SPCS2

Summary

SPCS2 (signal peptidase complex subunit 2, HGNC:28962) is a protein-coding gene on chromosome 11q13.4, encoding Signal peptidase complex subunit 2 (Q15005). Component of the signal peptidase complex (SPC) which catalyzes the cleavage of N-terminal signal sequences from nascent proteins as they are translocated into the lumen of the endoplasmic reticulum. It is a common-essential gene (DepMap: required in 93.1% of cancer cell lines).

Predicted to enable peptidase activity. Involved in obsolete signal peptide processing. Located in endoplasmic reticulum membrane.

Source: NCBI Gene 9789 — automated summary from GO annotations (Alliance of Genome Resources).

At a glance

• Clinical variants (ClinVar): 21 total
• GTEx eGene: eQTL in 18 tissues, sQTL in 22 (q < 0.05)
• Cancer dependency (DepMap): dependent in 93.1% of screened cell lines (common-essential)
• Constraint (gnomAD): pLI 0.99 (loss-of-function intolerant), LOEUF 0.39 (moderately constrained)
• MANE Select transcript: NM_014752

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28962
Approved symbol	SPCS2
Name	signal peptidase complex subunit 2
Location	11q13.4
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0102
Ensembl gene	ENSG00000118363
Ensembl biotype	protein_coding
OMIM	619411
Entrez	9789

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 12 protein_coding, 6 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined, 1 retained_intron

MANE Select: ENST00000263672

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

ENST00000263672, ENST00000526361, ENST00000526883, ENST00000527225, ENST00000527290, ENST00000528265, ENST00000530257, ENST00000532972, ENST00000931771, ENST00000931772, ENST00000931773, ENST00000996990, ENST00001040957, ENST00001040962, ENST00001040969, ENST00001070790, ENST00001070795, ENST00001070796, ENST00001070797, ENST00001103729, ENST00001139995

RefSeq mRNA: 1 — MANE Select: NM_014752 NM_014752

CCDS: CCDS44681

Canonical transcript exons

ENST00000263672 — 5 exons

Exon	Start	End
ENSE00000797566	74965763	74965923
ENSE00000797570	74969565	74969699
ENSE00003582689	74965034	74965117
ENSE00003846827	74949266	74949399
ENSE00003847578	74976857	74979033

Expression profiles

Bgee: expression breadth ubiquitous, 205 present calls, max score 99.08.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 14.8380 / max 221.5980, expressed in 1805 samples.

Highest expression (Bgee): ventricular zone, body of pancreas, bone marrow cell, embryo, ganglionic eminence.

Genetic regulation across tissues (GTEx eQTL / sQTL)

SPCS2 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 18 tissues and its splicing (sQTL) in 22 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 40 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Lung	sqtl	1.4e-14	-0.43	11:74950065:T:A
Cells EBV-transformed lymphocytes	sqtl	1.8e-14	-0.71	11:74950890:G:T
Cells Cultured fibroblasts	sqtl	5.7e-12	-0.47	11:74957036:G:C
Spleen	sqtl	1.0e-10	+0.63	11:74949459:A:C
Nerve Tibial	sqtl	1.1e-10	-0.42	11:74950065:T:A
Adipose Subcutaneous	sqtl	1.2e-10	+0.45	11:74927964:A:T
Thyroid	sqtl	2.7e-10	+0.34	11:74762123:T:C
Colon Transverse	sqtl	4.0e-09	+0.45	11:75026512:T:C
Esophagus Mucosa	sqtl	7.5e-09	+0.43	11:74965467:G:T
Adipose Visceral Omentum	sqtl	2.7e-07	-0.35	11:74972738:C:T
Skin Not Sun Exposed Suprapubic	sqtl	1.1e-06	+0.37	11:74931205:C:T
Pancreas	sqtl	5.1e-06	+0.49	11:74917959:C:A
Whole Blood	eqtl	2.6e-05	+0.13	11:74984167:A:G
Adipose Subcutaneous	eqtl	2.7e-05	-0.21	11:75043243:G:A
Esophagus Mucosa	eqtl	2.8e-05	+0.13	11:74892136:G:A
Lung	eqtl	5.2e-05	-0.13	11:74855355:G:A
Heart Atrial Appendage	sqtl	5.9e-05	-0.40	11:74839911:A:G
Skin Sun Exposed Lower leg	eqtl	1.1e-04	+0.13	11:74948257:A:T
Thyroid	eqtl	1.3e-04	-0.11	11:75040223:C:A
Cells Cultured fibroblasts	eqtl	2.3e-04	+0.09	11:74914952:T:C

