AGR2

Summary

AGR2 (anterior gradient 2, protein disulphide isomerase family member, HGNC:328) is a protein-coding gene on chromosome 7p21.1, encoding Anterior gradient protein 2 homolog (O95994). Required for MUC2 post-transcriptional synthesis and secretion. In precision oncology, AGR2 EXPRESSION is associated with resistance to Tamoxifen in Breast Cancer (CIViC Level B).

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 protein plays a role in cell migration, cellular transformation and metastasis and is as a p53 inhibitor. As an ER-localized molecular chaperone, it plays a role in the folding, trafficking, and assembly of cysteine-rich transmembrane receptors and the cysteine-rich intestinal gylcoprotein mucin. This gene has been implicated in inflammatory bowel disease and cancer progression.

Source: NCBI Gene 10551 — RefSeq curated summary.

At a glance

• Gene–disease (curated): respiratory infections, recurrent, and failure to thrive with or without diarrhea (Strong, GenCC)
• GWAS associations: 4
• Clinical variants (ClinVar): 42 total — 3 pathogenic, 6 likely-pathogenic
• Phenotypes (HPO): 43
• Precision-oncology evidence (CIViC): 1 curated variant–drug association
• MANE Select transcript: NM_006408

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:328
Approved symbol	AGR2
Name	anterior gradient 2, protein disulphide isomerase family member
Location	7p21.1
Locus type	gene with protein product
Status	Approved
Aliases	XAG-2, HAG-2, AG2, PDIA17
Ensembl gene	ENSG00000106541
Ensembl biotype	protein_coding
OMIM	606358
Entrez	10551

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 9 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000401412, ENST00000412973, ENST00000419304, ENST00000450569, ENST00000468419, ENST00000486219, ENST00000489523, ENST00000891197, ENST00000891198, ENST00000891199, ENST00000965169, ENST00000965170

RefSeq mRNA: 1 — MANE Select: NM_006408 NM_006408

CCDS: CCDS5364

Canonical transcript exons

ENST00000419304 — 8 exons

Exon	Start	End
ENSE00000672336	16799744	16799817
ENSE00000831826	16794936	16795019
ENSE00001811303	16804935	16804999
ENSE00001857025	16791811	16792957
ENSE00003553967	16801151	16801203
ENSE00003593874	16801320	16801383
ENSE00003685049	16801658	16801803
ENSE00003787956	16797631	16797694

Expression profiles

Bgee: expression breadth ubiquitous, 210 present calls, max score 99.94.

FANTOM5 (CAGE): breadth broad, TPM avg 64.3168 / max 7185.5694, expressed in 372 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
82898	63.8879	372
82897	0.4209	138
82899	0.0081	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of sigmoid colon	UBERON:0004993	99.94	gold quality
colonic mucosa	UBERON:0000317	99.87	gold quality
pylorus	UBERON:0001166	99.87	gold quality
nasal cavity epithelium	UBERON:0005384	99.86	gold quality
rectum	UBERON:0001052	99.80	gold quality
bronchial epithelial cell	CL:0002328	99.79	gold quality
epithelium of bronchus	UBERON:0002031	99.77	gold quality
bronchus	UBERON:0002185	99.77	gold quality
nasal cavity mucosa	UBERON:0001826	99.71	gold quality
palpebral conjunctiva	UBERON:0001812	99.64	gold quality
mucosa of transverse colon	UBERON:0004991	99.64	gold quality
corpus epididymis	UBERON:0004359	99.63	gold quality
right uterine tube	UBERON:0001302	99.62	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	99.53	gold quality
seminal vesicle	UBERON:0000998	99.48	gold quality
trachea	UBERON:0003126	99.47	gold quality
duodenum	UBERON:0002114	99.23	gold quality
gall bladder	UBERON:0002110	99.17	gold quality
jejunal mucosa	UBERON:0000399	98.96	gold quality
ileal mucosa	UBERON:0000331	98.89	gold quality
mucosa of paranasal sinus	UBERON:0005030	98.20	gold quality
cauda epididymis	UBERON:0004360	98.01	gold quality
urethra	UBERON:0000057	97.86	gold quality
endometrium epithelium	UBERON:0004811	97.46	gold quality
mucosa of stomach	UBERON:0001199	97.25	gold quality
caecum	UBERON:0001153	97.08	gold quality
vermiform appendix	UBERON:0001154	96.74	gold quality
mucosa of urinary bladder	UBERON:0001259	96.36	gold quality
caput epididymis	UBERON:0004358	96.31	gold quality
epithelium of nasopharynx	UBERON:0001951	95.97	gold quality

