AGR3

Summary

AGR3 (anterior gradient 3, protein disulphide isomerase family member, HGNC:24167) is a protein-coding gene on chromosome 7p21.1, encoding Anterior gradient protein 3 (Q8TD06). Required for calcium-mediated regulation of ciliary beat frequency and mucociliary clearance in the airway.

This gene encodes a member of the disulfide isomerase (PDI) family of endoplasmic reticulum (ER) proteins that catalyze protein folding and thiol-disulfide interchange reactions. The encoded protein has an N-terminal ER-signal sequence, a catalytically active thioredoxin domain, and a C-terminal ER-retention sequence. This gene is expressed in ciliated airway epithelial cells and, in mouse, plays a role in ciliary beat frequency in multiciliated cells. This gene is also over-expressed in breast, ovarian, and prostrate cancers.

Source: NCBI Gene 155465 — RefSeq curated summary.

At a glance

• GWAS associations: 14
• Clinical variants (ClinVar): 43 total
• MANE Select transcript: NM_176813

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24167
Approved symbol	AGR3
Name	anterior gradient 3, protein disulphide isomerase family member
Location	7p21.1
Locus type	gene with protein product
Status	Approved
Aliases	HAG3, hAG-3, BCMP11, PDIA18
Ensembl gene	ENSG00000173467
Ensembl biotype	protein_coding
OMIM	609482
Entrez	155465

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 5 protein_coding, 1 retained_intron

ENST00000310398, ENST00000402239, ENST00000414935, ENST00000486448, ENST00000878233, ENST00000878234

RefSeq mRNA: 1 — MANE Select: NM_176813 NM_176813

CCDS: CCDS5365

Canonical transcript exons

ENST00000310398 — 8 exons

Exon	Start	End
ENSE00001180218	16861384	16861447
ENSE00001180225	16861984	16862060
ENSE00001180227	16862610	16862662
ENSE00001180232	16873780	16873843
ENSE00001180236	16859412	16859631
ENSE00003467548	16878510	16878645
ENSE00003474844	16881944	16881983
ENSE00003785298	16860500	16860583

Expression profiles

Bgee: expression breadth ubiquitous, 170 present calls, max score 99.86.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 2.0407 / max 265.1728, expressed in 174 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
82901	2.0407	174

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
bronchial epithelial cell	CL:0002328	99.86	gold quality
bronchus	UBERON:0002185	99.71	gold quality
ileal mucosa	UBERON:0000331	99.49	gold quality
mucosa of sigmoid colon	UBERON:0004993	99.47	gold quality
right uterine tube	UBERON:0001302	99.37	gold quality
colonic mucosa	UBERON:0000317	99.26	gold quality
rectum	UBERON:0001052	98.93	gold quality
jejunal mucosa	UBERON:0000399	98.65	gold quality
mucosa of transverse colon	UBERON:0004991	98.38	gold quality
epithelial cell of pancreas	CL:0000083	97.41	gold quality
duodenum	UBERON:0002114	97.36	gold quality
trachea	UBERON:0003126	96.21	gold quality
oviduct epithelium	UBERON:0004804	96.16	gold quality
gall bladder	UBERON:0002110	95.55	gold quality
mucosa of paranasal sinus	UBERON:0005030	95.46	gold quality
lower lobe of lung	UBERON:0008949	95.22	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	94.90	gold quality
pancreatic ductal cell	CL:0002079	94.54	gold quality
epithelium of nasopharynx	UBERON:0001951	94.34	gold quality
nasopharynx	UBERON:0001728	94.32	gold quality
nasal cavity epithelium	UBERON:0005384	92.92	gold quality
upper lobe of lung	UBERON:0008948	92.39	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	92.31	gold quality
upper lobe of left lung	UBERON:0008952	92.14	gold quality
lung	UBERON:0002048	91.64	gold quality
fallopian tube	UBERON:0003889	91.53	gold quality
small intestine Peyer’s patch	UBERON:0003454	91.47	gold quality
small intestine	UBERON:0002108	89.84	gold quality
epithelium of mammary gland	UBERON:0003244	89.20	gold quality
mammary duct	UBERON:0001765	89.12	gold quality

Single-cell (SCXA)

Detected in 11 experiment(s), a significant marker in 11.

