CPE

Summary

CPE (carboxypeptidase E, HGNC:2303) is a protein-coding gene on chromosome 4q32.3, encoding Carboxypeptidase E (P16870). Sorting receptor that directs prohormones to the regulated secretory pathway.

This gene encodes a member of the M14 family of metallocarboxypeptidases. The encoded preproprotein is proteolytically processed to generate the mature peptidase. This peripheral membrane protein cleaves C-terminal amino acid residues and is involved in the biosynthesis of peptide hormones and neurotransmitters, including insulin. This protein may also function independently of its peptidase activity, as a neurotrophic factor that promotes neuronal survival, and as a sorting receptor that binds to regulated secretory pathway proteins, including prohormones. Mutations in this gene are implicated in type 2 diabetes.

Source: NCBI Gene 1363 — RefSeq curated summary.

At a glance

• Gene–disease (curated): BDV syndrome (Strong, GenCC)
• GWAS associations: 4
• Clinical variants (ClinVar): 163 total — 8 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 24
• MANE Select transcript: NM_001873

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2303
Approved symbol	CPE
Name	carboxypeptidase E
Location	4q32.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000109472
Ensembl biotype	protein_coding
OMIM	114855
Entrez	1363

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 8 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000402744, ENST00000431967, ENST00000480404, ENST00000511992, ENST00000513982, ENST00000871530, ENST00000871531, ENST00000871532, ENST00000957033

RefSeq mRNA: 1 — MANE Select: NM_001873 NM_001873

CCDS: CCDS3810

Canonical transcript exons

ENST00000402744 — 9 exons

Exon	Start	End
ENSE00000740488	165495559	165495677
ENSE00000740491	165493171	165493270
ENSE00000740495	165487438	165487577
ENSE00000740501	165467688	165467855
ENSE00000820535	165484422	165484604
ENSE00000820536	165482242	165482359
ENSE00001954594	165379008	165379528
ENSE00002052405	165497512	165498547
ENSE00003676321	165464390	165464586

Expression profiles

Bgee: expression breadth ubiquitous, 284 present calls, max score 99.91.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 80.3212 / max 2555.9426, expressed in 1339 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
50447	50.7005	1289
50446	12.7167	808
50443	5.0916	556
50450	3.0491	589
50445	2.1533	437
50448	1.8870	468
50449	1.8029	469
50451	1.7335	455
50444	1.1866	322

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
type B pancreatic cell	CL:0000169	99.91	gold quality
caudate nucleus	UBERON:0001873	99.79	gold quality
paraflocculus	UBERON:0005351	99.75	gold quality
nucleus accumbens	UBERON:0001882	99.71	gold quality
amygdala	UBERON:0001876	99.67	gold quality
putamen	UBERON:0001874	99.65	gold quality
lateral globus pallidus	UBERON:0002476	99.62	gold quality
cerebellar cortex	UBERON:0002129	99.61	gold quality
prefrontal cortex	UBERON:0000451	99.60	gold quality
cerebellum	UBERON:0002037	99.60	gold quality
cerebellar hemisphere	UBERON:0002245	99.60	gold quality
cerebellar vermis	UBERON:0004720	99.58	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	99.58	gold quality
islet of Langerhans	UBERON:0000006	99.57	gold quality
temporal lobe	UBERON:0001871	99.56	gold quality
right hemisphere of cerebellum	UBERON:0014890	99.56	gold quality
entorhinal cortex	UBERON:0002728	99.53	gold quality
right frontal lobe	UBERON:0002810	99.53	gold quality
Brodmann (1909) area 9	UBERON:0013540	99.53	gold quality
cartilage tissue	UBERON:0002418	99.52	gold quality
frontal cortex	UBERON:0001870	99.50	gold quality
telencephalon	UBERON:0001893	99.50	gold quality
cortical plate	UBERON:0005343	99.49	gold quality
postcentral gyrus	UBERON:0002581	99.48	gold quality
forebrain	UBERON:0001890	99.47	gold quality
brain	UBERON:0000955	99.46	gold quality
Ammon’s horn	UBERON:0001954	99.45	gold quality
substantia nigra pars reticulata	UBERON:0001966	99.45	gold quality
descending thoracic aorta	UBERON:0002345	99.45	gold quality
corpus epididymis	UBERON:0004359	99.44	gold quality

Single-cell (SCXA)

Detected in 37 experiment(s), a significant marker in 34.