FANTOM5 promoters

1 alternative TSS:

Promoter ID	TPM avg	Samples expressed
115859	14.8380	1805

Top tissues by expression

showing 100 of 247 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	99.08	gold quality
body of pancreas	UBERON:0001150	99.03	gold quality
bone marrow cell	CL:0002092	98.94	gold quality
embryo	UBERON:0000922	98.94	gold quality
ganglionic eminence	UBERON:0004023	98.94	gold quality
vermiform appendix	UBERON:0001154	98.88	gold quality
cortical plate	UBERON:0005343	98.69	gold quality
endocervix	UBERON:0000458	98.57	gold quality
right lobe of thyroid gland	UBERON:0001119	98.57	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	98.57	gold quality
colonic epithelium	UBERON:0000397	98.52	gold quality
rectum	UBERON:0001052	98.51	gold quality
islet of Langerhans	UBERON:0000006	98.47	gold quality
left lobe of thyroid gland	UBERON:0001120	98.44	gold quality
left adrenal gland	UBERON:0001234	98.40	gold quality
left adrenal gland cortex	UBERON:0035825	98.38	gold quality
adenohypophysis	UBERON:0002196	98.37	gold quality
smooth muscle tissue	UBERON:0001135	98.35	gold quality
right adrenal gland	UBERON:0001233	98.32	gold quality
Brodmann (1909) area 9	UBERON:0013540	98.30	gold quality
right adrenal gland cortex	UBERON:0035827	98.20	gold quality
body of uterus	UBERON:0009853	98.18	gold quality
left uterine tube	UBERON:0001303	98.15	gold quality
minor salivary gland	UBERON:0001830	98.15	gold quality
ectocervix	UBERON:0012249	98.13	gold quality
upper lobe of left lung	UBERON:0008952	98.12	gold quality
stromal cell of endometrium	CL:0002255	98.07	gold quality
body of stomach	UBERON:0001161	98.04	gold quality
left coronary artery	UBERON:0001626	98.01	gold quality
thoracic aorta	UBERON:0001515	97.99	gold quality
ascending aorta	UBERON:0001496	97.98	gold quality
right ovary	UBERON:0002118	97.98	gold quality
anterior cingulate cortex	UBERON:0009835	97.98	gold quality
peripheral nervous system	UBERON:0000010	97.97	gold quality
tibial nerve	UBERON:0001323	97.97	gold quality
right coronary artery	UBERON:0001625	97.93	gold quality
descending thoracic aorta	UBERON:0002345	97.93	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	97.92	gold quality
right lung	UBERON:0002167	97.91	gold quality
gall bladder	UBERON:0002110	97.87	gold quality
left ovary	UBERON:0002119	97.87	gold quality
mucosa of transverse colon	UBERON:0004991	97.86	gold quality
popliteal artery	UBERON:0002250	97.79	gold quality
tibial artery	UBERON:0007610	97.79	gold quality
right lobe of liver	UBERON:0001114	97.77	gold quality
metanephros cortex	UBERON:0010533	97.76	gold quality
transverse colon	UBERON:0001157	97.71	gold quality
leukocyte	CL:0000738	97.66	gold quality
muscle layer of sigmoid colon	UBERON:0035805	97.65	gold quality
monocyte	CL:0000576	97.60	gold quality
aorta	UBERON:0000947	97.54	gold quality
right frontal lobe	UBERON:0002810	97.54	gold quality
