PGA3

Summary

PGA3 (pepsinogen A3, HGNC:8885) is a protein-coding gene on chromosome 11q12.2, encoding Pepsin A-3 (P0DJD8). 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 643834 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 24 total
• MANE Select transcript: NM_001079807

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8885
Approved symbol	PGA3
Name	pepsinogen A3
Location	11q12.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000229859
Ensembl biotype	protein_coding
OMIM	169710
Entrez	643834

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 4 protein_coding, 4 retained_intron

ENST00000325558, ENST00000535551, ENST00000537954, ENST00000538258, ENST00000539649, ENST00000541699, ENST00000543125, ENST00000543505

RefSeq mRNA: 1 — MANE Select: NM_001079807 NM_001079807

CCDS: CCDS31574

Canonical transcript exons

ENST00000325558 — 9 exons

Exon	Start	End
ENSE00002478195	61208291	61208490
ENSE00002504852	61207497	61207615
ENSE00002505728	61212553	61213098
ENSE00002517867	61203515	61203620
ENSE00003458746	61204107	61204269
ENSE00003493454	61211337	61211435
ENSE00003651865	61211090	61211234
ENSE00003758100	61206510	61206627
ENSE00003786706	61209842	61209958

Expression profiles

Bgee: expression breadth ubiquitous, 123 present calls, max score 96.24.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.1118 / max 1557.1047, expressed in 55 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
114552	1.1118	55

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
body of stomach	UBERON:0001161	96.24	gold quality
stomach	UBERON:0000945	93.66	gold quality
fundus of stomach	UBERON:0001160	92.67	gold quality
right uterine tube	UBERON:0001302	88.90	gold quality
right coronary artery	UBERON:0001625	88.20	gold quality
endocervix	UBERON:0000458	86.74	gold quality
lower esophagus mucosa	UBERON:0035834	86.39	gold quality
ectocervix	UBERON:0012249	85.89	gold quality
left uterine tube	UBERON:0001303	83.47	gold quality
metanephros cortex	UBERON:0010533	81.79	gold quality
uterine cervix	UBERON:0000002	81.20	gold quality
right adrenal gland	UBERON:0001233	80.35	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	79.81	gold quality
body of pancreas	UBERON:0001150	79.80	gold quality
spleen	UBERON:0002106	77.61	gold quality
transverse colon	UBERON:0001157	77.39	gold quality
right ovary	UBERON:0002118	77.32	gold quality
fallopian tube	UBERON:0003889	77.11	gold quality
right lung	UBERON:0002167	76.82	gold quality
omental fat pad	UBERON:0010414	76.72	gold quality
subcutaneous adipose tissue	UBERON:0002190	76.67	gold quality
adipose tissue	UBERON:0001013	76.41	gold quality
left adrenal gland	UBERON:0001234	76.39	gold quality
left testis	UBERON:0004533	75.19	gold quality
thoracic mammary gland	UBERON:0005200	74.99	gold quality
esophagus mucosa	UBERON:0002469	74.94	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	74.82	gold quality
right lobe of liver	UBERON:0001114	74.71	gold quality
right adrenal gland cortex	UBERON:0035827	74.70	gold quality
mucosa of transverse colon	UBERON:0004991	74.66	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-MTAB-6058	no	22.22
E-ANND-3	no	2.12

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

5 targeting PGA3, 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

Literature-anchored findings (GeneRIF, showing 10)

• Higher levels of Pepsinogen I is associated with early gastric cancer (PMID:15688378)
• Helicobacter pylori eradication improves gastric histology and decreases serum gastrin, pepsinogen I and pepsinogen II levels in patients with duodenal ulcer. (PMID:17559360)
• pepsinogens may have a role in esophageal squamous dysplasia (PMID:18844222)
• Barrett’s esophagus is characterized by the absence of Helicobacter pylori infection and high levels of serum pepsinogen I concentration in Japan. (PMID:19196398)
• A significant negative correlation was found between the degree of corpus atrophy and the level of serum pepsinogen-I in atrophic gastritis patients with gastroesophageal reflux. (PMID:21175799)
• Significantly higher AUC was observed for the PGI/PGII ratio and is associated with atrophy and intestinal metaplasia. (PMID:23886209)
• High serum Pepsinogen I level is associ9ated with the progression of gastric precancerous lesions. (PMID:24895149)
• Low Pepsinogen I is associated with precancerous gastric lesions. (PMID:25292040)
• Serum pepsinogen (PG), gastrin, and Helicobacter pylori (H. pylori) IgG antibodies have become indicators for “serological biopsy” of the gastric mucosa lesion. (PMID:31414587)
• Diagnostic value of MRI-DWI signal intensity value combined with serum PGI, PGII and CA199 in early gastric cancer. (PMID:34817333)

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), PGA4 (ENSG00000229183), PGA5 (ENSG00000256713)

Protein

Protein identifiers

Pepsin A-3 — P0DJD8 (reviewed: P0DJD8)

Alternative names: Pepsinogen-3

All UniProt accessions (4): P0DJD8, F5GXL4, F5H0H6, F5H842

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 (1): NP_001073275* (*=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 (11 total): disulfide bond 3, sequence conflict 2, active site 2, signal peptide 1, propeptide 1, chain 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P0DJD8-F1	91.15	0.75