Experiment	Marker?	Max mean expression
E-HCAD-15	yes	1860.05
E-MTAB-10855	yes	1289.13
E-MTAB-8221	yes	1222.17
E-MTAB-9841	yes	503.81
E-HCAD-1	yes	76.21
E-CURD-114	yes	64.91
E-MTAB-8410	yes	47.45
E-MTAB-10287	yes	27.97
E-GEOD-130148	yes	17.38
E-GEOD-125970	yes	8.42
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR

miRNA regulators (miRDB)

17 targeting AGR3, 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-499A-5P	99.98	70.79	1323
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-7154-5P	99.69	70.52	1900
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-3616-5P	99.55	67.02	989
HSA-MIR-573	99.55	67.44	955
HSA-MIR-6505-3P	99.34	67.39	1071
HSA-MIR-455-5P	98.74	67.31	795
HSA-MIR-4330	95.44	66.39	993

Literature-anchored findings (GeneRIF, showing 18)

• hAG-2 and hAG-3, human homologues of genes involved in differentiation, are associated with oestrogen receptor-positive breast tumours and interact with metastasis gene C4.4a and dystroglycan [hAG-3 protein] (PMID:12592373)
• specific induction of Hag2 and Hag3 during hormone-induced breast carcinomas further support developmental specificity for the PDI/ERp family members (PMID:15935701)
• AGR3 could serve as a prognostic marker for survival in patients with low grade and high grade serous ovarian carcinomas. (PMID:21451362)
• AGR3 expression in ovarian cancer is independent of oestrogen-receptor expression. (PMID:22361111)
• AGR3 was is predominantly expressed in liver cholangiocytes but not present in liver hepatocytes, making this protain a good marker for differential diagnosis of intrahepatic cholangiocarcinoma (PMID:24747240)
• Relying on available data and in silico analyses, study shows that AGR2 and AGR3 proteins are co-expressed or uncoupled in context-dependent manners in diverse carcinomas and healthy tissues. (PMID:25666661)
• AGR3 is a specialized member of the PDI family that plays an unexpected role in the regulation of CBF and mucociliary clearance in the airway. (PMID:25751668)
• transcriptionally activated in hepatitis C virus-infected cells by HCV NS5A (PMID:25868611)
• Data show the potential usability of anterior gradient homolog 3 (AGR3) and anterior gradient homolog 2 (AGR2) as biomarkers for blood-based early detection of breast cancer. (PMID:25875093)
• Results show that AGR3 was highly upregulated in low-grade serous carcinoma (LGSC) compared to high-grade serous carcinoma (HGSC). It can be use along with p53 for differential diagnosis of HGSC and LGSC. (PMID:29620196)
• The recombinant expression, purification, crystallization and structure of the human AGR3 are described. (PMID:29969106)
• AGR3 promotes the stemness of colorectal cancer via modulating Wnt/beta-catenin signalling. (PMID:31526829)
• Anterior Gradient Protein 3 and S100 Calcium-Binding Protein P Levels in Different Endometrial Epithelial Compartments May Play an Important Role in Recurrent Pregnancy Failure. (PMID:33917163)
• Profile of anterior gradient 3 (AGR3) mRNA expression and serum levels in benign and malignant breast tumors. (PMID:34057117)
• Estrogen-regulated AGR3 activates the estrogen receptor signaling pathway to promote tamoxifen resistance in breast cancer. (PMID:34519905)
• Integrative analysis of genomic and transcriptomic alterations of AGR2 and AGR3 in cancer. (PMID:35857928)
• Over-expression of Anterior Gradient 3 Is Associated With Tumor Progression and Poor Survival in Gastric Cancer. (PMID:36593009)
• Prognostic Impact of AGR3 Protein Expression in Breast Cancer: A Systematic Review and Meta-analysis. (PMID:37944928)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
mus_musculus	Agr3	ENSMUSG00000036231
rattus_norvegicus	Agr3	ENSRNOG00000004994
caenorhabditis_elegans		WBGENE00013263
caenorhabditis_elegans		WBGENE00018656

Paralogs (2): AGR2 (ENSG00000106541), TXNDC12 (ENSG00000117862)

Protein

Protein identifiers

Anterior gradient protein 3 — Q8TD06 (reviewed: Q8TD06)

Alternative names: Anterior gradient 3 homolog, Breast cancer membrane protein 11, Protein disulfide isomerase family A, member 18

All UniProt accessions (3): Q8TD06, B5MC62, H7C040

UniProt curated annotations — full annotation on UniProt →

Function. Required for calcium-mediated regulation of ciliary beat frequency and mucociliary clearance in the airway. Might be involved in the regulation of intracellular calcium in tracheal epithelial cells.