Experiment	Marker?	Max mean expression
E-GEOD-84465	yes	6915.37
E-HCAD-31	yes	4953.30
E-MTAB-7316	yes	4523.07
E-MTAB-9154	yes	2621.35
E-GEOD-83139	yes	2536.13
E-GEOD-134144	yes	2164.58
E-HCAD-15	yes	2136.07
E-MTAB-8221	yes	1888.02
E-HCAD-5	yes	1652.46
E-MTAB-6308	yes	1614.18
E-CURD-126	yes	1283.09
E-MTAB-9841	yes	1210.92
E-HCAD-11	yes	1053.40
E-GEOD-114530	yes	871.43
E-MTAB-9435	yes	751.01

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): PDX1, SREBF1

miRNA regulators (miRDB)

56 targeting CPE, 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-3646	100.00	73.56	5283
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-552-5P	99.93	68.56	1583
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-652-5P	99.91	67.49	505
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-3065-3P	99.87	70.25	1407
HSA-MIR-383-3P	99.85	65.84	1359
HSA-MIR-369-3P	99.85	70.52	2264
HSA-MIR-5010-3P	99.83	70.60	2357
HSA-MIR-323A-3P	99.79	70.30	1739
HSA-MIR-7856-5P	99.75	69.99	2901
HSA-MIR-2681-5P	99.75	67.64	1655
HSA-MIR-1179	99.71	68.70	1040
HSA-MIR-646	99.68	67.84	1645
HSA-MIR-1284	99.67	73.56	1353
HSA-MIR-4804-3P	99.65	67.78	866
HSA-MIR-5700	99.64	69.88	2280
HSA-MIR-3975	99.62	65.97	697
HSA-MIR-1252-3P	99.55	67.71	2862
HSA-MIR-510-3P	99.54	70.06	2965

Literature-anchored findings (GeneRIF, showing 32)

