SPPL2C

Summary

SPPL2C (signal peptide peptidase like 2C, HGNC:28902) is a protein-coding gene on chromosome 17q21.31, encoding Signal peptide peptidase-like 2C (Q8IUH8). Sperm-specific intramembrane-cleaving aspartic protease (I-CLiP) that cleaves distinct tail-anchored proteins and SNARE proteins.

Enables protein homodimerization activity. Predicted to be involved in several processes, including acrosome assembly; fusion of sperm to egg plasma membrane involved in single fertilization; and membrane protein intracellular domain proteolysis. Located in cytoplasmic side of endoplasmic reticulum membrane and lumenal side of endoplasmic reticulum membrane.

Source: NCBI Gene 162540 — RefSeq curated summary.

At a glance

• GWAS associations: 16
• MANE Select transcript: NM_175882

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28902
Approved symbol	SPPL2C
Name	signal peptide peptidase like 2C
Location	17q21.31
Locus type	gene with protein product
Status	Approved
Aliases	IMP5
Ensembl gene	ENSG00000185294
Ensembl biotype	protein_coding
OMIM	608284
Entrez	162540

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000329196

RefSeq mRNA: 1 — MANE Select: NM_175882 NM_175882

CCDS: CCDS32673

Canonical transcript exons

ENST00000329196 — 1 exons

Exon	Start	End
ENSE00002385813	45844881	45847067

Expression profiles

Bgee: expression breadth broad, 32 present calls, max score 88.00.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0857 / max 84.8040, expressed in 4 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
161303	0.0857	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right testis	UBERON:0004534	88.00	gold quality
left testis	UBERON:0004533	87.18	gold quality
testis	UBERON:0000473	86.65	gold quality
cerebellum	UBERON:0002037	59.90	gold quality
cerebellar cortex	UBERON:0002129	59.73	gold quality
cerebellar hemisphere	UBERON:0002245	59.66	gold quality
right hemisphere of cerebellum	UBERON:0014890	58.32	gold quality
prefrontal cortex	UBERON:0000451	48.18	gold quality
ganglionic eminence	UBERON:0004023	47.48	gold quality
superior frontal gyrus	UBERON:0002661	46.75	silver quality
frontal cortex	UBERON:0001870	46.55	gold quality
primary visual cortex	UBERON:0002436	45.48	silver quality
right frontal lobe	UBERON:0002810	44.18	gold quality
cerebral cortex	UBERON:0000956	43.32	gold quality
brain	UBERON:0000955	42.57	gold quality
Brodmann (1909) area 9	UBERON:0013540	42.34	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	41.93	gold quality
anterior cingulate cortex	UBERON:0009835	41.25	silver quality
pituitary gland	UBERON:0000007	41.11	gold quality
temporal lobe	UBERON:0001871	40.80	gold quality
amygdala	UBERON:0001876	40.61	gold quality
adenohypophysis	UBERON:0002196	39.73	gold quality
Ammon’s horn	UBERON:0001954	38.94	silver quality
colonic epithelium	UBERON:0000397	37.20	gold quality
sural nerve	UBERON:0015488	36.62	gold quality
ventricular zone	UBERON:0003053	36.48	gold quality
bone marrow cell	CL:0002092	36.16	gold quality
hindlimb stylopod muscle	UBERON:0004252	35.50	gold quality
skeletal muscle tissue	UBERON:0001134	34.75	gold quality
right coronary artery	UBERON:0001625	34.39	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.04

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

12 targeting SPPL2C, 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-4753-3P	99.90	71.03	3786
HSA-MIR-130B-5P	99.83	68.50	1888
HSA-MIR-578	99.46	68.36	1787
HSA-MIR-130A-5P	99.33	70.26	2623
HSA-MIR-3194-3P	98.83	66.22	1167
HSA-MIR-5691	98.23	67.02	1335
HSA-MIR-6805-3P	98.23	67.02	1334
HSA-MIR-4659B-5P	98.03	66.84	979
HSA-MIR-4659A-5P	98.03	66.42	819
HSA-MIR-744-3P	97.99	67.76	637
HSA-MIR-3132	97.96	67.91	711
HSA-MIR-197-5P	97.23	68.10	596

Literature-anchored findings (GeneRIF, showing 4)