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

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: 30 (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, ZNF184_TARGET_GENES, ZNF512_TARGET_GENES, MIR4768_3P, MIR194_3P, MIR6793_5P

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

GO Molecular Function (3): aspartic-type endopeptidase activity (GO:0004190), 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
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

3 interactions, top by confidence:

A	B	Type	Score
PGA3	RMND1	psi-mi:“MI:0915”(physical association)	0.400
cagA	PGA3	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (2): RMND1 (Affinity Capture-MS), PGA3 (Negative Genetic)

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

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	18
Likely benign	5
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

885 predictions. Top by Δscore:

Variant	Effect	Δscore
11:61203621:G:GG	donor_gain	1.0000
11:61204102:CACA:C	acceptor_loss	1.0000
11:61204103:ACAG:A	acceptor_gain	1.0000
11:61204104:CA:C	acceptor_loss	1.0000
11:61204105:A:AC	acceptor_loss	1.0000
11:61204105:A:AG	acceptor_gain	1.0000
11:61204105:AG:A	acceptor_gain	1.0000
11:61204105:AGG:A	acceptor_gain	1.0000
11:61204106:G:GT	acceptor_gain	1.0000
11:61204106:GG:G	acceptor_gain	1.0000
11:61204106:GGG:G	acceptor_gain	1.0000
11:61204106:GGGT:G	acceptor_gain	1.0000
11:61204106:GGGTC:G	acceptor_gain	1.0000
11:61204203:A:T	donor_gain	1.0000
11:61204265:TGGAT:T	donor_gain	1.0000
11:61204266:GGAT:G	donor_gain	1.0000
11:61204266:GGATG:G	donor_gain	1.0000
11:61204267:GAT:G	donor_gain	1.0000
11:61204267:GATG:G	donor_gain	1.0000
11:61204268:AT:A	donor_gain	1.0000
11:61204269:TGTG:T	donor_loss	1.0000
11:61204270:G:GG	donor_gain	1.0000
11:61204270:GTG:G	donor_loss	1.0000
11:61204271:TGAG:T	donor_loss	1.0000
11:61204272:G:GT	donor_loss	1.0000
11:61204274:GT:G	donor_gain	1.0000
11:61207492:T:TA	acceptor_gain	1.0000
11:61207492:TGCA:T	acceptor_loss	1.0000
11:61207494:CA:C	acceptor_loss	1.0000
11:61207495:A:AG	acceptor_gain	1.0000

AlphaMissense

2544 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:61212626:G:T	G364V	0.999
11:61206571:A:T	D94V	0.998
11:61206572:C:A	D94E	0.998
11:61206572:C:G	D94E	0.998
11:61209941:G:C	W252C	0.998
11:61209941:G:T	W252C	0.998
11:61211146:A:T	D277V	0.998
11:61211147:C:A	D277E	0.998
11:61211147:C:G	D277E	0.998
11:61212616:T:A	W361R	0.998
11:61212616:T:C	W361R	0.998
11:61206571:A:C	D94A	0.997
11:61206574:C:T	T95I	0.997
11:61206591:T:A	W101R	0.997
11:61206591:T:C	W101R	0.997
11:61206611:C:G	C107W	0.997
11:61207511:T:C	F118L	0.997
11:61207513:C:A	F118L	0.997
11:61207513:C:G	F118L	0.997
11:61208330:A:C	S166R	0.997
11:61208332:C:A	S166R	0.997
11:61208332:C:G	S166R	0.997
11:61208384:G:T	G184W	0.997
11:61209939:T:A	W252R	0.997
11:61209939:T:C	W252R	0.997
11:61211145:G:C	D277H	0.997
11:61211146:A:C	D277A	0.997
11:61211146:A:G	D277G	0.997
11:61211383:T:C	F322S	0.997
11:61212625:G:C	G364R	0.997

dbSNP variants (sampled 300 via entrez): RS1002371559 (11:61202961 A>G), RS1002402654 (11:61203785 TA>T,TAA), RS1002738167 (11:61201875 T>C,G), RS1003991848 (11:61201732 A>G), RS1005745299 (11:61202438 T>A,C), RS1006012592 (11:61202878 G>A,C), RS1006838418 (11:61201937 G>C,T), RS1009728804 (11:61205338 A>G), RS1010119132 (11:61201925 G>A), RS1010193774 (11:61203830 G>A), RS1010481596 (11:61202094 G>A), RS1015331217 (11:61201747 T>G), RS1015956890 (11:61207610 G>C), RS1017123900 (11:61202923 G>A,C), RS1019955642 (11:61203886 AT>A)

Disease associations

OMIM: gene MIM:169710 | 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)

CTD chemical–gene interactions

10 total (human), top 10 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
quercitrin	increases expression	1
hydroxyhydroquinone	decreases expression	1
Grape Seed Proanthocyanidins	increases expression, affects cotreatment	1
Resveratrol	affects cotreatment, decreases expression	1
Catechin	affects cotreatment, increases expression	1
Copper	decreases expression, affects cotreatment	1
Lead	affects expression	1
Triclosan	decreases expression	1
Valproic Acid	increases methylation	1
Aflatoxin B1	decreases methylation	1

Clinical trials (associated diseases)

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