PGA4

Summary

PGA4 (pepsinogen A4, HGNC:8886) is a protein-coding gene on chromosome 11q12.2, encoding Pepsin A-4 (P0DJD7). Shows particularly broad specificity; although bonds involving phenylalanine and leucine are preferred, many others are also cleaved to some extent.

This gene encodes a protein precursor of the digestive enzyme pepsin, a member of the peptidase A1 family of endopeptidases. The encoded precursor is secreted by gastric chief cells and undergoes autocatalytic cleavage in acidic conditions to form the active enzyme, which functions in the digestion of dietary proteins. This gene is found in a cluster of related genes on chromosome 11, each of which encodes one of multiple pepsinogens. Pepsinogen levels in serum may serve as a biomarker for atrophic gastritis and gastric cancer.

Source: NCBI Gene 643847 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 9 total
• MANE Select transcript: NM_001079808

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8886
Approved symbol	PGA4
Name	pepsinogen A4
Location	11q12.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000229183
Ensembl biotype	protein_coding
OMIM	169720
Entrez	643847

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 4 retained_intron, 3 protein_coding, 1 TEC

ENST00000378149, ENST00000537932, ENST00000539581, ENST00000541743, ENST00000543193, ENST00000544899, ENST00000545726, ENST00000624544

RefSeq mRNA: 3 — MANE Select: NM_001079808 NM_001079808, NM_001422100, NM_001422101

CCDS: CCDS31575

Canonical transcript exons

ENST00000378149 — 9 exons

Exon	Start	End
ENSE00002455546	61222347	61222456
ENSE00002462544	61227120	61227319
ENSE00002508847	61231382	61231694
ENSE00002520217	61226326	61226444
ENSE00003563152	61228671	61228787
ENSE00003624060	61222943	61223105
ENSE00003671567	61229919	61230063
ENSE00003682565	61230166	61230264
ENSE00003692619	61225339	61225456

Expression profiles

Bgee: expression breadth ubiquitous, 128 present calls, max score 98.91.

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right uterine tube	UBERON:0001302	98.91	gold quality
body of stomach	UBERON:0001161	95.88	gold quality
stomach	UBERON:0000945	94.33	gold quality
lower esophagus mucosa	UBERON:0035834	92.71	gold quality
fundus of stomach	UBERON:0001160	92.39	gold quality
right coronary artery	UBERON:0001625	90.82	gold quality
mucosa of stomach	UBERON:0001199	88.92	gold quality
endocervix	UBERON:0000458	85.85	gold quality
ectocervix	UBERON:0012249	85.41	gold quality
left uterine tube	UBERON:0001303	83.23	gold quality
right lung	UBERON:0002167	82.07	gold quality
metanephros cortex	UBERON:0010533	81.94	gold quality
body of pancreas	UBERON:0001150	81.35	gold quality
right ovary	UBERON:0002118	80.60	gold quality
uterine cervix	UBERON:0000002	80.17	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	79.02	gold quality
fallopian tube	UBERON:0003889	78.93	gold quality
right lobe of liver	UBERON:0001114	78.07	gold quality
spleen	UBERON:0002106	77.88	gold quality
descending thoracic aorta	UBERON:0002345	77.84	gold quality
right adrenal gland	UBERON:0001233	77.34	gold quality
left ovary	UBERON:0002119	77.00	gold quality
transverse colon	UBERON:0001157	76.78	gold quality
subcutaneous adipose tissue	UBERON:0002190	76.51	gold quality
mucosa of transverse colon	UBERON:0004991	76.28	gold quality
left adrenal gland	UBERON:0001234	76.26	gold quality
esophagus mucosa	UBERON:0002469	76.25	gold quality
left adrenal gland cortex	UBERON:0035825	76.16	gold quality
adipose tissue	UBERON:0001013	75.97	gold quality
omental fat pad	UBERON:0010414	75.61	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.97

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

5 targeting PGA4, 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-6793-5P	99.97	65.95	758
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-4768-3P	98.16	66.02	2330
HSA-MIR-194-3P	97.36	65.96	1027