• SPP, SPPL2a, -2b, -2c, and -3 probably cleave type II-oriented substrate peptides as shown by consensus analysis [SPPL2c] (PMID:15385547)
• the sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA2)-regulating protein phospholamban (PLN) is identified as a physiological SPPL2c substrate. (PMID:30733280)
• These data suggest involvement of SPPL2c in acrosome formation during spermatogenesis. (PMID:30733281)
• Exome-wide age-of-onset analysis reveals exonic variants in ERN1 and SPPL2C associated with Alzheimer’s disease. (PMID:33637690)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Sppl2c	ENSMUSG00000049506
rattus_norvegicus	Sppl2c	ENSRNOG00000005104

Paralogs (4): SPPL2B (ENSG00000005206), HM13 (ENSG00000101294), SPPL2A (ENSG00000138600), SPPL3 (ENSG00000157837)

Protein

Protein identifiers

Signal peptide peptidase-like 2C — Q8IUH8 (reviewed: Q8IUH8)

Alternative names: Intramembrane protease 5

All UniProt accessions (1): Q8IUH8

UniProt curated annotations — full annotation on UniProt →

Function. Sperm-specific intramembrane-cleaving aspartic protease (I-CLiP) that cleaves distinct tail-anchored proteins and SNARE proteins. In elongated spermatids, modulates intracellular Ca(2+) homeostasis by controlling PLN abundance through proteolytic cleavage. During spermatogenesis, processes SNARE proteins and impacts vesicular trafficking which supports compartmental reorganization in maturating spermatids and may play a role in formation of the acrosome. In round spermatids, acts as a scaffold protein supporting FREY1 in IZUMO1 recruitment at the endoplasmic reticulum membrane and coordination of IZUMO1 complex assembly. Stabilizes FREY1 at the endoplasmic reticulum membrane through interaction. May recruit IZUMO1 interaction partners.

Subunit / interactions. Interacts (via active sites) with FREY; the interaction stabilizes FREY1 protein and inhibits SPPL2C proteolytic activity.

Subcellular location. Endoplasmic reticulum membrane.

Tissue specificity. Highly expressed in testis where it is primarily localised in spermatids (at protein level).

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.

RefSeq proteins (1): NP_787078* (*=MANE)

Domains & families (InterPro)

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

Pfam: PF02225, PF04258

Enzyme classification (BRENDA):

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

UniProt features (41 total): topological domain 10, transmembrane region 9, sequence variant 9, compositionally biased region 3, region of interest 2, active site 2, signal peptide 1, chain 1, domain 1, short sequence motif 1, glycosylation site 1, mutagenesis site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IUH8-F1	67.63	0.25

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): 386; 448

Glycosylation sites (1): 100

Mutagenesis-validated functional residues (1):

Position	Phenotype
448	loss of aspartyl protease activity.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 69 (showing top): GOBP_SINGLE_FERTILIZATION, GOCC_VACUOLAR_MEMBRANE, GOBP_VESICLE_ORGANIZATION, GOBP_MEMBRANE_FUSION, GOBP_PLASMA_MEMBRANE_ORGANIZATION, GOBP_MALE_GAMETE_GENERATION, GOBP_SECRETORY_GRANULE_ORGANIZATION, GOBP_CELLULAR_COMPONENT_ASSEMBLY_INVOLVED_IN_MORPHOGENESIS, GOBP_PROTEIN_STABILIZATION, GOBP_SPERM_EGG_RECOGNITION, GOBP_ACROSOME_ASSEMBLY, GOCC_GOLGI_ASSOCIATED_VESICLE, GOBP_ORGANELLE_ASSEMBLY, GOBP_MEMBRANE_PROTEIN_INTRACELLULAR_DOMAIN_PROTEOLYSIS, GOBP_CELLULAR_PROCESS_INVOLVED_IN_REPRODUCTION_IN_MULTICELLULAR_ORGANISM

GO Biological Process (11): acrosome assembly (GO:0001675), intracellular calcium ion homeostasis (GO:0006874), fusion of sperm to egg plasma membrane involved in single fertilization (GO:0007342), membrane protein proteolysis (GO:0033619), sperm-egg recognition (GO:0035036), maintenance of protein localization in endoplasmic reticulum (GO:0035437), protein stabilization (GO:0050821), protein localization involved in acrosome reaction (GO:0060476), protein-containing complex assembly (GO:0065003), proteolysis (GO:0006508), spermatogenesis (GO:0007283)