Single-cell (SCXA)

Detected in 21 experiment(s), a significant marker in 20.

Experiment	Marker?	Max mean expression
E-HCAD-1	yes	10700.44
E-CURD-114	yes	5790.45
E-MTAB-9906	yes	5132.77
E-CURD-46	yes	4980.39
E-MTAB-8410	yes	4534.73
E-CURD-88	yes	3127.78
E-MTAB-8221	yes	2486.69
E-MTAB-9841	yes	1779.53
E-HCAD-24	yes	1634.22
E-MTAB-6653	yes	1549.74
E-MTAB-7407	yes	1499.30
E-MTAB-10287	yes	1353.16
E-MTAB-10662	yes	1162.27
E-MTAB-10885	yes	836.94
E-ANND-5	yes	550.84

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets.

Target	Regulation
AREG	Activation
CDX2	Activation

Upstream regulators (CollecTRI, top): AHR, FOXA1, FOXA2, NFKB1, NFKB, PA2G4, SMAD4, SOX2, SPDEF, TCF3

miRNA regulators (miRDB)

17 targeting AGR2, 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-4666A-3P	99.96	71.71	3434
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-4302	99.89	67.94	1187
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-4526	99.68	67.07	1136
HSA-MIR-24-3P	99.59	69.97	1934
HSA-MIR-543	99.52	69.03	2595
HSA-MIR-1324	99.46	66.57	1302
HSA-MIR-302A-5P	99.39	68.21	1913
HSA-MIR-4284	99.36	65.25	1293
HSA-MIR-194-5P	99.01	69.65	1465
HSA-MIR-29B-1-5P	98.86	68.35	1364
HSA-MIR-3922-5P	98.77	66.53	1059
HSA-MIR-3613-5P	98.40	68.91	604
HSA-MIR-2681-3P	98.18	65.28	577
HSA-MIR-342-3P	96.44	67.48	1344

Literature-anchored findings (GeneRIF, showing 40)