Subunit / interactions. Interacts with LYPD3 and DAG1 (alphaDAG1).

Subcellular location. Endoplasmic reticulum.

Tissue specificity. Expressed in the lung, in the ciliated cells of the airway epithelium. Expression increased with differentiation of airway epithelial cells. Not detected in the mucous cells. Expressed in ciliated cells in the oviduct. Also detected in stomach, colon, prostate and liver. Expressed in breast, ovary, prostate and liver cancer. Expression is associated with the level of differentiation of breast cancer (at protein level).

Induction. Not induced as part of the cellular response to endoplasmic reticulum stress. Up-regulated by androgens and by estrogens in prostate cancer cells Up-regulated by a hormone (estrogen-receptor alpha) independent mechanism in ovarian cancer.

Similarity. Belongs to the AGR family.

RefSeq proteins (1): NP_789783* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR036249	Thioredoxin-like_sf	Homologous_superfamily
IPR051099	AGR/TXD	Family

Pfam: PF13899

UniProt features (14 total): helix 6, strand 4, signal peptide 1, chain 1, short sequence motif 1, mutagenesis site 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
3PH9	X-RAY DIFFRACTION	1.83

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8TD06-F1	89.28	0.79

Functional residue map

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

Mutagenesis-validated functional residues (1):

Position	Phenotype
163–166	leads to golgi localization;.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 75 (showing top): GOZGIT_ESR1_TARGETS_DN, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_1, SANSOM_APC_TARGETS_UP, HNF1_C, HAND1E47_01, SANSOM_APC_TARGETS, DODD_NASOPHARYNGEAL_CARCINOMA_DN, MMEF2_Q6, WAMUNYOKOLI_OVARIAN_CANCER_LMP_UP, WAMUNYOKOLI_OVARIAN_CANCER_GRADES_1_2_UP, KUMAR_PATHOGEN_LOAD_BY_MACROPHAGES, GOMF_DYSTROGLYCAN_BINDING, RB_DN.V1_DN, DLX2_TARGET_GENES, FOXD2_TARGET_GENES

GO Biological Process (0):

GO Molecular Function (2): dystroglycan binding (GO:0002162), protein binding (GO:0005515)

GO Cellular Component (1): endoplasmic reticulum (GO:0005783)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein binding	1
binding	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

624 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AGR3	LYPD3	O95274	893
AGR3	DAG1	Q14118	615
AGR3	ESR1	P03372	603
AGR3	BRICD5	Q6PL45	506
AGR3	ERP27	Q96DN0	496
AGR3	ERP29	P30040	462
AGR3	PDILT	Q8N807	459
AGR3	TMX1	Q9H3N1	453
AGR3	TMX3	Q96JJ7	450
AGR3	PDIA2	Q13087	448
AGR3	TECTB	Q96PL2	445
AGR3	TMX4	Q9H1E5	439
AGR3	ZPLD1	Q8TCW7	435
AGR3	CIB3	Q96Q77	424
AGR3	GABRP	O00591	423

IntAct

108 interactions, top by confidence:

A	B	Type	Score
SGTA	AGR3	psi-mi:“MI:0915”(physical association)	0.720
AGR3	ERLIN1	psi-mi:“MI:0915”(physical association)	0.720
NUP62	AGR3	psi-mi:“MI:0915”(physical association)	0.720
AGR3	SGTA	psi-mi:“MI:0915”(physical association)	0.720
AGR3	NUP62	psi-mi:“MI:0915”(physical association)	0.720
ERLIN1	AGR3	psi-mi:“MI:0915”(physical association)	0.720
AGR3	UBQLN1	psi-mi:“MI:0915”(physical association)	0.670
UBQLN1	AGR3	psi-mi:“MI:0915”(physical association)	0.560
AGR3	UBQLN1	psi-mi:“MI:0915”(physical association)	0.560
AGR3	SDC3	psi-mi:“MI:0915”(physical association)	0.560
AGR3	PDZK1IP1	psi-mi:“MI:0915”(physical association)	0.560
AGR3	CGRRF1	psi-mi:“MI:0915”(physical association)	0.560
CATSPER1	AGR3	psi-mi:“MI:0915”(physical association)	0.560
AGR3	LIME1	psi-mi:“MI:0915”(physical association)	0.560
SDC3	AGR3	psi-mi:“MI:0915”(physical association)	0.560
SPINT1	AGR3	psi-mi:“MI:0915”(physical association)	0.560
AGR3	UBQLN2	psi-mi:“MI:0915”(physical association)	0.560
AGR3	SGTB	psi-mi:“MI:0915”(physical association)	0.560
AP1B1	AGR3	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (48): AGR3 (Two-hybrid), AGR3 (Two-hybrid), AGR3 (Two-hybrid), AGR3 (Two-hybrid), AGR3 (Two-hybrid), AGR3 (Two-hybrid), AGR3 (Two-hybrid), AGR3 (Two-hybrid), AGR3 (Two-hybrid), AGR3 (Two-hybrid), AGR3 (Two-hybrid), NUP62 (Two-hybrid), UBQLN1 (Two-hybrid), AGR3 (Two-hybrid), AGR3 (Two-hybrid)