calcaneal tendon	UBERON:0003701	97.54	gold quality
granulocyte	CL:0000094	97.48	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	97.47	gold quality
lower esophagus	UBERON:0013473	97.44	gold quality
lower esophagus muscularis layer	UBERON:0035833	97.44	gold quality
right atrium auricular region	UBERON:0006631	97.43	gold quality
small intestine Peyer’s patch	UBERON:0003454	97.36	gold quality
artery	UBERON:0001637	97.26	gold quality
omental fat pad	UBERON:0010414	97.20	gold quality
peritoneum	UBERON:0002358	97.05	gold quality
skin of abdomen	UBERON:0001416	96.97	gold quality
pancreas	UBERON:0001264	96.93	gold quality
skin of leg	UBERON:0001511	96.90	gold quality
lower esophagus mucosa	UBERON:0035834	96.81	gold quality
mucosa of stomach	UBERON:0001199	96.78	gold quality
right uterine tube	UBERON:0001302	96.70	gold quality
prefrontal cortex	UBERON:0000451	96.68	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	96.52	gold quality
cerebellar hemisphere	UBERON:0002245	96.48	gold quality
apex of heart	UBERON:0002098	96.44	gold quality
right hemisphere of cerebellum	UBERON:0014890	96.38	gold quality
cerebellar cortex	UBERON:0002129	96.32	gold quality
adrenal tissue	UBERON:0018303	96.27	gold quality
thyroid gland	UBERON:0002046	96.23	gold quality
hindlimb stylopod muscle	UBERON:0004252	96.21	gold quality
esophagus	UBERON:0001043	96.19	gold quality
upper lobe of lung	UBERON:0008948	96.06	gold quality
gastrocnemius	UBERON:0001388	95.81	gold quality
muscle of leg	UBERON:0001383	95.79	gold quality
right testis	UBERON:0004534	95.78	gold quality
adrenal gland	UBERON:0002369	95.63	gold quality
spleen	UBERON:0002106	95.43	gold quality
left testis	UBERON:0004533	95.41	gold quality
esophagus mucosa	UBERON:0002469	95.40	gold quality
stomach	UBERON:0000945	95.24	gold quality
hypothalamus	UBERON:0001898	94.99	gold quality
coronary artery	UBERON:0001621	94.90	gold quality
heart left ventricle	UBERON:0002084	94.34	gold quality
adrenal cortex	UBERON:0001235	94.33	gold quality
caudate nucleus	UBERON:0001873	94.33	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	94.27	gold quality
adipose tissue of abdominal region	UBERON:0007808	94.18	gold quality
pituitary gland	UBERON:0000007	94.17	gold quality
cardiac atrium	UBERON:0002081	94.08	gold quality
amygdala	UBERON:0001876	94.01	gold quality
small intestine	UBERON:0002108	93.80	gold quality
cerebellum	UBERON:0002037	93.69	gold quality
nucleus accumbens	UBERON:0001882	93.68	gold quality

Single-cell (SCXA)

Detected in 14 experiment(s), a significant marker in 13.

Experiment	Marker?	Max mean expression
E-MTAB-9543	yes	1594.74
E-CURD-88	yes	113.14
E-HCAD-4	yes	64.89
E-MTAB-9467	yes	64.37
E-CURD-46	yes	62.90
E-HCAD-1	yes	61.57
E-MTAB-8410	yes	52.83
E-CURD-122	yes	47.64
E-HCAD-9	yes	24.27
E-HCAD-11	yes	21.29
E-MTAB-8142	yes	14.02
E-MTAB-10553	yes	11.67
E-GEOD-81383	no	1135.47
E-ANND-3	no	0.00