• missense polymorphism encoding altered activity (PMID:11462236)
• Carboxypeptidase E is differently expressed in subcutaneous and visceral fat of obese subjects (PMID:12530526)
• protein binding with Con A in seminal plasma (PMID:14690244)
• cDNA microarray analysis led to the identification of 2 novel biomarkers that should facilitate molecular diagnosis and further study of pulmonary neuroendocrine tumors. (PMID:15492986)
• A possible role for mutations in CPE in the development of coronary heart disease. (PMID:17957445)
• the severity of the coronary atherosclerosis estimated by Gensini score was significantly influenced by the presence of the A2925G mutant and G2855A mutant of the CPE gene (PMID:18080843)
• polymorphism in the CPE exon5 gene may contribute to the angiographical characteristics of coronary atherosclerosis in the Chinese population (PMID:18501121)
• Carboxypeptidase E degradation contributes to palmitate-induced beta-cell ER stress and apoptosis; CPE is a major link between hyperlipidemia and beta-cell death pathways in diabetes. (PMID:18550819)
• CPH-Abs may allow discrimination of a more latent subset of adult-onset autoimmune diabetes (LADA). (PMID:19120309)
• Carboxypeptidase E may be a key molecule to regulate Caspr2 (carboxypeptidase E) trafficking to the cell membrane. (PMID:19166515)
• Neither high glucose nor insulin (with low glucose) regulates beta-cell CPE (but either up-regulates CPD). (PMID:21628999)
• CPE forms a complex, probably through sequences located at its N-terminal domain, with Wnt3a and the extracellular cysteine rich domain of Fz1. (PMID:22824791)
• CPE is essential in the process and targeting of neuropeptides and neurotrophins, its participation in the pathological progression of Alzheimer’s disease may be suggested (PMID:22998035)
• Data suggest that splice variant of carboxypeptidase E (CPE-DeltaN) that CPE-DeltaN expression might be a potential prognostic marker for colorectal cancer patients. (PMID:23852859)
• Upregulation of CPE promotes cell proliferation and tumorigenicity in colorectal cancer. (PMID:24006921)
• Disruption of insulin receptor (IR) expression in beta cells has a direct impact on the expression of the convertase enzyme carboxypeptidase E (CPE) by inhibition of the eukaryotic translation initiation factor Eif4g1. (PMID:24843127)
• Downregulation of CPE regulates cell proliferation and chemosensitivity in pancreatic cancer. (PMID:25374060)
• Down-expression of liver carboxypeptidase E may reduce the secretion of serum cholecystokinin and contribute to the formation of cholesterol gallstone. (PMID:26228366)
• High-level CPE [ carboxypeptidase E] expression was associated with a poor prognosis in early-stage cervical cancer. CPE may serve as a biomarker for predicting PLNM [ pelvic lymph node metastasis ] and survival in these patients. (PMID:26695643)
• Low carboxypeptidase E expression is associated with recurrence in early-stage hepatocellular carcinoma. (PMID:26803519)
• CPE through its N’-terminal sequence, forms aggregates with Wnt3a and possible endoplasmic reticulum (ER) stress leading to its loss of function. (PMID:27375026)
• This study has uncovered a human CPE/NF-alpha1 gene mutation that could lead to comorbidity of dementia and depression, emphasizing the importance of this gene in cognitive function. (PMID:27922637)
• we have identified a novel SNP in the CPE gene which results in the loss of its neuroprotective function in cells and may confer neurological disorders in humans (PMID:28114332)
• Our results implicate a novel role for Carboxypeptidase E that mainly affects the expression of motility-associated genes via several signal pathways (PMID:28656234)
• Carboxypeptidase E down-regulation regulates transcriptional and epigenetic profiles in pancreatic cancer cell line: A network analysis. (PMID:32675394)
• In silico analysis of non-synonymous missense SNPs (nsSNPs) in CPE, GNAS genes and experimental validation in type II diabetes mellitus through Next Generation Sequencing. (PMID:34029697)
• BDV Syndrome: An Emerging Syndrome With Profound Obesity and Neurodevelopmental Delay Resembling Prader-Willi Syndrome. (PMID:34383079)
• Carboxypeptidase E mRNA: Overexpression predicts recurrence and death in lung adenocarcinoma cancer patients. (PMID:34511486)
• Novel interaction between neurotrophic factor-alpha1/carboxypeptidase E and serotonin receptor, 5-HTR1E, protects human neurons against oxidative/neuroexcitotoxic stress via beta-arrestin/ERK signaling. (PMID:34966948)
• Silencing of Carboxypeptidase E expression inhibits proliferation and invasion of Panc-1 pancreatic cancer cells. (PMID:35528956)
• Carboxypeptidase E conditional knockout mice exhibit learning and memory deficits and neurodegeneration. (PMID:37100779)
• Endoplasmic reticulum stress-dependent regulation of carboxypeptidase E expression in glioblastoma cells. (PMID:39352777)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	cpe	ENSDARG00000055874
mus_musculus	Cpe	ENSMUSG00000037852
rattus_norvegicus	Cpe	ENSRNOG00000043387

Paralogs (7): CPXM1 (ENSG00000088882), AEBP1 (ENSG00000106624), CPD (ENSG00000108582), CPZ (ENSG00000109625), CPN1 (ENSG00000120054), CPXM2 (ENSG00000121898), CPM (ENSG00000135678)

Protein

Protein identifiers

Carboxypeptidase E — P16870 (reviewed: P16870)

Alternative names: Carboxypeptidase H, Enkephalin convertase, Prohormone-processing carboxypeptidase

All UniProt accessions (5): P16870, A0A384N679, C9JE88, D6R930, D6RF88

UniProt curated annotations — full annotation on UniProt →

Function. Sorting receptor that directs prohormones to the regulated secretory pathway. Also acts as a prohormone processing enzyme in neuro/endocrine cells, removing dibasic residues from the C-terminal end of peptide hormone precursors after initial endoprotease cleavage.

Subunit / interactions. Interacts with secretogranin III/SCG3.

Subcellular location. Cytoplasmic vesicle. Secretory vesicle. Secretory vesicle membrane. Secreted.

Disease relevance. BDV syndrome (BDVS) [MIM:619326] An autosomal recessive disorder characterized by obesity, intellectual disability, and hypogonadotropic hypogonadism. Additional variable features include central hypothyroidism, hypotonia, and developmental delay. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Binds 1 zinc ion per subunit.

Similarity. Belongs to the peptidase M14 family.

