0016020), Golgi-associated vesicle membrane (GO:0030660), endoplasmic reticulum-Golgi intermediate compartment membrane (GO:0033116), lumenal side of endoplasmic reticulum membrane (GO:0098553), cytoplasmic side of endoplasmic reticulum membrane (GO:0098554), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), endomembrane system (GO:0012505)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	2
endomembrane system	2
intracellular membrane-bounded organelle	2
cellular anatomical structure	2
bounding membrane of organelle	2
endoplasmic reticulum membrane	2
regulation of biological quality	1
proteolysis	1
antigen receptor-mediated signaling pathway	1
calcineurin-NFAT signaling cascade	1
regulation of calcineurin-NFAT signaling cascade	1
positive regulation of calcineurin-mediated signaling	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
endoplasmic reticulum	1
membrane	1
cell periphery	1
Golgi-associated vesicle	1
cytoplasmic vesicle membrane	1
endoplasmic reticulum-Golgi intermediate compartment	1
lumenal side of membrane	1
cytoplasmic side of membrane	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
vacuole	1
plasma membrane	1

Protein interactions and networks

STRING

1018 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SPPL3	HM13	Q8TCT9	593
SPPL3	B3GNT2	Q9NY97	564
SPPL3	RNF126	Q9BV68	493
SPPL3	NEDD4L	Q96PU5	434
SPPL3	LHPP	Q9H008	434
SPPL3	MAN1A2	O60476	433
SPPL3	CENPA	P49450	433
SPPL3	NAGPA	Q9UK23	432
SPPL3	MGAT5	Q09328	416
SPPL3	TTC19	Q6DKK2	415
SPPL3	APIP	Q96GX9	415
SPPL3	B3GNT5	Q9BYG0	407
SPPL3	OLFM4	Q6UX06	405
SPPL3	PIGY	Q3MUY2	404
SPPL3	SLC35A1	P78382	402
SPPL3	PSENEN	Q9NZ42	402

IntAct

57 interactions, top by confidence:

A	B	Type	Score
NIPAL1	ESYT2	psi-mi:“MI:0914”(association)	0.640
SLC1A1	AGPAT2	psi-mi:“MI:0914”(association)	0.640
YIPF3	TMEM120B	psi-mi:“MI:0914”(association)	0.530
C3AR1	TMEM120B	psi-mi:“MI:0914”(association)	0.530
ADGRG5	KLRG2	psi-mi:“MI:0914”(association)	0.530
SLC15A1	METTL15	psi-mi:“MI:0914”(association)	0.530
SLC2A12	METTL15	psi-mi:“MI:0914”(association)	0.530
PDCD1	RTL8C	psi-mi:“MI:0914”(association)	0.530
SLC1A5	GPR89A	psi-mi:“MI:0914”(association)	0.530
SLC22A9	GPR89A	psi-mi:“MI:0914”(association)	0.530
CHRND	TPST2	psi-mi:“MI:0914”(association)	0.530
SLC9A8	ZNF432	psi-mi:“MI:0914”(association)	0.530
SLC22A16	APBA3	psi-mi:“MI:0914”(association)	0.530
TMED10	PGRMC1	psi-mi:“MI:0914”(association)	0.350
CHRNA4	TMEM223	psi-mi:“MI:0914”(association)	0.350
CRELD1	TMEM223	psi-mi:“MI:0914”(association)	0.350
AVPR2	GXYLT2	psi-mi:“MI:0914”(association)	0.350
SLC7A14	TMEM120B	psi-mi:“MI:0914”(association)	0.350
GPR17	TMEM120B	psi-mi:“MI:0914”(association)	0.350
EMC1	TMEM120B	psi-mi:“MI:0914”(association)	0.350
CHRNB2	TMEM131L	psi-mi:“MI:0914”(association)	0.350
TSPAN10	KLRG2	psi-mi:“MI:0914”(association)	0.350
P2RY10	POTEF	psi-mi:“MI:0914”(association)	0.350
C5AR1	TCAF2	psi-mi:“MI:0914”(association)	0.350
GPR182	METTL15	psi-mi:“MI:0914”(association)	0.350
OPRL1	METTL15	psi-mi:“MI:0914”(association)	0.350
DGCR2	CCDC85C	psi-mi:“MI:0914”(association)	0.350
SLC22A4	RTL8C	psi-mi:“MI:0914”(association)	0.350
TMEM59	GPR89A	psi-mi:“MI:0914”(association)	0.350
CCR6	GPR89A	psi-mi:“MI:0914”(association)	0.350

BioGRID (908): SPPL3 (Affinity Capture-MS), SPPL3 (Affinity Capture-MS), SPPL3 (Affinity Capture-MS), SPPL3 (Affinity Capture-MS), SPPL3 (Affinity Capture-MS), SPPL3 (Affinity Capture-MS), SPPL3 (Affinity Capture-MS), SPPL3 (Affinity Capture-MS), SPPL3 (Affinity Capture-MS), SPPL3 (Affinity Capture-MS), SPPL3 (Affinity Capture-MS), SPPL3 (Affinity Capture-MS), SPPL3 (Affinity Capture-MS), SPPL3 (Affinity Capture-MS), SPPL3 (Affinity Capture-MS)