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Epididymis	tissue	208.0	high
Pons	tissue	170.3
Substantia nigra	tissue	166.4
Spinal cord	tissue	163.5
Midbrain	tissue	161.4
Medulla oblongata	tissue	160.6
Thalamus	tissue	156.9
Hypothalamus	tissue	153.2
Superior colliculi	tissue	150.7
Periaqueductal gray	tissue	150.7
Corpus callosum	tissue	149.8
Putamen	tissue	147.7
Septum	tissue	145.8
Tonsil	tissue	145.3	high
Liver	tissue	142.0	medium
Parathyroid gland	tissue	139.3	low
Thyroid gland	tissue	135.3	high
Salivary gland	tissue	131.4	high
Ventral forebrain	tissue	127.6
Hippocampal formation	tissue	126.9
Cervix	tissue	119.7	high
Cerebral cortex	tissue	115.4	high
Somatosensory cortex	tissue	115.4
Motor cortex	tissue	114.7
Occipital cortex	tissue	114.0
Colon	tissue	112.0	high
Basal ganglia	tissue	110.9	medium
Pancreas	tissue	109.5	high
Prefrontal cortex	tissue	108.7
Entorhinal cortex	tissue	108.7
Rectum	tissue	108.1	high
Amygdala	tissue	107.3
Olfactory bulb	tissue	105.9
Retrosplenial cortex	tissue	101.8
Breast	tissue	101.5	medium
Retrosplenial and cingulate cortex	tissue	100.9
Prostate	tissue	100.8	medium
Temporal cortex	tissue	100.0
Stomach 1	tissue	99.7	high
Caudate putamen	tissue	99.4
Appendix	tissue	99.3	medium
Kidney	tissue	98.5	medium
Adrenal gland	tissue	94.2	medium
Cerebellum	tissue	92.4	medium
Lymph node	tissue	92.1	high
Thymus	tissue	91.3
Insular cortex	tissue	91.2
Fallopian tube	tissue	90.3	medium
Urinary bladder	tissue	88.9	medium
Seminal vesicle	tissue	88.1	medium
Smooth muscle	tissue	87.0	not detected
Endometrium 1	tissue	86.3	medium
Ovary	tissue	85.9	low
Duodenum	tissue	85.4	high
Nucleus accumbens	tissue	84.8
Choroid plexus	tissue	84.5
Locus coeruleus	tissue	83.7
Frontal cortex	tissue	82.7
Small intestine	tissue	78.8	high
Placenta	tissue	76.3	high

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Ventral spinal cord (163.5), White matter (149.8), Dorsal spinal cord (149.7), Dorsal hippocampus (126.9), Corpus callosum, genu (white matter) (120.0).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting SPCS2 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 109 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3162-3P	100.00	65.37	363
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-329-3P	99.91	66.56	1234
HSA-MIR-362-3P	99.91	66.38	1267
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

Functional genomics

gnomAD constraint: pLI 0.993, LOEUF 0.389, missense Z 1.85 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000263672 splits into 2 regions with different missense tolerance; 0 are missense-constrained. Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
11:74,949,286–74,949,365	51 / 37.8	1.35	no
11:74,949,366–74,977,040	118 / 243.1	0.49	no
DepMap (CRISPR cell-line fitness): dependent in 93.1% of screened cell lines, common-essential.

Most-dependent cell lines (DepMap gene-effect, lower = stronger; ≤ −0.5 shown): KP-N-SI9s (-1.723), MEL-HO (-1.623), C8166 (-1.507), IST-MES2 (-1.506), KMS-20 (-1.45), KP-N-YN (-1.449), NCI-H1915 (-1.447), PA-TU-8988T (-1.426), IMR-32 (-1.399), PSN1 (-1.391), KP-N-RT-BM-1 (-1.391), NMC-G1 (-1.337), SNU-245 (-1.328), SNU-886 (-1.327), MHH-ES-1 (-1.314).