• 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. (PMID:12592373)
• AGR2 may serve as a potential therapeutic target and/or molecular marker for prostate cancer. (PMID:15834940)
• specific induction of Hag2 and Hag3 during hormone-induced breast carcinomas further support developmental specificity for the PDI/ERp family members (PMID:15935701)
• represents an interesting new avenue into the etiopathophysiology of inflammatory bowel disease and the maintenance of epithelial integrity. (PMID:16222343)
• A prognostic effect of AGR2 for overall survival could be shown, which became independently significant for the group of nodal-negative tumors. (PMID:16551856)
• increased AGR2 expression is a valuable prognostic factor to predict the clinical outcome of the prostate cancer patients. (PMID:17457305)
• Elevated levels of AGR2 are associated with the metastatic potential of breast cancer (PMID:17694278)
• qRT-PCR assay targeted to plakophilin 3 and anterior gradient-2 mRNAs might be helpful to detect circulating tumor cells in patients with gastrointestinal cancer. (PMID:18801625)
• AGR2 is expressed and secreted during pancreatic cancer development and plays an important role in cancer cell growth and survival. (PMID:18829536)
• Anterior gradient-2 is overexpressed in the majority of fibrolamellar carcinomas but is only rarely overexpressed in hepatocellular carcinomas. (PMID:18973922)
• A prognostic value of AGR2 seems unlikely. (PMID:19609859)
• Data suggest that the presence of anterior gradient 2 protein in primary tumors is a possible prognostic indicator of poor patient outcome in breast cancer. (PMID:19834055)
• our results reveal an EBP1-Foxa-AGR2 signaling circuit with functional significance in metastatic prostate cancer. (PMID:20048076)
• aryl hydrocarbon receptor ligands might contribute to tumor progression by inhibiting p53 regulation via the increased expression of the metastasis marker AGR2 (PMID:20299546)
• High serum AGR2 is associated with ovarian cancer. (PMID:20525245)
• High AGR2 is associated with breast neoplasms. (PMID:20525379)
• elevation of AGR2 levels in pancreatic juice occurs in early pancreatic cancer progression and could be further investigated as a potential candidate juice biomarker for early detection of pancreatic cancer. (PMID:20550709)
• The Reptin docking site was mapped to a divergent octapeptide loop in the AGR2 superfamily between amino acids 104 and 111. Mutations at codon Y104 or F111 in full-length AGR2 destabilized the binding of Reptin. (PMID:20888340)
• AGR2 enhances the invasion phenotype of prostate cancer cells while at the same time attenuating cell-cycle progression. (PMID:20945500)
• Despite an increase in AGR2 expression in prostate cancer compared to non-malignant cells, relatively lower levels of AGR2 are highly predictive of disease recurrence following radical prostatectomy. (PMID:21144054)
• AGR2 is a potential biomarker for the diagnosis of mucinous ovarian cancer. (PMID:21200134)
• Our study shows that the differential expression of AGR2 is a phenotypic feature of the cholangiocytes covering different segments of the biliary tree. (PMID:21281432)
• AGR2 induction of AREG is mediated by activation of the Hippo signaling pathway co-activator, YAP1. (PMID:21454516)
• AGR2 protein expression may support the histologic subtyping of nonsmall-cell lung cancer and be of clinical value in differentiating lung AdC from SCC. (PMID:21768879)
• AGR2 is a novel surface antigen that promotes the dissemination of pancreatic cancer cells through regulation of cathepsins B and D. (PMID:21948970)
• AGR2 expression is controlled by the unfolded protein response and is in turn is involved in the maintenance of ER homeostasis. (PMID:22025610)
• AGR2, encoding a 19-kDa secreted protein that might be found in urine, is detected in tissue digestion media of tumor specimens and culture media of AGR2-secreting prostate cancer cell lines. (PMID:22072305)
• investigation of expression of AGR2, S100P, and S100A4 at cellular level within endometrium of normal fertile women across menstrual cycle and comparison with expression in eutopic and peritoneal ectopic endometrial tissue in endometriosis (PMID:22147918)
• AGR2 gene function requires a unique endoplasmic reticulum localization motif. (PMID:22184114)
• containes epitopes identified a tumor-associated antigens against colorectal cancer (PMID:22231555)
• Positive serum AGR2 expression in patients with lung adenocarcinoma was significantly associated with the incidence of recurrence after surgery and with a poor prognosis for overall survival (PMID:22430137)
• AGR2 depletion resulted in accumulation of cells at the G(0)/G(1) phase and induction of cellular senescence in all three PCa cell lines (PMID:22467239)
• Anterior gradient 2 overexpression affects the whole spectrum of the metaplastic/neo-plastic lesions involved in Barrett carcinogenesis. (PMID:22521076)
• High AGR2/LGR5 was associated with poor progression-free survival by multivariate analysis. (PMID:22605983)
• In vitro, knockdown of CD147 or AGR2 decreased cellular proliferation, migration and invasion. In vivo, knockdown of CD147 or AGR2 expression decreased primary tumor growth as well as regional and distant metastasis. (PMID:22659167)
• Anterior gradient homolog 2 and MUC5AC are useful positive markers of adenocarcinoma. (PMID:22748473)
• AGR2 expression identifies highly aggressive Ovarian high-grade serous carcinoma with a compromised prognosis (PMID:22752467)
• High expression levels of AGR2 exist in metastatic hepatocellular carcinoma cell lines and patient livers. (PMID:22828706)
• Anterior gradient 2 (AGR2) is a blood-based biomarker elevated in metastatic prostate cancer associated with the neuroendocrine phenotype (PMID:22911164)
• We show that the downregulation of AGR2 in human pancreatic cancer cells is SMAD4 dependent. (PMID:22945649)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	agr2	ENSDARG00000070480
mus_musculus	Agr2	ENSMUSG00000020581
rattus_norvegicus	Agr2	ENSRNOG00000005023
caenorhabditis_elegans		WBGENE00013263
caenorhabditis_elegans		WBGENE00018656