ESM2 similar proteins: B3M2I7, B3P113, B4GFM7, B4IBX2, B4JT39, B4PR07, B4QX46, F4JIN3, G4WAW9, G5EFE7, O44342, O77277, O88312, O95994, P20348, P29402, P34669, P42659, P52183, P54364, P55868, P83752, P83753, Q09332, Q0WT48, Q17688, Q18484, Q19892, Q295V5, Q5R7P1, Q5RZ65, Q6DJ58, Q6GP98, Q7JW12, Q7SIA2, Q7ZZH4, Q8CGC7, Q8R3W7, Q8TD06, Q90Y05

Diamond homologs: H9D1R1, O88312, O95881, O95994, P55868, P55869, Q28ID5, Q498E0, Q5E936, Q5R7P1, Q5RZ65, Q6DJ58, Q6NVS9, Q7ZZH4, Q8R3W7, Q8TD06, Q90Y05, Q9C9Y6, Q9CQU0

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	26
Likely benign	3
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

848 predictions. Top by Δscore:

Variant	Effect	Δscore
7:16859630:CA:C	acceptor_gain	1.0000
7:16859632:C:CC	acceptor_gain	1.0000
7:16860498:A:AC	donor_gain	1.0000
7:16860499:C:CC	donor_gain	1.0000
7:16860499:CATAG:C	donor_gain	1.0000
7:16862663:C:CC	acceptor_gain	1.0000
7:16859627:TATCA:T	acceptor_gain	0.9900
7:16859629:TCA:T	acceptor_gain	0.9900
7:16859630:CAC:C	acceptor_gain	0.9900
7:16860491:AATAC:A	donor_loss	0.9900
7:16860492:ATACT:A	donor_loss	0.9900
7:16860493:TACT:T	donor_loss	0.9900
7:16860494:ACTTA:A	donor_loss	0.9900
7:16860495:C:T	donor_loss	0.9900
7:16860496:TTAC:T	donor_loss	0.9900
7:16860497:T:TC	donor_loss	0.9900
7:16860499:C:CT	donor_loss	0.9900
7:16860499:CAT:C	donor_gain	0.9900
7:16860499:CATA:C	donor_gain	0.9900
7:16860584:C:CC	acceptor_gain	0.9900
7:16861378:ACAT:A	donor_loss	0.9900
7:16861380:AT:A	donor_loss	0.9900
7:16861381:TACCT:T	donor_loss	0.9900
7:16861382:ACCT:A	donor_loss	0.9900
7:16861383:CCTAC:C	donor_loss	0.9900
7:16861443:TCATG:T	acceptor_gain	0.9900
7:16861444:CATG:C	acceptor_gain	0.9900
7:16861444:CATGC:C	acceptor_gain	0.9900
7:16861446:TG:T	acceptor_gain	0.9900
7:16861448:C:CC	acceptor_gain	0.9900