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	spcs2	ENSDARG00000042823
mus_musculus	Spcs2	ENSMUSG00000035227
rattus_norvegicus	Spcs2	ENSRNOG00000018164
drosophila_melanogaster	Spase25	FBGN0030306
caenorhabditis_elegans		WBGENE00012550

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Canis lupus familiaris	Q28250	95.1%	Diamond
Macaca fascicularis	Q4R512	95.1%	Diamond
Pongo abelii	Q5RAY6	95.1%	Diamond
Caenorhabditis briggsae	Q615A2	87.2%	Diamond
Xenopus tropicalis	Q5M8Y1	85.2%	Diamond

Genomic neighbors (locus context)

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

Symbol	Type	Entrez
XRRA1	protein-coding	143570
RNF169	protein-coding	254225
NEU3	protein-coding	10825
OR2AT4	protein-coding	341152

Protein

Protein identifiers

Signal peptidase complex subunit 2 — Q15005 (reviewed: Q15005)

Alternative names: Microsomal signal peptidase 25 kDa subunit

All UniProt accessions (5): E9PI68, E9PL01, E9PRB9, H0YE04, Q15005

UniProt curated annotations — full annotation on UniProt →

Function. Component of the signal peptidase complex (SPC) which catalyzes the cleavage of N-terminal signal sequences from nascent proteins as they are translocated into the lumen of the endoplasmic reticulum. Enhances the enzymatic activity of SPC and facilitates the interactions between different components of the translocation site.

Subunit / interactions. Component of the signal peptidase complex paralog A (SPC-A) composed of a catalytic subunit SEC11A and three accessory subunits SPCS1, SPCS2 and SPCS3. Component of the signal peptidase complex paralog C (SPC-C) composed of a catalytic subunit SEC11C and three accessory subunits SPCS1, SPCS2 and SPCS3. Within the complex, interacts with SEC11A or SEC11C and SPCS1. The complex induces a local thinning of the ER membrane which is used to measure the length of the signal peptide (SP) h-region of protein substrates. This ensures the selectivity of the complex towards h-regions shorter than 18-20 amino acids.

Subcellular location. Endoplasmic reticulum membrane.

Similarity. Belongs to the SPCS2 family.

RefSeq proteins (1): NP_055567* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR009582	Spc2/SPCS2	Family

Pfam: PF06703

Enzyme classification (BRENDA)

• EC 3.4.21.89 — Signal peptidase I (BRENDA: 61 organisms, 177 substrates, 150 inhibitors, 43 Km, 55 kcat entries)

Substrate kinetics (BRENDA)

15 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
FSASALAKI	0.43–0.8	19
YFSASALA-4-METHYLCOUMARIN 7-AMIDE	0.0328–0.0354	5
PREPROTEIN SUBSTRATE PONA	0.0166–0.044	4
PHE-SER-ALA-SER-ALA-LEU-ALA-LYS-ILE	0.33–0.52	2
PRO-OMPA-NUCLEASE A	0.0165–0.032	2
Y-NO2-FSASALAKIK-2-AMINOBENZOYL-NH2	0.0006–0.11	2
ALKALINE PHOSPHATASE SIGNAL PEPTIDE FUSED TO FUL	0.05	1
DECANOYL-LT-P-TAKA-A-SKIDD-OH	0.988	1
DECANOYL-LTPTAKAASKIDD-OH	0.029	1
PHE-SER-ALA-SER-ALA-LEU-ALA-LYS-ILE-NH2	1	1
PRO-OMPA-NUCLEASE	0.0165	1
TOSYL-GLY-PRO-LYS-P-NITROANILIDE	0.319	1
VAL-LEU-LYS-P-NITROANILIDE	0.727	1
ALA-ALA-PHE-4-METHYLCOUMARYL-7-AMIDE	—	0
FSASALA-KI	—	0

UniProt features (13 total): modified residue 3, topological domain 3, transmembrane region 2, initiator methionine 1, chain 1, sequence conflict 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