Isoforms (2)

UniProt ID	Names	Canonical?
P16870-1	1	yes
P16870-2	2, CPE delta-N

RefSeq proteins (1): NP_001864* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000834	Peptidase_M14	Domain
IPR008969	CarboxyPept-like_regulatory	Homologous_superfamily
IPR034232	M14_CPE_CPD	Domain
IPR050753	Peptidase_M14_domain	Family
IPR057246	CARBOXYPEPT_ZN_1	Binding_site
IPR057247	CARBOXYPEPT_ZN_2	Binding_site

Pfam: PF00246, PF13620

Enzyme classification (BRENDA):

• EC 3.4.17.10 — carboxypeptidase E (BRENDA: 14 organisms, 50 substrates, 29 inhibitors, 16 Km, 3 kcat entries)

Substrate kinetics (BRENDA)

4 substrates with measured Km, best-characterized 4. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
DANSYL-PHE-ALA-ARG	0.018–0.034	4
DANSYL-PHE-LEU-ARG	0.0175–0.07	3
HIPPURYL-ARG	0.4	1
IODO-ACETYL-TYR-ALA-ARG	0.028	1

UniProt features (17 total): sequence variant 4, binding site 3, sequence conflict 2, glycosylation site 2, signal peptide 1, propeptide 1, splice variant 1, chain 1, domain 1, active site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P16870-F1	90.83	0.83

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 (1): 342 (proton donor/acceptor)

Ligand- & substrate-binding residues (3): 114; 117; 248

Glycosylation sites (2): 139, 390

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-264876	Insulin processing
R-HSA-2980736	Peptide hormone metabolism
R-HSA-392499	Metabolism of proteins

MSigDB gene sets: 332 (showing top): GOBP_CARDIAC_CHAMBER_DEVELOPMENT, WAMUNYOKOLI_OVARIAN_CANCER_LMP_DN, KOBAYASHI_EGFR_SIGNALING_24HR_UP, chr4q32, GOBP_CARDIAC_LEFT_VENTRICLE_MORPHOGENESIS, GOMF_METALLOPEPTIDASE_ACTIVITY, GOBP_CARDIAC_CHAMBER_MORPHOGENESIS, XU_GH1_AUTOCRINE_TARGETS_UP, GOCC_SECRETORY_GRANULE, BECKER_TAMOXIFEN_RESISTANCE_UP, KAAB_HEART_ATRIUM_VS_VENTRICLE_UP, GOZGIT_ESR1_TARGETS_DN, GOBP_REGULATION_OF_HORMONE_LEVELS, GOBP_HORMONE_TRANSPORT, TAL1ALPHAE47_01

GO Biological Process (14): cardiac left ventricle morphogenesis (GO:0003214), peptide metabolic process (GO:0006518), neuropeptide signaling pathway (GO:0007218), Wnt signaling pathway (GO:0016055), protein processing (GO:0016485), insulin processing (GO:0030070), peptide hormone secretion (GO:0030072), protein localization to secretory granule (GO:0033366), protein modification process (GO:0036211), protein localization to membrane (GO:0072657), proteolysis (GO:0006508), cell communication (GO:0007154), intracellular protein localization (GO:0008104), signaling (GO:0023052)

GO Molecular Function (10): carboxypeptidase activity (GO:0004180), metallocarboxypeptidase activity (GO:0004181), zinc ion binding (GO:0008270), neurexin family protein binding (GO:0042043), cell adhesion molecule binding (GO:0050839), protein binding (GO:0005515), peptidase activity (GO:0008233), metallopeptidase activity (GO:0008237), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (13): obsolete extracellular space (GO:0005615), Golgi apparatus (GO:0005794), plasma membrane (GO:0005886), transport vesicle membrane (GO:0030658), secretory granule membrane (GO:0030667), extracellular exosome (GO:0070062), extracellular region (GO:0005576), cytoplasm (GO:0005737), endomembrane system (GO:0012505), membrane (GO:0016020), transport vesicle (GO:0030133), secretory granule (GO:0030141), cytoplasmic vesicle (GO:0031410)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Peptide hormone metabolism	1
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
endomembrane system	3
protein metabolic process	2
cytoplasm	2
cytoplasmic vesicle membrane	2
bounding membrane of organelle	2
cardiac ventricle morphogenesis	1
metabolic process	1
G protein-coupled receptor signaling pathway	1
cell surface receptor signaling pathway	1
proteolysis	1
protein maturation	1
peptide hormone processing	1
insulin metabolic process	1
peptide secretion	1
hormone secretion	1
nitrogen compound transport	1
protein localization to organelle	1
macromolecule modification	1
intracellular protein localization	1
localization within membrane	1
cellular process	1
macromolecule localization	1
regulation of biological process	1
exopeptidase activity	1
carboxypeptidase activity	1
metalloexopeptidase activity	1
transition metal ion binding	1
signaling receptor binding	1
protein binding	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
peptidase activity	1
catalytic activity	1
cation binding	1
intracellular membrane-bounded organelle	1
membrane	1
cell periphery	1
transport vesicle	1