Cross-species orthologs

14 orthologs

Organism	Symbol	Gene ID
drosophila_melanogaster	Bace	FBGN0032049
drosophila_melanogaster	CG6508	FBGN0032303
drosophila_melanogaster	CG17134	FBGN0032304
drosophila_melanogaster	CG33128	FBGN0053128
caenorhabditis_elegans		WBGENE00000214
caenorhabditis_elegans		WBGENE00000218
caenorhabditis_elegans		WBGENE00012681
caenorhabditis_elegans		WBGENE00012682
caenorhabditis_elegans		WBGENE00012683
caenorhabditis_elegans		WBGENE00013973
caenorhabditis_elegans		WBGENE00017678
caenorhabditis_elegans		WBGENE00019104
caenorhabditis_elegans		WBGENE00019105
caenorhabditis_elegans		WBGENE00077655

Paralogs (9): PGC (ENSG00000096088), CTSD (ENSG00000117984), NAPSA (ENSG00000131400), REN (ENSG00000143839), BACE2 (ENSG00000182240), BACE1 (ENSG00000186318), CTSE (ENSG00000196188), PGA3 (ENSG00000229859), PGA5 (ENSG00000256713)

Protein

Protein identifiers

Pepsin A-4 — P0DJD7 (reviewed: P0DJD7)

Alternative names: Pepsinogen-4

All UniProt accessions (4): P0DJD7, A0A1S5UZ02, F5GXL4, F5H0H6

UniProt curated annotations — full annotation on UniProt →

Function. Shows particularly broad specificity; although bonds involving phenylalanine and leucine are preferred, many others are also cleaved to some extent.

Subcellular location. Secreted.

Similarity. Belongs to the peptidase A1 family.

RefSeq proteins (3): NP_001073276, NP_001409029, NP_001409030 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001461	Aspartic_peptidase_A1	Family
IPR001969	Aspartic_peptidase_AS	Active_site
IPR012848	Aspartic_peptidase_N	Domain
IPR021109	Peptidase_aspartic_dom_sf	Homologous_superfamily
IPR033121	PEPTIDASE_A1	Domain
IPR034162	Pepsin_A	Domain

Pfam: PF00026, PF07966

UniProt features (53 total): strand 26, helix 11, turn 4, disulfide bond 3, sequence conflict 2, active site 2, signal peptide 1, propeptide 1, chain 1, domain 1, modified residue 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
1QRP	X-RAY DIFFRACTION	1.96
1PSO	X-RAY DIFFRACTION	2
1PSN	X-RAY DIFFRACTION	2.2
1FLH	X-RAY DIFFRACTION	2.45
3UTL	X-RAY DIFFRACTION	2.61

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P0DJD7-F1	91.15	0.74

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): 94; 277

Post-translational modifications (1): 130

Disulfide bonds (3): 107–112, 268–272, 311–344

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-5683826	Surfactant metabolism

MSigDB gene sets: 19 (showing top): GOBP_DIGESTION, NIKOLSKY_BREAST_CANCER_11Q12_Q14_AMPLICON, GOCC_MULTIVESICULAR_BODY, GOCC_ENDOSOME_LUMEN, GOBP_PROTEOLYSIS, GOMF_PEPTIDASE_ACTIVITY, GOMF_ASPARTIC_TYPE_PEPTIDASE_ACTIVITY, GOCC_LATE_ENDOSOME_LUMEN, GOCC_MULTIVESICULAR_BODY_LUMEN, REACTOME_SURFACTANT_METABOLISM, MIR4768_3P, MIR194_3P, MIR6793_5P, WP_GASTRIC_ACID_PRODUCTION, FOURATI_BLOOD_TWINRIX_AGE_25_83YO_RESPONDERS_VS_POOR_RESPONDERS_0DY_DN

GO Biological Process (2): proteolysis (GO:0006508), digestion (GO:0007586)

GO Molecular Function (4): aspartic-type endopeptidase activity (GO:0004190), protein binding (GO:0005515), peptidase activity (GO:0008233), hydrolase activity (GO:0016787)

GO Cellular Component (3): extracellular exosome (GO:0070062), multivesicular body lumen (GO:0097486), extracellular region (GO:0005576)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein metabolic process	1
multicellular organismal process	1
endopeptidase activity	1
aspartic-type peptidase activity	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
catalytic activity	1
extracellular vesicle	1
multivesicular body	1
late endosome lumen	1
cellular anatomical structure	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

29 interactions, top by confidence:

A	B	Type	Score
PGA4	SPAG4	psi-mi:“MI:0915”(physical association)	0.560
CD74	PGA4	psi-mi:“MI:0915”(physical association)	0.560
PGA4	STOM	psi-mi:“MI:0915”(physical association)	0.560
PGA4	TMEM106C	psi-mi:“MI:0915”(physical association)	0.560
PGA4	HHLA2	psi-mi:“MI:0915”(physical association)	0.560
PGA4	FIMP	psi-mi:“MI:0915”(physical association)	0.560
PGA4	AMIGO1	psi-mi:“MI:0915”(physical association)	0.560
PGA4	FNDC9	psi-mi:“MI:0915”(physical association)	0.560
PGA4	PVR	psi-mi:“MI:0915”(physical association)	0.560
NTNG1	AMY1A	psi-mi:“MI:0914”(association)	0.350
SPAG4	PGA4	psi-mi:“MI:0915”(physical association)	0.000
PGA4	SPAG4	psi-mi:“MI:0915”(physical association)	0.000
PGA4	CD74	psi-mi:“MI:0915”(physical association)	0.000
PGA4	STOM	psi-mi:“MI:0915”(physical association)	0.000
PGA4	TMEM106C	psi-mi:“MI:0915”(physical association)	0.000
PGA4	HHLA2	psi-mi:“MI:0915”(physical association)	0.000
PGA4	FIMP	psi-mi:“MI:0915”(physical association)	0.000
PGA4	AMIGO1	psi-mi:“MI:0915”(physical association)	0.000
PGA4	FNDC9	psi-mi:“MI:0915”(physical association)	0.000
PGA4	PVR	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (11): PGA4 (Two-hybrid), PGA4 (Two-hybrid), PGA4 (Two-hybrid), PGA4 (Two-hybrid), PGA4 (Two-hybrid), PGA4 (Two-hybrid), PGA4 (Two-hybrid), PGA4 (Two-hybrid), PGA4 (Two-hybrid), PGA4 (Affinity Capture-MS), PGA4 (Affinity Capture-MS)

ESM2 similar proteins: O93428, P00791, P00792, P00793, P00794, P00795, P03954, P03955, P04073, P0DJD7, P0DJD8, P0DJD9, P11489, P14091, P16228, P16476, P18276, P20142, P25796, P27677, P27678, P27821, P27822, P27823, P28712, P28713, P43159, P56272, P70269, P81497, P81498, Q03168, Q28389, Q64411, Q689Z7, Q800A0, Q805F2, Q805F3, Q8SQ41, Q9D7R7

Diamond homologs: A0A146F0J0, A1CBR4, A1DDK1, A2R3L3, B0Y1V8, B6HL60, B8MF81, B8NLY9, C5FBS2, C5FW52, C5FZ57, C5PEI9, D4AIC4, D4ANC3, D4AT39, D4D7C5, D4DE18, D4DGR1, E5A7T3, E5R1B9, O01530, O13340, O60020, O65390, O76856, O93885, P00791, P00792, P00798, P03954, P03955, P04073, P06026, P0CU33, P0DJD7, P0DJD8, P0DJD9, P10602, P11489, P11838

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	8
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

848 predictions. Top by Δscore:

Variant	Effect	Δscore
11:61222457:G:GG	donor_gain	1.0000
11:61222939:ACAG:A	acceptor_gain	1.0000
11:61222941:A:AG	acceptor_gain	1.0000
11:61222941:AG:A	acceptor_gain	1.0000
11:61222941:AGG:A	acceptor_gain	1.0000
11:61222942:G:GA	acceptor_gain	1.0000
11:61222942:GG:G	acceptor_gain	1.0000
11:61222942:GGG:G	acceptor_gain	1.0000
11:61222942:GGGT:G	acceptor_gain	1.0000
11:61222942:GGGTC:G	acceptor_gain	1.0000
11:61223039:A:T	donor_gain	1.0000
11:61223101:TGGAT:T	donor_gain	1.0000
11:61223102:GGAT:G	donor_gain	1.0000
11:61223102:GGATG:G	donor_gain	1.0000
11:61223103:GAT:G	donor_gain	1.0000
11:61223103:GATG:G	donor_gain	1.0000
11:61223104:AT:A	donor_gain	1.0000
11:61223104:ATGTG:A	donor_loss	1.0000
11:61223105:TGT:T	donor_loss	1.0000
11:61223106:G:GG	donor_gain	1.0000
11:61223106:GT:G	donor_loss	1.0000
11:61223107:T:A	donor_loss	1.0000
11:61226321:T:TA	acceptor_gain	1.0000
11:61226321:TGCA:T	acceptor_loss	1.0000
11:61226322:GCAG:G	acceptor_loss	1.0000
11:61226323:CAGC:C	acceptor_loss	1.0000
11:61226324:A:AG	acceptor_gain	1.0000
11:61226324:AGC:A	acceptor_loss	1.0000
11:61226325:G:GC	acceptor_gain	1.0000
11:61226325:GC:G	acceptor_gain	1.0000

