CPA4

Summary

CPA4 (carboxypeptidase A4, HGNC:15740) is a protein-coding gene on chromosome 7q32.2, encoding Carboxypeptidase A4 (Q9UI42). Metalloprotease that cleaves hydrophobic C-terminal residues with a preference for -Phe, -Leu, -Ile, -Met, -Tyr and -Val.

This gene is a member of the carboxypeptidase A/B subfamily, and it is located in a cluster with three other family members on chromosome 7. Carboxypeptidases are zinc-containing exopeptidases that catalyze the release of carboxy-terminal amino acids, and are synthesized as zymogens that are activated by proteolytic cleavage. This gene could be involved in the histone hyperacetylation pathway. It is imprinted and may be a strong candidate gene for prostate cancer aggressiveness.

Source: NCBI Gene 51200 — RefSeq curated summary.

At a glance

• GWAS associations: 9
• Clinical variants (ClinVar): 148 total
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_016352

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15740
Approved symbol	CPA4
Name	carboxypeptidase A4
Location	7q32.2
Locus type	gene with protein product
Status	Approved
Aliases	CPA3
Ensembl gene	ENSG00000128510
Ensembl biotype	protein_coding
OMIM	607635
Entrez	51200

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 6 protein_coding, 4 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000222482, ENST00000445470, ENST00000470542, ENST00000473956, ENST00000474254, ENST00000486598, ENST00000488025, ENST00000490117, ENST00000492072, ENST00000493259, ENST00000497388

RefSeq mRNA: 2 — MANE Select: NM_016352 NM_001163446, NM_016352

CCDS: CCDS55163, CCDS5818

Canonical transcript exons

ENST00000222482 — 11 exons

Exon	Start	End
ENSE00000723233	130305816	130305920
ENSE00000723234	130306787	130306897
ENSE00000723236	130308307	130308397
ENSE00002275969	130322489	130324180
ENSE00003486175	130293161	130293248
ENSE00003492230	130299270	130299404
ENSE00003498239	130310787	130310986
ENSE00003505102	130300816	130300914
ENSE00003533738	130312038	130312122
ENSE00003573373	130304478	130304579
ENSE00003613971	130298746	130298827

Expression profiles

Bgee: expression breadth ubiquitous, 116 present calls, max score 93.52.

FANTOM5 (CAGE): breadth broad, TPM avg 12.6312 / max 986.2525, expressed in 689 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
81070	12.2381	672
81069	0.3932	176

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
skin of abdomen	UBERON:0001416	93.52	gold quality
zone of skin	UBERON:0000014	92.54	gold quality
skin of leg	UBERON:0001511	91.75	gold quality
body of pancreas	UBERON:0001150	87.90	gold quality
lower esophagus mucosa	UBERON:0035834	86.28	gold quality
pancreas	UBERON:0001264	85.64	gold quality
islet of Langerhans	UBERON:0000006	85.19	gold quality
esophagus mucosa	UBERON:0002469	83.88	gold quality
right adrenal gland	UBERON:0001233	77.28	gold quality
left adrenal gland	UBERON:0001234	75.96	gold quality
vagina	UBERON:0000996	75.94	gold quality
thymus	UBERON:0002370	75.83	silver quality
left adrenal gland cortex	UBERON:0035825	75.51	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	74.49	gold quality
right adrenal gland cortex	UBERON:0035827	74.26	gold quality
adrenal gland	UBERON:0002369	72.57	gold quality
placenta	UBERON:0001987	70.26	gold quality
cerebellar vermis	UBERON:0004720	70.12	gold quality
spleen	UBERON:0002106	68.27	gold quality
minor salivary gland	UBERON:0001830	67.31	gold quality
saliva-secreting gland	UBERON:0001044	66.78	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	66.16	gold quality
spinal cord	UBERON:0002240	65.44	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	65.37	gold quality
omental fat pad	UBERON:0010414	65.15	gold quality
hypothalamus	UBERON:0001898	63.26	gold quality
esophagus	UBERON:0001043	62.49	gold quality
quadriceps femoris	UBERON:0001377	61.63	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	61.57	gold quality
smooth muscle tissue	UBERON:0001135	61.53	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.69