ESM2 similar proteins: A2AF53, A4FV75, A5A6S6, A6ZIQ8, B8AT51, D3ZEH5, O60337, Q08DE2, Q0JAW2, Q0VC58, Q15005, Q28250, Q2TBU2, Q2V4F9, Q3TMP8, Q4R512, Q4R5B4, Q58DA4, Q5JZQ8, Q5M8Y1, Q5R8H8, Q5R9W1, Q5RAY6, Q5REE3, Q5RF53, Q5XIK2, Q5ZK43, Q6GLK9, Q6P2T0, Q6P8F8, Q6ZQ89, Q7SYC7, Q7ZY07, Q80YV4, Q8CIF6, Q8NBJ9, Q8NFB2, Q8R3R5, Q8TCT6, Q8VIJ8

Diamond homologs: A2A6C4, B9FJ61, O81062, P49049, Q3TD49, Q5F383, Q5PQL3, Q6ZGL9, Q8IUH8, Q8TCT6, Q8TCT7, Q8TCT8, Q9CUS9, Q9JJF9, Q9UTA3, O22925, O80977, P25152, P34248, Q02PA2, Q0DWA9, Q0WMJ8, Q2HXL6, Q4V3B8, Q53P98, Q56ZQ3, Q5N808, Q5Z413, Q6GQB9, Q8L7E3, Q8W469, Q9BZQ6, Q9HZQ8, Q9MA44, Q9BSG0, Q9D9N8, Q9W1W9, Q7G7C7, Q8TCT9, Q9D8V0

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 84 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
R-HSA-425366	5	17.1×	5e-04
SLC-mediated transmembrane transport	10	11.2×	2e-06
Transport of small molecules	10	4.8×	8e-04

GO biological processes:

GO term	Partners	Fold	FDR
monoatomic ion transport	6	12.0×	3e-03
chemical synaptic transmission	7	6.9×	6e-03
G protein-coupled receptor signaling pathway	11	5.1×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	22
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2582 predictions. Top by Δscore:

Variant	Effect	Δscore
12:120767390:TTACC:T	donor_loss	1.0000
12:120767391:TA:T	donor_loss	1.0000
12:120767393:C:CT	donor_loss	1.0000
12:120767393:CCTA:C	donor_gain	1.0000
12:120767594:C:CC	acceptor_gain	1.0000
12:120768319:TCTTA:T	donor_loss	1.0000
12:120768320:CTTAC:C	donor_loss	1.0000
12:120768321:TTA:T	donor_loss	1.0000
12:120768322:TA:T	donor_loss	1.0000
12:120768323:A:T	donor_loss	1.0000
12:120768489:CT:C	acceptor_loss	1.0000
12:120782648:CACT:C	donor_loss	1.0000
12:120782649:ACTC:A	donor_loss	1.0000
12:120782650:CTCA:C	donor_loss	1.0000
12:120782651:T:TC	donor_loss	1.0000
12:120782652:C:CG	donor_loss	1.0000
12:120782654:C:T	donor_loss	1.0000
12:120783672:A:AC	donor_gain	1.0000
12:120783673:C:CC	donor_gain	1.0000
12:120783753:C:CC	acceptor_gain	1.0000
12:120784590:ATGCC:A	acceptor_loss	1.0000
12:120784591:TGC:T	acceptor_gain	1.0000
12:120784591:TGCC:T	acceptor_loss	1.0000
12:120784592:GCC:G	acceptor_loss	1.0000
12:120784593:CCT:C	acceptor_loss	1.0000
12:120784595:T:G	acceptor_loss	1.0000
12:120791467:A:AC	donor_gain	1.0000
12:120791468:C:CA	donor_gain	1.0000
12:120791468:CT:C	donor_gain	1.0000
12:120791468:CTA:C	donor_gain	1.0000

AlphaMissense

2509 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:120765052:A:G	W368R	1.000
12:120765052:A:T	W368R	1.000
12:120765054:A:G	M367T	1.000
12:120766273:G:T	A358D	1.000
12:120766285:A:T	L354H	1.000
12:120766288:G:C	P353R	1.000
12:120766288:G:T	P353Q	1.000
12:120766303:G:C	P348R	1.000
12:120766303:G:T	P348Q	1.000
12:120766309:A:C	L346W	1.000
12:120766309:A:G	L346S	1.000
12:120766315:A:G	L344P	1.000
12:120766315:A:T	L344H	1.000
12:120766318:A:G	L343P	1.000
12:120766318:A:T	L343H	1.000
12:120766321:G:T	A342D	1.000
12:120766324:G:A	P341L	1.000
12:120766324:G:C	P341R	1.000
12:120766324:G:T	P341H	1.000
12:120766325:G:A	P341S	1.000
12:120766325:G:T	P341T	1.000
12:120766360:G:T	A329D	1.000
12:120766361:C:G	A329P	1.000
12:120766369:A:G	L326P	1.000
12:120766372:C:A	G325V	1.000
12:120766372:C:T	G325D	1.000
12:120767394:C:A	G325C	1.000
12:120767394:C:G	G325R	1.000
12:120767403:A:G	Y322H	1.000
12:120767405:C:A	G321V	1.000