Protein interactions and networks

STRING

1502 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CPE	POMC	P01189	965
CPE	PCSK1N	Q9UHG2	886
CPE	PCSK1	P29120	882
CPE	CHGA	P10645	853
CPE	CPB2	Q96IY4	811
CPE	PCSK2	P16519	807
CPE	CPB1	P15086	804
CPE	INS	P01308	784
CPE	SCG3	Q8WXD2	783
CPE	SCG2	P13521	751
CPE	BDNF	P23560	747
CPE	CHGB	P05060	728
CPE	NOS1AP	O75052	692
CPE	PAM	P19021	687
CPE	PENK	P01210	684

IntAct

43 interactions, top by confidence:

A	B	Type	Score
PSEN1	CPE	psi-mi:“MI:0915”(physical association)	0.560
SCGB1D1	FAM234B	psi-mi:“MI:0914”(association)	0.530
PSG8	PEX7	psi-mi:“MI:0914”(association)	0.530
CPE	PRKAA1	psi-mi:“MI:0915”(physical association)	0.400
TFAP2A	CPE	psi-mi:“MI:0915”(physical association)	0.370
PRNP	WDR91	psi-mi:“MI:0914”(association)	0.350
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350
DYRK1A	TEX13D	psi-mi:“MI:0914”(association)	0.350
PSMC3	PSMD1	psi-mi:“MI:0914”(association)	0.350
CSTL1	DENND11	psi-mi:“MI:0914”(association)	0.350
LLCFC1	POTEF	psi-mi:“MI:0914”(association)	0.350
BRICD5	POTEF	psi-mi:“MI:0914”(association)	0.350
ST14	LIPT2	psi-mi:“MI:0914”(association)	0.350
RLN1	RTL8C	psi-mi:“MI:0914”(association)	0.350
CEACAM8	PRRT4	psi-mi:“MI:0914”(association)	0.350
GPIHBP1	SAC3D1	psi-mi:“MI:0914”(association)	0.350
GPM6A	KIF2A	psi-mi:“MI:0914”(association)	0.350
PATE1	MANBA	psi-mi:“MI:0914”(association)	0.350
DHFR2	MANBA	psi-mi:“MI:0914”(association)	0.350
TMPRSS13	TOR1A	psi-mi:“MI:0914”(association)	0.350
UGGT2	MAP2K7	psi-mi:“MI:0914”(association)	0.350
GIP	GNPAT	psi-mi:“MI:0914”(association)	0.350
B3GALT5	TTI1	psi-mi:“MI:0914”(association)	0.350
HYOU1	SNX2	psi-mi:“MI:0914”(association)	0.350
TAFA2	ERN1	psi-mi:“MI:0914”(association)	0.350
TMEM87A	PC	psi-mi:“MI:0914”(association)	0.350
PROK2	CPE	psi-mi:“MI:0914”(association)	0.350

BioGRID (57): CPE (Affinity Capture-MS), CPE (Affinity Capture-MS), CPE (Affinity Capture-MS), CPE (Affinity Capture-MS), CPE (Affinity Capture-MS), CPE (Affinity Capture-MS), CPE (Affinity Capture-MS), CPE (Affinity Capture-MS), CPE (Affinity Capture-MS), CPE (Affinity Capture-MS), CPE (Affinity Capture-MS), CPE (Affinity Capture-MS), CPE (Affinity Capture-MS), CPE (Two-hybrid), CPE (Reconstituted Complex)

ESM2 similar proteins: A5A6K7, O17754, O54858, O75976, O89001, P04836, P14384, P15087, P15169, P16870, P21661, P23188, P23377, P28841, P29122, P37892, P38836, P42787, Q00493, Q0II73, Q16769, Q28193, Q2KIG3, Q2KJ83, Q4R4M3, Q4R7R2, Q5REC2, Q5RFD6, Q5U901, Q63415, Q66K79, Q80V42, Q8IVL8, Q8N436, Q8QGP3, Q8R4H4, Q8R4V4, Q8WXQ8, Q90240, Q96IY4