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

68 targeting CPA4, 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-8485	100.00	77.57	4731
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-4650-5P	99.98	64.69	999
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-4715-3P	99.98	66.03	670
HSA-MIR-548AN	99.97	70.91	2817
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-6768-5P	99.92	67.36	1942

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 15)

• CPA4 gene is imprinted, with preferential expression from the maternal allele in many fetal tissues, but not in fetal brain. (PMID:12552318)
• The three-dimensional structure of procarboxypeptidase-A4 (hPCPA4) has been solved and shows the features of related metallocarboxypeptidase zymogens, with a preformed alpha/beta/-hydrolase active-enzyme moiety (hCPA4) and an inhibiting pro-domain (PD). (PMID:16091843)
• genetic polymorphism is associated with an increased risk of aggressive prostate cancer among younger patients (< 66 years) (PMID:19245716)
• CPA4 functions in neuropeptide processing and regulation in the extracellular environment (PMID:20385563)
• NvCL form Nerita versicolor is a tight-binding inhibitor that interacts with the active site of the CPA4 in a substrate-like manner. (PMID:22294694)
• The crystal structure of the human CPA4 carboxypeptidase in complex with SmCI, a peptide protease inhibitor. (PMID:23746805)
• Serum CPA4 concentration combined with lymph node involvement may be used as accurate predictors of liver metastasis in colorectal cancer. (PMID:27780921)
• CPA4 as a negative regulator of adipogenesis that is down-regulated by FGF-1. Expression of CPA4 in subcutaneous adipose tissue correlated negatively with insulin sensitivity. (PMID:28209092)
• we revealed that CPA4 downregulation may induce apoptosis and G1-S arrest by suppressing the protein kinase B/c-MYC pathway. These results suggest that CPA4 has an oncogenic effect on lung cancer growth. Taken together, we identified a novel gene in lung cancer that might provide a basis for new therapeutic targets. (PMID:31397502)
• Findings suggest that the angiotensin II (Ang II) generation from hAng-(1-12) is primarily mediated by chymase rather than carboxypeptidase A (CPA). (PMID:31466718)
• Carboxypeptidase A4 promotes cardiomyocyte hypertrophy through activating PI3K-AKT-mTOR signaling. (PMID:32347291)
• Carboxypeptidase A4 negatively correlates with p53 expression and regulates the stemness of breast cancer cells. (PMID:33746592)
• circCPA4 induces malignant behaviors of prostate cancer via miR-491-5p/SHOC2 feedback loop. (PMID:38219533)
• CircCPA4 induces ASCT2 expression to promote tumor property of non-small cell lung cancer cells in a miR-145-5p-dependent manner. (PMID:38400818)
• Macrophage-Induced Carboxypeptidase A4 Promotes the Progression of Anaplastic Thyroid Cancer. (PMID:38666696)

Cross-species orthologs

22 orthologs

Organism	Symbol	Gene ID
mus_musculus	Cpa4	ENSMUSG00000039070
drosophila_melanogaster	CG3097	FBGN0029804
drosophila_melanogaster	CG3108	FBGN0029807
drosophila_melanogaster	CG18585	FBGN0031929
drosophila_melanogaster	CG7025	FBGN0031930
drosophila_melanogaster	CG4017	FBGN0032143
drosophila_melanogaster	CG17633	FBGN0032144
drosophila_melanogaster	CG2915	FBGN0033241
drosophila_melanogaster	CG12374	FBGN0033774
drosophila_melanogaster	CG14820	FBGN0035718
drosophila_melanogaster	CG8563	FBGN0035777
drosophila_melanogaster	CG8562	FBGN0035779
drosophila_melanogaster	CG18417	FBGN0035780
drosophila_melanogaster	CG8560	FBGN0035781
drosophila_melanogaster	CG8539	FBGN0035791
drosophila_melanogaster	CG4408	FBGN0039073
drosophila_melanogaster	CG32379	FBGN0052379
drosophila_melanogaster	CG42264	FBGN0259149
caenorhabditis_elegans		WBGENE00004747
caenorhabditis_elegans	T06A4.1	WBGENE00020281
caenorhabditis_elegans	Y47G6A.19	WBGENE00021645
caenorhabditis_elegans		WBGENE00021984