GO Molecular Function (7): aspartic endopeptidase activity, intramembrane cleaving (GO:0042500), protein homodimerization activity (GO:0042803), molecular adaptor activity (GO:0060090), aspartic-type endopeptidase activity (GO:0004190), protein binding (GO:0005515), peptidase activity (GO:0008233), hydrolase activity (GO:0016787)

GO Cellular Component (7): lysosomal membrane (GO:0005765), endoplasmic reticulum membrane (GO:0005789), Golgi-associated vesicle membrane (GO:0030660), lumenal side of endoplasmic reticulum membrane (GO:0098553), cytoplasmic side of endoplasmic reticulum membrane (GO:0098554), endoplasmic reticulum (GO:0005783), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
developmental process involved in reproduction	2
cellular process involved in reproduction in multicellular organism	2
single fertilization	2
binding	2
endoplasmic reticulum membrane	2
spermatid development	1
cellular component assembly involved in morphogenesis	1
secretory granule organization	1
organelle assembly	1
intracellular monoatomic cation homeostasis	1
calcium ion homeostasis	1
proteolysis	1
cell-cell recognition	1
endoplasmic reticulum	1
protein localization to endoplasmic reticulum	1
maintenance of protein localization in organelle	1
regulation of protein stability	1
acrosome reaction	1
intracellular protein localization	1
actin filament-based process	1
cellular component assembly	1
protein-containing complex organization	1
protein metabolic process	1
male gamete generation	1
aspartic-type endopeptidase activity	1
identical protein binding	1
protein dimerization activity	1
molecular_function	1
endopeptidase activity	1
aspartic-type peptidase activity	1
hydrolase activity	1
catalytic activity, acting on a protein	1
catalytic activity	1
lysosome	1
lytic vacuole membrane	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
Golgi-associated vesicle	1
cytoplasmic vesicle membrane	1

Protein interactions and networks

STRING

710 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SPPL2C	TOLLIP	Q9H0E2	635
SPPL2C	KANSL1	Q7Z3B3	630
SPPL2C	MDGA2	Q7Z553	576
SPPL2C	STH	Q8IWL8	575
SPPL2C	FAM13A	O94988	570
SPPL2C	STPG3	Q8N7X2	566
SPPL2C	SLFNL1	Q499Z3	547
SPPL2C	TEX36	Q5VZQ5	545
SPPL2C	ATP11A	P98196	544
SPPL2C	CRHR1	P34998	525
SPPL2C	MAPT	P10636	520
SPPL2C	DPP9	Q86TI2	519
SPPL2C	MUC5B	Q9HC84	506
SPPL2C	GLT6D1	Q7Z4J2	499
SPPL2C	ARL17B	I3L3L1	480

IntAct

8 interactions, top by confidence:

A	B	Type	Score
NOTCH2NLC	SPPL2C	psi-mi:“MI:0915”(physical association)	0.560
CYSRT1	SPPL2C	psi-mi:“MI:0915”(physical association)	0.560
MAGI1	CIT	psi-mi:“MI:0914”(association)	0.350
SPPL2C	NOTCH2NLC	psi-mi:“MI:0915”(physical association)	0.000
SPPL2C	CYSRT1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (4): CYSRT1 (Two-hybrid), NOTCH2NL (Two-hybrid), NBPF19 (Two-hybrid), SPPL2C (Affinity Capture-MS)

ESM2 similar proteins: A0A8C2M425, A1L1J9, A1L504, B0BNG2, D3ZBP4, F1MH07, O08984, O75908, O77759, O88496, O88908, P38435, P70606, Q07175, Q0P4Y8, Q32LM8, Q3U9G9, Q3UDW8, Q5KR61, Q5RF50, Q5RKL5, Q5T197, Q5T1A1, Q5ZKZ9, Q643R3, Q658P3, Q68CP4, Q6NVG1, Q767L9, Q7TNJ2, Q7TPN3, Q7TQM4, Q7ZWN0, Q8BKF1, Q8C3X8, Q8CI59, Q8IUH8, Q8IZY2, Q8R1J1, Q8TDZ2