Diamond homologs: A2RUV9, A5A6K7, O14786, O17754, O18806, O35276, O35375, O35474, O43854, O54858, O54991, O60462, O75976, O88783, O89001, P00451, P02886, P02887, P02888, P04836, P12259, P12263, P14384, P15087, P15169, P16870, P21956, P28824, P29068, P37892, P39041, P42787, P70490, P78357, P79385, P79795, P83852, P97333, P97846, P98092

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
CPE	“up-regulates activity”	Oxytocin	cleavage

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	8
Likely pathogenic	1
Uncertain significance	80
Likely benign	56
Benign	9

Top pathogenic / likely-pathogenic (9)

Variant ID	HGVS	Classification
1096917	NM_001873.4(CPE):c.405C>A (p.Tyr135Ter)	Pathogenic
1209851	NM_001873.4(CPE):c.361C>T (p.Arg121Ter)	Pathogenic
2194543	NM_001873.4(CPE):c.768T>A (p.Tyr256Ter)	Pathogenic
2281765	NM_001873.4(CPE):c.1150C>T (p.Gln384Ter)	Pathogenic
4812840	NM_001873.4(CPE):c.274G>T (p.Glu92Ter)	Pathogenic
649127	NM_001873.4(CPE):c.994del (p.Ser333fs)	Pathogenic
685559	GRCh37/hg19 4q32.3-34.2(chr4:165069355-177189728)x3	Pathogenic
689401	NM_001873.4(CPE):c.76_98del (p.Glu26fs)	Pathogenic
3340503	NM_001873.4(CPE):c.1208dup (p.Ser404fs)	Likely pathogenic

SpliceAI

1786 predictions. Top by Δscore:

Variant	Effect	Δscore
4:165379524:GCCTG:G	donor_gain	1.0000
4:165464585:AGGT:A	donor_loss	1.0000
4:165464586:GGTG:G	donor_loss	1.0000
4:165464587:G:GG	donor_gain	1.0000
4:165467686:A:AG	acceptor_gain	1.0000
4:165467686:A:AT	acceptor_loss	1.0000
4:165467686:AGCCT:A	acceptor_gain	1.0000
4:165467687:G:GG	acceptor_gain	1.0000
4:165467687:GC:G	acceptor_gain	1.0000
4:165467687:GCC:G	acceptor_gain	1.0000
4:165467687:GCCT:G	acceptor_gain	1.0000
4:165467687:GCCTG:G	acceptor_gain	1.0000
4:165467798:T:TA	donor_gain	1.0000
4:165467799:G:GA	donor_gain	1.0000
4:165482224:A:AG	acceptor_gain	1.0000
4:165482232:A:AG	acceptor_gain	1.0000
4:165482232:ATCT:A	acceptor_gain	1.0000
4:165482233:T:G	acceptor_gain	1.0000
4:165482235:T:A	acceptor_gain	1.0000
4:165482238:ACAG:A	acceptor_loss	1.0000
4:165482239:CAGC:C	acceptor_loss	1.0000
4:165482240:A:AG	acceptor_gain	1.0000
4:165482240:A:AT	acceptor_loss	1.0000
4:165482240:AGCTT:A	acceptor_gain	1.0000
4:165482241:G:GA	acceptor_gain	1.0000
4:165482241:G:T	acceptor_loss	1.0000
4:165482241:GC:G	acceptor_gain	1.0000
4:165482241:GCTT:G	acceptor_gain	1.0000
4:165482241:GCTTG:G	acceptor_gain	1.0000
4:165482355:GAGTG:G	donor_gain	1.0000

AlphaMissense

3148 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:165464413:G:T	G111W	1.000
4:165464418:T:A	N112K	1.000
4:165464418:T:G	N112K	1.000
4:165464425:G:T	G115W	1.000
4:165464426:G:A	G115E	1.000
4:165464426:G:T	G115V	1.000
4:165464430:T:A	N116K	1.000
4:165464430:T:G	N116K	1.000
4:165464432:A:T	E117V	1.000
4:165467747:C:A	N188K	1.000
4:165467747:C:G	N188K	1.000
4:165467749:G:C	R189P	1.000
4:165482311:C:G	H248D	1.000
4:165482345:A:T	D259V	1.000
4:165484586:T:A	W319R	1.000
4:165484586:T:C	W319R	1.000
4:165484588:G:C	W319C	1.000
4:165484588:G:T	W319C	1.000
4:165464414:G:A	G111E	0.999
4:165464422:C:A	H114N	0.999
4:165464422:C:G	H114D	0.999
4:165464424:T:A	H114Q	0.999
4:165464424:T:G	H114Q	0.999
4:165464425:G:A	G115R	0.999
4:165464425:G:C	G115R	0.999
4:165464429:A:T	N116I	0.999
4:165464431:G:A	E117K	0.999
4:165464433:G:C	E117D	0.999
4:165464433:G:T	E117D	0.999
4:165464440:G:A	G120R	0.999