Paralogs (8): CPB2 (ENSG00000080618), CPA1 (ENSG00000091704), CPO (ENSG00000144410), CPB1 (ENSG00000153002), CPA2 (ENSG00000158516), CPA5 (ENSG00000158525), CPA3 (ENSG00000163751), CPA6 (ENSG00000165078)

Protein

Protein identifiers

Carboxypeptidase A4 — Q9UI42 (reviewed: Q9UI42)

Alternative names: Carboxypeptidase A3

All UniProt accessions (6): Q9UI42, A4D1M3, B7Z5J4, C9J3P4, C9J6N7, C9J7D6

UniProt curated annotations — full annotation on UniProt →

Function. Metalloprotease that cleaves hydrophobic C-terminal residues with a preference for -Phe, -Leu, -Ile, -Met, -Tyr and -Val. May function in peptide hormone and/or neuropeptide catabolism.

Subunit / interactions. Monomer. Interacts with LXN.

Subcellular location. Secreted.

Tissue specificity. Fetal expression in the adrenal gland, brain, heart, intestine, kidney, liver and lung. Except for fetal brain that shows no imprinting, expression was found preferentially from the maternal allele.

Activity regulation. Inhibited by interaction with the metallocarboxypeptidase inhibitor (MCPI) from N.versicolor that binds to the catalytic zinc ion. Also inhibited by interaction with the S.magnifica carboxypeptidase inhibitor SmCI that penetrates the active site groove and inhibits activity by emulating a C-terminal substrate. Additionally inhibited by a carboxypeptidase inhibitor from H.medicinalis (leech) and R.bursa (tick).

Cofactor. Binds 1 zinc ion per subunit.

Induction. Induced by the histone deacetylase inhibitors trichostatin A and sodium butyrate.

Similarity. Belongs to the peptidase M14 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9UI42-1	1	yes
Q9UI42-2	2

RefSeq proteins (2): NP_001156918, NP_057436* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000834	Peptidase_M14	Domain
IPR003146	M14A_act_pep	Domain
IPR034248	CPA_M14_CPD	Domain
IPR036990	M14A-like_propep	Homologous_superfamily
IPR057246	CARBOXYPEPT_ZN_1	Binding_site
IPR057247	CARBOXYPEPT_ZN_2	Binding_site

Pfam: PF00246, PF02244

Enzyme classification (BRENDA):

• EC 3.4.17.1 — carboxypeptidase A (BRENDA: 32 organisms, 224 substrates, 281 inhibitors, 110 Km, 101 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
HIPPURYL-L-PHENYLALANINE	0.075–1.5	11
HIPPURYL-L-PHE	0.33–60	8
CARBOBENZOXY-GLY-L-PHE	0.21–16.1	5
BENZOYL-GLY-L-PHE	0.23–10	3
HIPPURYL-L-PHENYLLACTATE	0.062–0.11	3
N-[3-(2-FURYL)ACRYLOYL]-PHE-PHE	27–340	3
O-(TRANS-P-CHLOROCINNAMOYL)-L-BETA-PHENYLLACTATE	0.49–120	3
ANGIOTENSIN I	0.227–0.78	2
CARBOBENZOXY-GLY-L-LEU	0.16–33	2
HIPPURYL-DL-BETA-PHENYLLACTATE	780–1300	2
N-(3-[2-FURYL]ACRYLOYL)-PHE-PHE	0.024–0.034	2
N-CARBOBENZOXY-GLY-GLY-L-LEU	0.74–6.53	2
N-CARBOBENZOXY-GLY-GLY-L-PHE	0.0346–0.314	2
N-CARBOBENZOXY-GLY-L-PHE	0.0449–0.985	2
N-CARBOBENZOXY-GLY-L-TYR	0.143–0.145	2