AlphaMissense

2544 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:61229974:G:C	D277H	0.999
11:61229975:A:C	D277A	0.999
11:61229975:A:T	D277V	0.999
11:61229976:C:A	D277E	0.999
11:61229976:C:G	D277E	0.999
11:61231445:T:A	W361R	0.999
11:61231445:T:C	W361R	0.999
11:61231455:G:T	G364V	0.999
11:61225400:A:C	D94A	0.998
11:61225400:A:T	D94V	0.998
11:61225401:C:A	D94E	0.998
11:61225401:C:G	D94E	0.998
11:61225403:C:T	T95I	0.998
11:61225420:T:A	W101R	0.998
11:61225420:T:C	W101R	0.998
11:61225439:G:A	C107Y	0.998
11:61225440:C:G	C107W	0.998
11:61227213:G:A	G184R	0.998
11:61227213:G:C	G184R	0.998
11:61227213:G:T	G184W	0.998
11:61228768:T:A	W252R	0.998
11:61228768:T:C	W252R	0.998
11:61228770:G:C	W252C	0.998
11:61228770:G:T	W252C	0.998
11:61229975:A:G	D277G	0.998
11:61229981:G:T	G279V	0.998
11:61231454:G:C	G364R	0.998
11:61231454:G:T	G364C	0.998
11:61225367:G:A	G83E	0.997
11:61225399:G:C	D94H	0.997

dbSNP variants (sampled 300 via entrez): RS1003927024 (11:61221636 T>A), RS1014015090 (11:61230954 C>G), RS1015851097 (11:61230061 G>A), RS1033619332 (11:61230519 CT>C), RS1039301952 (11:61221250 G>A), RS1050756118 (11:61221406 G>A), RS1157001068 (11:61230081 T>C,G), RS1158348237 (11:61221422 T>TCCC), RS1159196638 (11:61230759 A>G), RS1159313250 (11:61221813 C>A,T), RS1159616288 (11:61221055 G>A), RS1159681231 (11:61231335 C>G,T), RS11607442 (11:61220859 G>T), RS1161035083 (11:61232043 C>T), RS1162278516 (11:61230965 G>A)

Disease associations

OMIM: gene MIM:169720 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

Binding affinities (BindingDB)

5 measured of 5 human assays (5 total across all organisms); most potent 5 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
N-[(1Z)-amino[(3-hydroxypropyl)amino]methylidene]-2-[2-(2-chlorophenyl)-5-(4-propoxyphenyl)-1H-pyrrol-1-yl]acetamide	IC50	110 nM
2-[2-(2-chlorophenyl)-5-[4-(4-acetylphenoxy)phenyl]-1H-pyrrol-1-yl]-N-(diaminomethylidene)acetamide	IC50	160 nM
2-[2-(adamantan-1-yl)-5-phenyl-1H-pyrrol-1-yl]-N-[(1Z)-amino[(3-hydroxypropyl)amino]methylidene]acetamide	IC50	240 nM
2-[2-(adamantan-1-yl)-5-phenyl-1H-pyrrol-1-yl]-N-(diaminomethylidene)acetamide	IC50	600 nM
(N-(diaminomethylene)-2,4-diphenyl-1H-pyrrole-1-acetamide)	IC50	3700 nM

CTD chemical–gene interactions

4 total (human), top 4 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression	1
Lead	affects expression	1
Tretinoin	increases expression	1
Valproic Acid	increases methylation	1

Clinical trials (associated diseases)

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