Paralogs (2): TXNDC12 (ENSG00000117862), AGR3 (ENSG00000173467)

Protein

Protein identifiers

Anterior gradient protein 2 homolog — O95994 (reviewed: O95994)

Alternative names: HPC8, Secreted cement gland protein XAG-2 homolog

All UniProt accessions (5): O95994, B5MC07, C9J3E2, H7C3Z9, Q4JM46

UniProt curated annotations — full annotation on UniProt →

Function. Required for MUC2 post-transcriptional synthesis and secretion. May play a role in the production of mucus by intestinal cells. Proto-oncogene that may play a role in cell migration, cell differentiation and cell growth. Promotes cell adhesion.

Subunit / interactions. Monomer and homodimer. Interacts with LYPD3 and DAG1 (alphaDAG1). Interacts with MUC2; disulfide-linked.

Subcellular location. Secreted. Endoplasmic reticulum.

Tissue specificity. Expressed strongly in trachea, lung, stomach, colon, prostate and small intestine. Expressed weakly in pituitary gland, salivary gland, mammary gland, bladder, appendix, ovary, fetal lung, uterus, pancreas, kidney, fetal kidney, testis, placenta, thyroid gland and in estrogen receptor (ER)-positive breast cancer cell lines.

Disease relevance. Respiratory infections, recurrent, and failure to thrive with or without diarrhea (RIFTD) [MIM:620233] An autosomal recessive disorder characterized by neonatal onset of recurrent pulmonary infections, coughing, wheezy episodes, interstitial lung disease, and bronchiectasis. Episodes of vomiting and chronic diarrhea result in failure to thrive. Results of sweat chloride and pancreatic elastase tests are normal. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the AGR family.

RefSeq proteins (1): NP_006399* (*=MANE)

Domains & families (InterPro)

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

Pfam: PF13899

UniProt features (28 total): strand 7, turn 5, mutagenesis site 4, helix 4, sequence variant 3, short sequence motif 2, signal peptide 1, chain 1, region of interest 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
9I3F	X-RAY DIFFRACTION	1.9
9I3U	ELECTRON MICROSCOPY	2.9
2LNS	SOLUTION NMR
2LNT	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O95994-F1	86.52	0.73

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 (4):

Position	Phenotype
64	disrupted dimerization.
81	loss of interaction with muc2.
60	monomer only, and reduced cell adhesion efficiency.
63	disrupted dimerization.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 344 (showing top): GOBP_EPITHELIUM_DEVELOPMENT, GOBP_LUNG_EPITHELIUM_DEVELOPMENT, GOBP_IRE1_MEDIATED_UNFOLDED_PROTEIN_RESPONSE, GOBP_REGULATION_OF_ERBB_SIGNALING_PATHWAY, GOBP_CELL_CHEMOTAXIS, YANG_BREAST_CANCER_ESR1_LASER_UP, GOBP_INFLAMMATORY_RESPONSE, GOBP_REGULATION_OF_DEVELOPMENTAL_GROWTH, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GOBP_LUNG_CELL_DIFFERENTIATION, GOZGIT_ESR1_TARGETS_DN, GOBP_GROWTH, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION, LINDGREN_BLADDER_CANCER_CLUSTER_3_DN, GGGTGGRR_PAX4_03