UniProt features (67 total): strand 18, helix 17, binding site 15, sequence variant 4, turn 4, signal peptide 1, propeptide 1, chain 1, glycosylation site 1, disulfide bond 1, splice variant 1, sequence conflict 1, domain 1, active site 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
2BO9	X-RAY DIFFRACTION	1.6
2PCU	X-RAY DIFFRACTION	1.6
4A94	X-RAY DIFFRACTION	1.7
2BOA	X-RAY DIFFRACTION	2.2
4BD9	X-RAY DIFFRACTION	2.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UI42-F1	93.88	0.88

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): 382 (proton donor/acceptor)

Ligand- & substrate-binding residues (15): 125; 127; 163; 181; 184; 196; 197; 248; 270; 308; 69; 71 …

Disulfide bonds (1): 250–273

Glycosylation sites (1): 260

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 287 (showing top): MODULE_172, RNGTGGGC_UNKNOWN, chr3q24, GOBP_REGULATION_OF_SYSTEMIC_ARTERIAL_BLOOD_PRESSURE_BY_CIRCULATORY_RENIN_ANGIOTENSIN, GRUETZMANN_PANCREATIC_CANCER_DN, GOBP_REGULATION_OF_BLOOD_PRESSURE, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOMF_METALLOPEPTIDASE_ACTIVITY, JAEGER_METASTASIS_DN, GOCC_SECRETORY_GRANULE, LI_PROSTATE_CANCER_EPIGENETIC, GOBP_REGULATION_OF_SYSTEMIC_ARTERIAL_BLOOD_PRESSURE, GOBP_REGULATION_OF_HORMONE_LEVELS, CAGGTCC_MIR492, SREBP1_02

GO Biological Process (3): proteolysis (GO:0006508), hormone catabolic process (GO:0042447), peptide catabolic process (GO:0043171)

GO Molecular Function (8): metallocarboxypeptidase activity (GO:0004181), zinc ion binding (GO:0008270), carboxypeptidase activity (GO:0004180), protein binding (GO:0005515), peptidase activity (GO:0008233), metallopeptidase activity (GO:0008237), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (2): obsolete extracellular space (GO:0005615), extracellular region (GO:0005576)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
catabolic process	2
protein metabolic process	1
hormone metabolic process	1
peptide metabolic process	1
carboxypeptidase activity	1
metalloexopeptidase activity	1
transition metal ion binding	1
exopeptidase activity	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
peptidase activity	1
catalytic activity	1
cation binding	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1118 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CPA4	LXN	Q9BS40	935
CPA4	CMA1	P23946	837
CPA4	TPSAB1	P15157	726
CPA4	MEST	Q5EB52	721
CPA4	CTSG	P08311	685
CPA4	SRGN	P10124	678
CPA4	FCER1A	P12319	660
CPA4	A0A087X1U0	A0A087X1U0	629
CPA4	MS4A1	P08984	617
CPA4	TSGA13	Q96PP4	590
CPA4	GATA2	P23769	587
CPA4	MS4A2	Q01362	578
CPA4	HDC	P19113	482
CPA4	MRGPRX2	Q96LB1	469
CPA4	TPSG1	Q9NRR2	460

IntAct

96 interactions, top by confidence:

A	B	Type	Score
POC5	CETN3	psi-mi:“MI:0914”(association)	0.770
POLR2L	RCCD1	psi-mi:“MI:0914”(association)	0.640
CCNC	MED19	psi-mi:“MI:0914”(association)	0.640
CFAP298	PEX7	psi-mi:“MI:0914”(association)	0.620
ZSCAN12	A2ML1	psi-mi:“MI:0914”(association)	0.530
NPPA	A2ML1	psi-mi:“MI:0914”(association)	0.530
FTH1	A2ML1	psi-mi:“MI:0914”(association)	0.530
GMCL1	A2ML1	psi-mi:“MI:0914”(association)	0.530
TBC1D22B	A2ML1	psi-mi:“MI:0914”(association)	0.530
CCDC51	TGM5	psi-mi:“MI:0914”(association)	0.530
AIRE	ALOX12B	psi-mi:“MI:0914”(association)	0.530
B3GALNT1	DUSP14	psi-mi:“MI:0914”(association)	0.530
RAB9B	CHM	psi-mi:“MI:0914”(association)	0.530
NDUFS5	NDUFS4	psi-mi:“MI:0914”(association)	0.530
KIR3DS1	PPL	psi-mi:“MI:0914”(association)	0.530
ZIC1	CTSV	psi-mi:“MI:0914”(association)	0.530
PDPK1	HSPA8	psi-mi:“MI:0914”(association)	0.530
CLINT1	PIK3C2A	psi-mi:“MI:0914”(association)	0.530
CPA4	ENDOG	psi-mi:“MI:0915”(physical association)	0.400
CDK15	A2ML1	psi-mi:“MI:0914”(association)	0.350
ASCC1	IGLL5	psi-mi:“MI:0914”(association)	0.350

BioGRID (116): CPA4 (Affinity Capture-MS), CPA4 (Affinity Capture-MS), CPA4 (Affinity Capture-MS), CPA4 (Affinity Capture-MS), CPA4 (Affinity Capture-MS), CPA4 (Affinity Capture-MS), CPA4 (Affinity Capture-MS), ENDOG (Affinity Capture-MS), CPA4 (Affinity Capture-MS), CPA4 (Affinity Capture-MS), CPA4 (Affinity Capture-MS), CPA4 (Affinity Capture-MS), CPA4 (Affinity Capture-MS), CPA4 (Affinity Capture-MS), CPA4 (Affinity Capture-MS)

ESM2 similar proteins: A0A1S4F020, A6XGK3, B6V865, B8JLQ9, B8XGR3, C5FH26, C5FVN6, D4AS12, D4B5N0, D4D675, D4DL57, O02350, O17754, O97397, P00730, P00731, P00732, P09954, P09955, P15085, P15086, P15088, P15089, P16406, P19222, P19223, P21961, P37892, P38836, P42787, P48052, P54969, P55261, Q0II73, Q29NC4, Q2KIG3, Q2KJ83, Q3T905, Q4R7R2, Q504N0

Diamond homologs: A1CSU3, A1DGH9, A2QZA2, A6RCF5, A6XGK3, A7EUC0, B0XRS8, B6H233, B6Q972, B6V865, B8M2K0, B8NBP9, B8XGR3, C0NM08, C0SAI5, C1GDH9, C1HE31, C4JEE1, C5FH26, C5FPR9, C5FVN6, C5G6U8, C5JZS0, C5PHW9, C6H4F1, D4AKU7, D4AS12, D4B5N0, D4D675, D4DIW7, D4DL57, E4UPZ6, E5A0U8, E9DD69, O02350, O74818, P00730, P00731, P00732, P04069

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	120
Likely benign	7
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

2778 predictions. Top by Δscore:

Variant	Effect	Δscore
3:148865457:ATTT:A	acceptor_gain	1.0000
3:148865460:T:TA	acceptor_gain	1.0000
3:148865467:A:AG	acceptor_gain	1.0000
3:148865469:A:AG	acceptor_gain	1.0000
3:148865470:A:G	acceptor_gain	1.0000
3:148865546:GAG:G	donor_gain	1.0000
3:148865548:GGT:G	donor_loss	1.0000
3:148865549:G:GA	donor_loss	1.0000
3:148865550:T:A	donor_loss	1.0000
3:148868911:GCA:G	acceptor_loss	1.0000
3:148868912:CAG:C	acceptor_loss	1.0000
3:148868913:A:AG	acceptor_gain	1.0000
3:148868913:AGC:A	acceptor_loss	1.0000
3:148868914:G:GG	acceptor_gain	1.0000
3:148868914:GCTT:G	acceptor_gain	1.0000
3:148869038:GA:G	donor_gain	1.0000
3:148869040:G:GG	donor_gain	1.0000
3:148878431:T:A	acceptor_gain	1.0000
3:148878435:A:AG	acceptor_gain	1.0000
3:148878436:A:G	acceptor_gain	1.0000
3:148878438:CAG:C	acceptor_loss	1.0000
3:148878439:A:AG	acceptor_gain	1.0000
3:148878440:G:GA	acceptor_loss	1.0000
3:148878440:G:GG	acceptor_gain	1.0000
3:148878440:GA:G	acceptor_gain	1.0000
3:148878440:GAAT:G	acceptor_gain	1.0000
3:148878539:AAAAG:A	donor_loss	1.0000
3:148878542:AGGTA:A	donor_loss	1.0000
3:148878544:GT:G	donor_loss	1.0000
3:148878545:T:G	donor_loss	1.0000

AlphaMissense

2786 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:130308391:T:C	F263L	0.992
7:130308393:T:A	F263L	0.992
7:130308393:T:G	F263L	0.992
7:130322581:T:C	F391L	0.991
7:130322583:C:A	F391L	0.991
7:130322583:C:G	F391L	0.991
7:130310918:A:C	S309R	0.989
7:130310920:C:A	S309R	0.989
7:130310920:C:G	S309R	0.989
7:130305882:T:A	W185R	0.987
7:130305882:T:C	W185R	0.987
7:130305884:G:C	W185C	0.986
7:130305884:G:T	W185C	0.986
7:130308379:T:A	W259R	0.985
7:130308379:T:C	W259R	0.985
7:130306867:T:A	N224K	0.984
7:130306867:T:G	N224K	0.984
7:130322500:G:T	G364W	0.984
7:130322506:A:C	S366R	0.984
7:130322508:C:A	S366R	0.984
7:130322508:C:G	S366R	0.984
7:130322614:G:C	A402P	0.984
7:130304560:G:C	R156P	0.982
7:130304548:C:G	S152W	0.981
7:130305880:A:T	E184V	0.981
7:130308378:C:A	N258K	0.981
7:130308378:C:G	N258K	0.981
7:130308318:G:C	W238C	0.980
7:130308318:G:T	W238C	0.980
7:130306871:G:C	D226H	0.978

dbSNP variants (sampled 300 via entrez): RS1000337607 (7:130318646 G>C), RS1000552890 (7:130301545 C>T), RS1000611902 (7:130324048 G>A), RS1000674594 (7:130317347 G>C), RS1000873467 (7:130301782 A>G), RS1000882555 (7:130297963 C>G), RS1000993924 (7:130314914 G>A), RS1001027228 (7:130298144 C>G,T), RS1001169192 (7:130305224 G>A), RS1001217564 (7:130299106 C>T), RS1001236750 (7:130303805 T>TG), RS1001449025 (7:130320340 T>A), RS1001489155 (7:130292058 G>C), RS1001508905 (7:130291414 A>G), RS1001612519 (7:130299244 C>A,T)

Disease associations

OMIM: gene MIM:607635 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST002989_6	LDL peak particle diameter (total fat intake interaction)	9.000000e-07
GCST005146_22	Birth weight	6.000000e-10
GCST005958_14	Waist-to-hip ratio adjusted for BMI (age >50)	1.000000e-07
GCST005962_34	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	6.000000e-07
GCST006585_421	Blood protein levels	0.000000e+00
GCST007843_10	Rheumatoid arthritis	6.000000e-12
GCST008362_211	Birth weight	2.000000e-13
GCST90002381_191	Eosinophil count	5.000000e-12
GCST90020026_595	Hip index	3.000000e-11

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0007677	LDL peak particle diameter measurement
EFO:0007678	total fat intake measurement
EFO:0004344	birth weight
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0004842	eosinophil count
EFO:0008039	BMI-adjusted hip circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2644 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — M14: Carboxypeptidase A