AlphaMissense

1083 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:16873823:A:G	W44R	0.992
7:16873823:A:T	W44R	0.992
7:16873821:C:A	W44C	0.991
7:16873821:C:G	W44C	0.991
7:16873841:A:G	W38R	0.987
7:16873841:A:T	W38R	0.987
7:16873839:C:A	W38C	0.983
7:16873839:C:G	W38C	0.983
7:16861994:A:G	L98P	0.979
7:16873802:C:G	G51R	0.978
7:16862645:A:T	V64D	0.977
7:16861389:A:G	F121S	0.973
7:16861389:A:C	F121C	0.972
7:16861397:T:A	R118S	0.972
7:16861397:T:G	R118S	0.972
7:16861401:G:T	P117H	0.972
7:16862057:A:G	L77P	0.972
7:16860568:A:T	V128D	0.970
7:16861990:G:C	N99K	0.969
7:16861990:G:T	N99K	0.969
7:16861388:A:C	F121L	0.968
7:16861388:A:T	F121L	0.968
7:16861390:A:G	F121L	0.968
7:16873801:C:T	G51D	0.968
7:16862003:A:G	F95S	0.967
7:16861401:G:C	P117R	0.965
7:16862002:G:C	F95L	0.965
7:16862002:G:T	F95L	0.965
7:16862004:A:G	F95L	0.965
7:16861988:A:G	L100P	0.964

dbSNP variants (sampled 300 via entrez): RS1000005630 (7:16864097 C>G,T), RS1000230103 (7:16873359 A>T), RS1000245303 (7:16868242 G>A,T), RS1000517860 (7:16881612 T>A), RS1000540102 (7:16863817 C>T), RS1000553984 (7:16858360 T>A), RS1000734787 (7:16871985 C>A,T), RS1000744295 (7:16876557 T>A), RS1000826381 (7:16863526 C>G), RS1000845645 (7:16867376 C>A,T), RS1000949033 (7:16883343 C>A,T), RS1000955638 (7:16872151 C>A,T), RS1001000345 (7:16862937 G>A), RS1001035234 (7:16878142 A>T), RS1001093117 (7:16876772 G>A)

Disease associations

OMIM: gene MIM:609482 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

14 associations (top):

Study	Trait	p-value
GCST001843_2	Type 2 diabetes (dietary heme iron intake interaction)	6.000000e-06
GCST003061_3	Cutaneous malignant melanoma	7.000000e-09
GCST004142_5	Melanoma	7.000000e-09
GCST004291_5	Residual cognition	8.000000e-07
GCST004749_17	Lung cancer in ever smokers	3.000000e-07
GCST005330_4	Coffee consumption	5.000000e-07
GCST005790_2	Rosacea symptom severity	3.000000e-06
GCST006463_11	Urinary albumin excretion (no hypertensive medication)	1.000000e-18
GCST006586_17	Urinary albumin excretion	3.000000e-25
GCST007637_28	Diffusing capacity of carbon monoxide	4.000000e-07
GCST009801_3	Coffee consumption	8.000000e-68
GCST010002_344	Refractive error	9.000000e-12
GCST010148_11	Cutaneous squamous cell carcinoma	8.000000e-09
GCST010304_69	Cutaneous malignant melanoma	1.000000e-08

EFO canonical traits (9, from GWAS)

EFO ID	Trait name
EFO:0008355	dietary heme iron intake measurement
EFO:0003925	cognition
EFO:0022597	aging
EFO:0006782	cups of coffee per day measurement
EFO:0009180	rosacea severity measurement
EFO:0004285	albuminuria
EFO:0009369	diffusing capacity of the lung for carbon monoxide
EFO:0006781	coffee consumption measurement
EFO:1001927	cutaneous squamous cell carcinoma

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

23 total (human), top 23 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	increases abundance, increases expression	2
Particulate Matter	increases abundance, increases expression, decreases expression	2
2,3-bis(3’-hydroxybenzyl)butyrolactone	increases expression, affects cotreatment	1
brequinar	decreases expression	1
bisphenol B	increases expression	1
bisphenol Z	increases expression	1
(+)-JQ1 compound	decreases expression	1
bisphenol AF	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Temozolomide	affects response to substance	1
Acetaminophen	decreases expression	1
Carmustine	affects response to substance	1
Coumestrol	affects cotreatment, increases expression	1
Diethylnitrosamine	decreases expression	1
Hydrogen Peroxide	affects expression	1
Phthalic Acids	decreases methylation	1
Rotenone	decreases expression	1
Silicon Dioxide	decreases expression	1
Smoke	increases abundance, increases expression	1
Tetrachlorodibenzodioxin	decreases expression	1
Tobacco Smoke Pollution	affects expression	1
Aflatoxin M1	decreases expression	1
Okadaic Acid	increases expression	1

Clinical trials (associated diseases)

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