dbSNP variants (sampled 300 via entrez): RS1000017131 (4:165446739 G>A,T), RS10000308 (4:165398072 C>A), RS10000363 (4:165419071 T>A,C), RS1000042088 (4:165382085 G>A), RS1000071038 (4:165460784 C>T), RS1000093768 (4:165498923 G>A), RS1000152863 (4:165446558 G>T), RS1000161745 (4:165430606 G>A,T), RS1000166113 (4:165442033 T>G), RS1000234274 (4:165423522 A>G), RS1000257704 (4:165478143 C>A,G,T), RS1000281693 (4:165473208 T>C), RS1000305389 (4:165429720 A>G), RS1000366202 (4:165454121 C>G), RS1000401265 (4:165448372 T>A)

Disease associations

OMIM: gene MIM:114855 | disease phenotypes: MIM:619326

GenCC curated gene-disease

Disease	Classification	Inheritance
BDV syndrome	Strong	Autosomal recessive

Mondo (1): BDV syndrome (MONDO:0859150)

Orphanet (1): CPE-related Prader-Willi-like syndrome (Orphanet:633028)

HPO phenotypes

24 total (24 of 24 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000044	Hypogonadotropic hypogonadism
HP:0000054	Micropenis
HP:0000293	Full cheeks
HP:0000311	Round face
HP:0000347	Micrognathia
HP:0000400	Macrotia
HP:0000771	Gynecomastia
HP:0000786	Primary amenorrhea
HP:0000823	Delayed puberty
HP:0000842	Hyperinsulinemia
HP:0001249	Intellectual disability
HP:0001270	Motor delay
HP:0001513	Obesity
HP:0001631	Atrial septal defect
HP:0005978	Type II diabetes mellitus
HP:0008947	Floppy infant
HP:0011787	Central hypothyroidism
HP:0030341	Decreased circulating follicle stimulating hormone concentration
HP:0031098	Decreased thyroid-stimulating hormone level
HP:0033078	Decreased circulating free T4 concentration
HP:0033082	Reduced TSH response to thyrotrophin-releasing hormone stimulation test
HP:0040171	Decreased serum testosterone concentration

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST003225_22	Pelvic organ prolapse (moderate/severe)	2.000000e-06
GCST003225_23	Pelvic organ prolapse (moderate/severe)	1.000000e-07
GCST009723_86	Vertical cup-disc ratio (adjusted for vertical disc diameter)	3.000000e-07
GCST009724_39	Vertical cup-disc ratio (multi-trait analysis)	3.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0006939	cup-to-disc ratio measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — M14: Carboxypeptidase A

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	10
trichostatin A	affects cotreatment, increases expression	3
Silicon Dioxide	decreases expression, increases expression	3
sodium arsenite	increases abundance, increases expression	2
mercuric bromide	increases expression, affects cotreatment	2
Arsenic Trioxide	decreases expression, increases expression	2
Vorinostat	affects cotreatment, increases expression	2
Panobinostat	affects cotreatment, increases expression	2
Arsenic	increases abundance, increases expression, decreases expression	2
Estradiol	affects expression, affects cotreatment, decreases expression, increases expression	2
Nickel	decreases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Cyclosporine	decreases expression	2
tert-Butylhydroperoxide	decreases expression, increases expression	2
aristolochic acid I	decreases expression	1
afuresertib	increases expression	1
sotorasib	affects cotreatment, increases expression	1
methylmercuric chloride	increases expression	1
bisphenol A	increases expression	1
sodium arsenate	decreases expression, increases abundance	1
kojic acid	increases expression	1
terbufos	increases methylation	1
potassium chromate(VI)	decreases expression	1
4-hydroxy-2-nonenal	decreases expression	1
nickel sulfate	decreases expression	1
epigallocatechin gallate	decreases expression	1
cylindrospermopsin	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
nutlin 3	affects cotreatment, increases expression, increases secretion	1
ICG 001	increases expression	1

Clinical trials (associated diseases)

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