ChEMBL bioactivities

11 potent at pChembl≥5 of 11 total, top 11 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.41	Ki	0.39	nM	CHEMBL4460840
8.72	Ki	1.9	nM	CHEMBL4436298
8.59	Ki	2.6	nM	CHEMBL4483485
8.48	Ki	3.3	nM	CHEMBL4528407
8.46	Ki	3.5	nM	CHEMBL4454162
8.27	Ki	5.4	nM	CHEMBL4513310
8.24	Ki	5.7	nM	CHEMBL4445882
8.12	Ki	7.5	nM	CHEMBL4453900
7.59	Ki	25.4	nM	CHEMBL4532731
7.41	Ki	38.6	nM	CHEMBL4448096
7.22	Ki	60.6	nM	CHEMBL4440735

PubChem BioAssay actives

11 with measured affinity, of 11 total; 11 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
(2S)-2-[[[(1R)-1-[[(2S)-2-acetamido-4-methylpentanoyl]amino]-2-phenylethyl]-hydroxyphosphoryl]methyl]-3-phenylpropanoic acid	1614547: Inhibition of human CPA4 using AAFP as substrate preincubated for 45 mins to 2 hrs measured at 30 sec intervals for 15 mins by UV/vis-spectrophotometry	ki	0.0004	uM
(2S)-2-[[[(1R)-1-[[(2S)-2-acetamido-4-methylpentanoyl]amino]-2-phenylethyl]-hydroxyphosphoryl]methyl]-4-phenylbutanoic acid	1614547: Inhibition of human CPA4 using AAFP as substrate preincubated for 45 mins to 2 hrs measured at 30 sec intervals for 15 mins by UV/vis-spectrophotometry	ki	0.0019	uM
(2S)-2-[[[(1R)-1-[[(2S)-2-acetamido-3-(4-hydroxyphenyl)propanoyl]amino]ethyl]-hydroxyphosphoryl]methyl]-4-phenylbutanoic acid	1614547: Inhibition of human CPA4 using AAFP as substrate preincubated for 45 mins to 2 hrs measured at 30 sec intervals for 15 mins by UV/vis-spectrophotometry	ki	0.0026	uM
(2S)-2-[[[(1R)-1-[[(2S)-2-acetamido-4-methylpentanoyl]amino]ethyl]-hydroxyphosphoryl]methyl]-4-phenylbutanoic acid	1614547: Inhibition of human CPA4 using AAFP as substrate preincubated for 45 mins to 2 hrs measured at 30 sec intervals for 15 mins by UV/vis-spectrophotometry	ki	0.0033	uM
(2S)-2-[[[(1R)-1-[[(2S)-2-[[2-[2-(2-acetamidoethoxy)ethoxy]acetyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]ethyl]-hydroxyphosphoryl]methyl]-4-phenylbutanoic acid	1614547: Inhibition of human CPA4 using AAFP as substrate preincubated for 45 mins to 2 hrs measured at 30 sec intervals for 15 mins by UV/vis-spectrophotometry	ki	0.0035	uM
(2S)-2-[[[(1R)-1-[[(2S)-2-[[2-[2-(2-aminoethoxy)ethoxy]acetyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]ethyl]-hydroxyphosphoryl]methyl]-4-phenylbutanoic acid	1614547: Inhibition of human CPA4 using AAFP as substrate preincubated for 45 mins to 2 hrs measured at 30 sec intervals for 15 mins by UV/vis-spectrophotometry	ki	0.0054	uM
(2E)-2-[(2Z,4E)-3-[4-[3-[2-[2-[2-[3-[2-[2-[2-[[(2S)-1-[[(1R)-1-[[(2S)-2-carboxy-4-phenylbutyl]-hydroxyphosphoryl]ethyl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-2-oxoethoxy]ethoxy]ethylamino]-3-oxopropoxy]ethoxy]ethoxy]ethylamino]-3-oxopropyl]phenyl]-5-[1,1-dimethyl-6,8-disulfo-3-(4-sulfobutyl)benzo[e]indol-3-ium-2-yl]penta-2,4-dienylidene]-1,1-dimethyl-8-sulfo-3-(4-sulfobutyl)benzo[e]indole-6-sulfonate	1614547: Inhibition of human CPA4 using AAFP as substrate preincubated for 45 mins to 2 hrs measured at 30 sec intervals for 15 mins by UV/vis-spectrophotometry	ki	0.0057	uM