dbSNP variants (sampled 300 via entrez): RS1000061871 (12:120876292 G>T), RS1000101528 (12:120838422 G>A), RS1000137310 (12:120773023 G>C), RS1000148568 (12:120809013 G>A), RS1000150823 (12:120812536 C>A,T), RS1000177205 (12:120814205 A>G), RS1000287319 (12:120820781 G>C), RS1000295887 (12:120784346 G>A,C), RS1000321952 (12:120841760 T>C), RS1000353856 (12:120847917 C>T), RS1000363440 (12:120859616 G>A), RS1000377077 (12:120806520 A>T), RS1000418957 (12:120905194 C>A,T), RS1000454125 (12:120770590 G>A), RS1000477370 (12:120861200 A>C,G)

Disease associations

OMIM: gene MIM:608240 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

38 associations (top):

Study	Trait	p-value
GCST000337_10	Quantitative traits	5.000000e-06
GCST004628_54	Immature fraction of reticulocytes	7.000000e-20
GCST004867_19	Systemic lupus erythematosus	8.000000e-07
GCST005038_80	Allergic disease (asthma, hay fever or eczema)	2.000000e-15
GCST005312_3	Menopause (age at onset)	4.000000e-08
GCST005650_3	Serum metabolite ratios in chronic kidney disease	3.000000e-40
GCST006041_24	Major depressive disorder	2.000000e-07
GCST006249_31	Serum metabolite levels	3.000000e-45
GCST006409_12	Allergic rhinitis	4.000000e-11
GCST007797_49	Asthma onset (childhood vs adult)	2.000000e-06
GCST007798_152	Asthma	6.000000e-11
GCST007800_74	Asthma (childhood onset)	2.000000e-20
GCST007994_11	Asthma (age of onset)	7.000000e-07
GCST007995_37	Asthma (childhood onset)	1.000000e-11
GCST008156_97	Hip circumference adjusted for BMI	7.000000e-06
GCST008916_76	Asthma	3.000000e-08
GCST009600_128	Anorexia nervosa, attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, or Tourette syndrome (pleiotropy)	5.000000e-08
GCST009600_52	Anorexia nervosa, attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, or Tourette syndrome (pleiotropy)	4.000000e-08
GCST010002_176	Refractive error	8.000000e-11
GCST010042_5	Asthma	2.000000e-11
GCST010043_62	Asthma	2.000000e-15
GCST010984_33	Allergic disease (asthma, hay fever and/or eczema) (multivariate analysis)	4.000000e-11
GCST010985_44	Allergic disease (asthma, hay fever and/or eczema) (age of onset)	2.000000e-11
GCST011703_12	Smoking initiation	6.000000e-09
GCST012020_190	Serum metabolite levels	8.000000e-11
GCST012020_328	Serum metabolite levels	9.000000e-54
GCST012020_329	Serum metabolite levels	4.000000e-184
GCST012020_330	Serum metabolite levels	1.000000e-53
GCST012020_331	Serum metabolite levels	1.000000e-65
GCST012020_376	Serum metabolite levels	4.000000e-13

EFO canonical traits (11, from GWAS)

EFO ID	Trait name
EFO:0004458	C-reactive protein measurement
EFO:0007986	reticulocyte count
EFO:0004704	age at menopause
EFO:0004847	age at onset
EFO:0008039	BMI-adjusted hip circumference
EFO:0005670	smoking initiation
EFO:0004980	appendicular lean mass
EFO:0004842	eosinophil count
EFO:0007991	eosinophil percentage of leukocytes
EFO:0007989	monocyte percentage of leukocytes
EFO:0004736	aspartate aminotransferase measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
aristolochic acid I	decreases expression	1
bisphenol F	affects cotreatment, decreases expression	1
beta-lapachone	increases expression	1
sodium arsenite	increases expression	1
butyraldehyde	decreases expression	1
benzo(e)pyrene	increases methylation	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
Sunitinib	increases expression	1
Benzo(a)pyrene	increases methylation	1
Carbamazepine	affects expression	1
Dexamethasone	affects cotreatment, decreases expression	1
Doxorubicin	decreases expression	1
Indomethacin	affects cotreatment, decreases expression	1
Methapyrilene	increases methylation	1
Testosterone	decreases expression	1
Dronabinol	increases expression	1
Urethane	increases expression	1
Valproic Acid	affects expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, decreases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	1

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D9SX	Ubigene HEK293 SPPL3 KO	Transformed cell line	Female

Clinical trials (associated diseases)

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