4 structures by resolution:

PDB	Title	Method	Resolution (Å)
9RJB	Human Signal Peptidase in complex with artificial Signal Peptide L11	ELECTRON MICROSCOPY	2.6
9RJC	Apo Structure of the Human Signal Peptidase	ELECTRON MICROSCOPY	4.2
7P2P	Human Signal Peptidase Complex Paralog A (SPC-A)	ELECTRON MICROSCOPY	4.9
7P2Q	Human Signal Peptidase Complex Paralog C (SPC-C)	ELECTRON MICROSCOPY	4.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q15005-F1	65.48	0.00

Human Protein Atlas

Protein class: Metabolic proteins, Predicted membrane proteins, Predicted intracellular proteins, Plasma proteins, Essential proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): vesicles

Antibody reliability (HPA): IH approved · IF approved

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (3)

Type	Positions
N6-acetyllysine	169, 191
N-acetylalanine	2

Function

Pathways and Gene Ontology

Reactome pathways

4 curated (TAS) of 23; 7 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

23 pathways:

ID	Pathway	Evidence
R-HSA-9918432	Maturation of DENV proteins ⚕	curated
R-HSA-9828806	Maturation of hRSV A proteins ⚕	curated
R-HSA-9768727	Regulation of CDH1 posttranslational processing and trafficking to plasma membrane	curated
R-HSA-422085	Synthesis, secretion, and deacylation of Ghrelin	curated
R-HSA-1643685	Disease ⚕	—
R-HSA-5663205	Infectious disease ⚕	—
R-HSA-9820952	Respiratory Syncytial Virus Infection Pathway ⚕	—
R-HSA-9820965	Respiratory syncytial virus (RSV) genome replication, transcription and translation ⚕	—
R-HSA-9824446	Viral Infection Pathways ⚕	—
R-HSA-418990	Adherens junctions interactions	—
R-HSA-446728	Cell junction organization	—
R-HSA-1500931	Cell-Cell communication	—
R-HSA-421270	Cell-cell junction organization	—
R-HSA-400508	Incretin synthesis, secretion, and inactivation	—
R-HSA-392499	Metabolism of proteins	—
R-HSA-2980736	Peptide hormone metabolism	—
R-HSA-9764265	Regulation of CDH1 Expression and Function	—
R-HSA-9764274	Regulation of Expression and Function of Type I Classical Cadherins	—
R-HSA-9759476	Regulation of Homotypic Cell-Cell Adhesion	—
R-HSA-1799339	SRP-dependent cotranslational protein targeting to membrane	electronic
R-HSA-381771	Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1)	electronic
R-HSA-400511	Synthesis, secretion, and inactivation of Glucose-dependent Insulinotropic Polypeptide (GIP)	electronic
R-HSA-72766	Translation	—

MSigDB gene sets: 192 (showing top): MORF_MTA1, FLECHNER_PBL_KIDNEY_TRANSPLANT_REJECTED_VS_OK_UP, YAGI_AML_WITH_INV_16_TRANSLOCATION, PAL_PRMT5_TARGETS_UP, GOBP_PROTEIN_TARGETING, MORF_RAD21, HSIAO_HOUSEKEEPING_GENES, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ENDOPLASMIC_RETICULUM, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ORGANELLE, MORF_PSMC2, chr11q13, YY1_Q6, ATGTTAA_MIR302C, REACTOME_ADHERENS_JUNCTIONS_INTERACTIONS, OUELLET_OVARIAN_CANCER_INVASIVE_VS_LMP_UP

GO Biological Process (2): protein targeting to ER (GO:0045047), protein processing (GO:0016485)

GO Molecular Function (2): protein binding (GO:0005515), peptidase activity (GO:0008233)

GO Cellular Component (3): signal peptidase complex (GO:0005787), endoplasmic reticulum membrane (GO:0005789), membrane (GO:0016020)

Reactome top-level categories

14 top-level categories:

Category	Pathways
Incretin synthesis, secretion, and inactivation	2
Peptide hormone metabolism	2
Metabolism of proteins	2
Translation	1
Regulation of CDH1 Expression and Function	1
Respiratory syncytial virus (RSV) genome replication, transcription and translation	1
Dengue Virus Genome Translation and Replication	1
Cell-cell junction organization	1
Cell junction organization	1
Cell-Cell communication	1
Disease	1
Adherens junctions interactions	1
Regulation of Expression and Function of Type I Classical Cadherins	1
Regulation of Homotypic Cell-Cell Adhesion	1

GO top-level categories

15 GO namespaces:

Category	Terms
protein targeting	1
establishment of protein localization to endoplasmic reticulum	1
proteolysis	1
protein maturation	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
endoplasmic reticulum membrane	1
membrane protein complex	1
endoplasmic reticulum protein-containing complex	1
serine-type endopeptidase complex	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
cellular anatomical structure	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 1 of 8 annotations. The rest are phylogenetic / computational / electronic (IEA).

1 experimentally-supported GO terms:

GO term	NS	Evidence
endoplasmic reticulum membrane	CC	direct assay

Protein interactions and networks

STRING

showing 15 of 1,529 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SPCS2	SPCS1	Q9Y6A9	989
SPCS2	SPCS3	P12280	763
SPCS2	SEC11C	Q9BY50	685
SPCS2	H0YNG3	H0YNG3	675
SPCS2	XRRA1	Q6P2D8	617
SPCS2	SRP68	Q9UHB9	564
SPCS2	SRP54	P13624	561
SPCS2	SRP72	O76094	543
SPCS2	SRP19	P09132	532
SPCS2	SRP14	P37108	530
SPCS2	SRPRA	P08240	513
SPCS2	EMC4	Q5J8M3	501
SPCS2	SEC61G	P38384	491
SPCS2	SRPRB	Q9Y5M8	490
SPCS2	SEC63	Q9UGP8	488

IntAct

Human interaction partners of SPCS2 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

14 partners by confidence:

Partner	Interaction type	MIscore	Records
EGFR	physical association	0.550	2
ALPL	association	0.530	2
GPC4	association	0.530	2
S	physical association	0.500	1
E7	physical association	0.370	8
ATP13A2	physical association	0.370	1
S100A9	physical association	0.370	1
BTN2A3P	association	0.350	1
HNRNPH3	association	0.350	1
HSPA5	association	0.350	1
DDX56	physical association	0.000	1
STMN3	physical association	0.000	1
TEFM	physical association	0.000	1
TNFRSF14	physical association	0.000	1

BioGRID (250 interactions; top human partners by supporting records): SEC11C (Affinity Capture-MS; 4 records), DNASE1L1 (Affinity Capture-MS; 3 records), PVRIG (Affinity Capture-MS; 3 records), SEC11A (Affinity Capture-MS; 3 records), SPCS3 (Affinity Capture-MS; 3 records), TCTN2 (Proximity Label-MS; 3 records), TM2D3 (Affinity Capture-MS; 3 records), ADAM30 (Affinity Capture-MS; 2 records), ALPL (Affinity Capture-MS; 2 records), CANX (Proximity Label-MS; 2 records), DDX39A (Affinity Capture-RNA; 2 records), FBXL14 (Affinity Capture-MS; 2 records), GABRE (Affinity Capture-MS; 2 records), GPC1 (Affinity Capture-MS; 2 records), GPC4 (Affinity Capture-MS; 2 records)

SIGNOR signaling

2 signaling interactions:

A	Effect	B	Mechanism
SPCS2	“form complex”	“Signal peptidase complex, SEC11C variant”	binding
SPCS2	“form complex”	“Signal peptidase complex, SEC11A variant”	binding

Disease & clinical

Genetic variants

Variant evidence for SPCS2: 21 ClinVar records (0 pathogenic / likely pathogenic).