(2S)-2-[[[(1R)-1-[[(2S)-1-acetylpyrrolidine-2-carbonyl]amino]ethyl]-hydroxyphosphoryl]methyl]-4-phenylbutanoic acid	1614547: Inhibition of human CPA4 using AAFP as substrate preincubated for 45 mins to 2 hrs measured at 30 sec intervals for 15 mins by UV/vis-spectrophotometry	ki	0.0075	uM
(2S)-2-[[[(1R)-1-[[(2S)-2-acetamido-6-aminohexanoyl]amino]ethyl]-hydroxyphosphoryl]methyl]-4-phenylbutanoic acid	1614547: Inhibition of human CPA4 using AAFP as substrate preincubated for 45 mins to 2 hrs measured at 30 sec intervals for 15 mins by UV/vis-spectrophotometry	ki	0.0254	uM
(4S)-4-acetamido-5-[[(1R)-1-[[(2S)-2-carboxy-4-phenylbutyl]-hydroxyphosphoryl]ethyl]amino]-5-oxopentanoic acid	1614547: Inhibition of human CPA4 using AAFP as substrate preincubated for 45 mins to 2 hrs measured at 30 sec intervals for 15 mins by UV/vis-spectrophotometry	ki	0.0386	uM
(2S)-2-[[[(1R)-1-[[(2S)-2-acetamido-3-hydroxypropanoyl]amino]ethyl]-hydroxyphosphoryl]methyl]-4-phenylbutanoic acid	1614547: Inhibition of human CPA4 using AAFP as substrate preincubated for 45 mins to 2 hrs measured at 30 sec intervals for 15 mins by UV/vis-spectrophotometry	ki	0.0606	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects cotreatment, increases abundance, affects binding, increases reaction, decreases expression	4
Air Pollutants	increases abundance, increases expression, decreases expression	4
Particulate Matter	increases abundance, affects cotreatment, decreases expression	4
bisphenol A	decreases expression, increases expression	3
Cadmium Chloride	increases expression	3
(+)-JQ1 compound	decreases expression, increases expression	2
Benzo(a)pyrene	decreases methylation, increases expression	2
Cadmium	affects expression, increases expression	2
Silicon Dioxide	decreases expression, increases expression	2
aristolochic acid I	increases expression	1
methyleugenol	increases expression	1
propionaldehyde	increases expression	1
2,5,2’,5’-tetrachlorobiphenyl	decreases expression	1
arsenite	decreases expression	1
mono-(2-ethylhexyl)phthalate	decreases expression	1
sulforaphane	decreases expression	1
cobaltous chloride	decreases secretion	1
butyraldehyde	increases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
didecyldimethylammonium	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
isobutyl alcohol	affects cotreatment, decreases expression, increases abundance	1
pentanal	increases expression	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
erucylphospho-N,N,N-trimethylpropylammonium	decreases expression	1
nutlin 3	affects cotreatment, increases secretion	1
abrine	increases expression	1
palbociclib	increases expression	1
archazolid B	increases expression	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
CHEMBL4413960	Binding	Inhibition of human CPA4 using AAFP as substrate preincubated for 45 mins to 2 hrs measured at 30 sec intervals for 15 mins by UV/vis-spectrophotometry	Synthesis and Structural/Functional Characterization of Selective M14 Metallocarboxypeptidase Inhibitors Based on Phosphinic Pseudopeptide Scaffold: Implications on the Design of Specific Optical Probes. — J Med Chem

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1P4	Abcam HeLa CPA4 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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