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, P25152, Q2HXL6, Q6GQB9, Q9BZQ6

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

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

Top pathogenic / likely-pathogenic (0)

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

4429 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:45846440:A:C	S512R	0.989
17:45846442:C:A	S512R	0.989
17:45846442:C:G	S512R	0.989
17:45846290:T:C	F462L	0.979
17:45846292:T:A	F462L	0.979
17:45846292:T:G	F462L	0.979
17:45845759:T:C	F285L	0.975
17:45845761:T:A	F285L	0.975
17:45845761:T:G	F285L	0.975
17:45845259:T:C	L118P	0.967
17:45846077:T:C	F391L	0.964
17:45846079:C:A	F391L	0.964
17:45846079:C:G	F391L	0.964
17:45846283:T:G	C459W	0.964
17:45846294:A:T	D463V	0.964
17:45846453:C:A	A516D	0.963
17:45845426:G:C	A174P	0.962
17:45846425:A:C	S507R	0.957
17:45846427:C:A	S507R	0.957
17:45846427:C:G	S507R	0.957
17:45846264:G:A	G453D	0.956
17:45846261:C:A	P452H	0.954
17:45846357:T:C	L484P	0.954
17:45846273:T:A	V456D	0.952
17:45845984:T:C	C360R	0.951
17:45845262:T:C	L119P	0.944
17:45846480:T:C	F525S	0.943
17:45845235:C:A	A110D	0.942
17:45846110:A:C	S402R	0.942
17:45846112:C:A	S402R	0.942

dbSNP variants (sampled 300 via entrez): RS1000006319 (17:45844010 C>G,T), RS1000748758 (17:45846673 T>A,C), RS1002268192 (17:45844526 A>G), RS1003879828 (17:45844302 A>G), RS1004075082 (17:45843434 A>G), RS1005321468 (17:45844953 T>G), RS1006699397 (17:45847522 G>A), RS1006825921 (17:45844573 GA>G), RS1007207339 (17:45844280 C>T), RS1007718061 (17:45843581 T>G), RS1008183351 (17:45843910 A>C), RS1008370232 (17:45846623 G>A,C), RS1008912016 (17:45843249 T>G), RS1009784919 (17:45843062 G>A,C), RS1010234292 (17:45846371 A>G)

Disease associations

OMIM: gene MIM:608284 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

16 associations (top):

Study	Trait	p-value
GCST000567_1	Parkinson’s disease	6.000000e-08
GCST001974_3	Idiopathic pulmonary fibrosis	6.000000e-09
GCST004601_146	Red blood cell count	3.000000e-36
GCST004902_11	Parkinson’s disease	1.000000e-68
GCST005232_131	Neuroticism	8.000000e-26
GCST005830_31	Hand grip strength	2.000000e-08
GCST006661_281	Male-pattern baldness	8.000000e-29
GCST006716_14	Alcohol use disorder (total score)	5.000000e-10
GCST007692_3	Chronic obstructive pulmonary disease	1.000000e-09
GCST010083_20	Hemoglobin levels	4.000000e-61
GCST010083_3	Hemoglobin levels	2.000000e-61
GCST010703_91	Brain morphology (MOSTest)	2.000000e-65
GCST011766_35	Chronic obstructive pulmonary disease	2.000000e-10
GCST012099_20	Hypertrophic cardiomyopathy (sarcomere negative)	2.000000e-09
GCST012101_8	Hypertrophic cardiomyopathy	4.000000e-12
GCST90020027_423	Waist-hip index	3.000000e-08

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0000768	idiopathic pulmonary fibrosis
EFO:0004305	erythrocyte count
EFO:0007660	neuroticism measurement
EFO:0006941	grip strength measurement
EFO:0009458	alcohol use disorder measurement
EFO:0004509	hemoglobin measurement
EFO:0004346	neuroimaging measurement
EFO:0007788	BMI-adjusted waist-hip ratio

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

5 total (human), top 5 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Resveratrol	affects cotreatment, decreases expression	1
Arsenic Trioxide	decreases expression	1
Carbamazepine	affects expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Valproic Acid	increases methylation	1

Clinical trials (associated diseases)

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