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	18
Likely benign	1
Benign	0

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 28 predictions of 605):

Position(s)	Effect	Δscore	Sites
11:74965032–74965033	acceptor_loss	1.0000	6
11:74965118–74965119	donor_loss	1.0000	5
11:74949400–74949401	donor_loss	0.9900	5
11:74965031	acceptor_loss	0.9900
11:74965119	donor_loss	0.9900
11:74969531	acceptor_gain	0.9900
11:74969536	acceptor_gain	0.9900
11:74969560	acceptor_gain	0.9900
11:74969568	acceptor_gain	0.9900
11:74976855–74976856	acceptor_loss	0.9900	6

AlphaMissense

908 missense substitutions predicted likely pathogenic (of 1,506 scored), across 184 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M125	9	0.985	0.999
D61	8	0.999	1.000
D62	8	0.999	1.000
D102	8	0.999	1.000
D52	8	0.998	0.999
F107	8	0.992	1.000
N58	8	0.989	1.000
D82	8	0.987	0.998
F140	8	0.987	0.999
D49	8	0.986	0.996
F122	8	0.985	0.999
D167	8	0.982	0.996
D168	8	0.980	0.997
F197	8	0.980	0.998
D147	8	0.974	0.989
D198	8	0.959	0.992
H216	8	0.952	0.997
F94	8	0.946	0.991
D155	8	0.883	0.969
D152	8	0.870	0.963

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

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

1 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	3e-06

Disease associations

OMIM: gene MIM:619411 | disease phenotypes:

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067262 (SINGLE PROTEIN)

PharmGKB: 1 entry (CPIC guideline: no)

Binding affinities (BindingDB)

1 measured of 1 human assays (2 total across all organisms); most potent 1 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CHEMBL5653589	KD	1440 nM

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.04	Kd	916.1	nM	CHEMBL3752910
6.04	ED50	916.1	nM	CHEMBL3752910
5.53	Kd	2987	nM	CHEMBL5653589
5.53	ED50	2987	nM	CHEMBL5653589

PubChem BioAssay actives

2 with measured affinity, of 4 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
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149470: Binding affinity to human SPCS2 incubated for 45 mins by Kinobead based pull down assay	kd	0.9161	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149470: Binding affinity to human SPCS2 incubated for 45 mins by Kinobead based pull down assay	kd	2.9871	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects expression, decreases expression, affects cotreatment, increases abundance, increases expression	4
Tunicamycin	increases expression	2
bisphenol F	increases expression	1
dicrotophos	decreases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance, increases expression	1
di-n-butylphosphoric acid	affects expression	1
2,3,5-(triglutathion-S-yl)hydroquinone	increases ADP-ribosylation	1
bisphenol B	increases expression	1
bisphenol AF	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	affects cotreatment, decreases expression, increases abundance, increases expression	1
Atrazine	increases expression	1
Cadmium	affects expression	1
Cisplatin	decreases expression, decreases reaction	1
Diuron	decreases expression	1
Ethyl Methanesulfonate	decreases expression	1
Ivermectin	decreases expression	1
Manganese	affects cotreatment, decreases expression, increases abundance, increases expression	1
Piroxicam	decreases expression, decreases reaction	1
Ribonucleotides	affects binding	1
Rotenone	increases expression	1
Selenium	affects cotreatment, decreases expression	1
Dihydrotestosterone	increases expression	1
Vitamin E	affects cotreatment, decreases expression	1
Zinc	increases expression	1
Cyclosporine	increases methylation, increases expression	1
Thapsigargin	increases expression	1
Copper Sulfate	decreases expression	1
Lactic Acid	increases expression	1
Particulate Matter	decreases expression, increases abundance	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652512	Binding	Binding affinity to human SPCS2 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — *ChemMedChem*

Clinical trials (associated diseases)

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

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for SPCS2 across ~30M SureChEMBL compounds — explore on Sugi Predict.