GO Biological Process (14): inflammatory response (GO:0006954), positive regulation of gene expression (GO:0010628), positive regulation of cell-substrate adhesion (GO:0010811), endoplasmic reticulum unfolded protein response (GO:0030968), protein folding in endoplasmic reticulum (GO:0034975), positive regulation of epidermal growth factor receptor signaling pathway (GO:0045742), digestive tract morphogenesis (GO:0048546), positive regulation of developmental growth (GO:0048639), cell chemotaxis (GO:0060326), lung goblet cell differentiation (GO:0060480), mucus secretion (GO:0070254), positive regulation of protein localization to plasma membrane (GO:1903078), positive regulation of IRE1-mediated unfolded protein response (GO:1903896), positive regulation of PERK-mediated unfolded protein response (GO:1903899)

GO Molecular Function (5): dystroglycan binding (GO:0002162), epidermal growth factor receptor binding (GO:0005154), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), protein binding (GO:0005515)

GO Cellular Component (3): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), endoplasmic reticulum (GO:0005783)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
positive regulation of endoplasmic reticulum unfolded protein response	2
protein binding	2
defense response	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
regulation of cell-substrate adhesion	1
cell-substrate adhesion	1
positive regulation of cell adhesion	1
cellular response to unfolded protein	1
response to endoplasmic reticulum stress	1
intracellular signal transduction	1
protein folding	1
epidermal growth factor receptor signaling pathway	1
regulation of epidermal growth factor receptor signaling pathway	1
positive regulation of ERBB signaling pathway	1
tube morphogenesis	1
digestive tract development	1
positive regulation of growth	1
developmental growth	1
regulation of developmental growth	1
positive regulation of developmental process	1
chemotaxis	1
cell migration	1
cellular response to chemical stimulus	1
lobar bronchus epithelium development	1
lung secretory cell differentiation	1
body fluid secretion	1
secretion by tissue	1
protein localization to plasma membrane	1
regulation of protein localization to plasma membrane	1
positive regulation of protein localization to cell periphery	1
positive regulation of protein localization to membrane	1
IRE1-mediated unfolded protein response	1
regulation of IRE1-mediated unfolded protein response	1
PERK-mediated unfolded protein response	1
regulation of PERK-mediated unfolded protein response	1
growth factor receptor binding	1
identical protein binding	1
protein dimerization activity	1

Protein interactions and networks

STRING

2854 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AGR2	LYPD3	O95274	972
AGR2	DAG1	Q14118	801
AGR2	ESR1	P03372	766
AGR2	TFF3	Q07654	679
AGR2	SPDEF	O95238	665
AGR2	MUC5AC	P98088	645
AGR2	FOXA1	P55317	642
AGR2	ZG16	O60844	631
AGR2	WFDC2	Q14508	591
AGR2	CD59	P13987	560
AGR2	CLCA1	A8K7I4	541
AGR2	ERBB3	P21860	521
AGR2	ERVFRD-1	P60508	503
AGR2	ERV3-1	Q14264	503
AGR2	FCGBP	Q9Y6R7	497

IntAct

356 interactions, top by confidence:

A	B	Type	Score
NDUFS3	NDUFS8	psi-mi:“MI:0914”(association)	0.730
KRT31	AGR2	psi-mi:“MI:0915”(physical association)	0.720
UBQLN1	AGR2	psi-mi:“MI:0915”(physical association)	0.720
CATSPER1	AGR2	psi-mi:“MI:0915”(physical association)	0.720
AGR2	NUP62CL	psi-mi:“MI:0915”(physical association)	0.720
AGR2	KRT31	psi-mi:“MI:0915”(physical association)	0.720
AGR2	UBQLN1	psi-mi:“MI:0915”(physical association)	0.720
AGR2	CATSPER1	psi-mi:“MI:0915”(physical association)	0.720
FABP2	AGR2	psi-mi:“MI:0915”(physical association)	0.670
AGR2	POM121	psi-mi:“MI:0915”(physical association)	0.670
AGR2	FABP2	psi-mi:“MI:0915”(physical association)	0.670
MUC2	AGR2	psi-mi:“MI:0915”(physical association)	0.660
LYRM4	NDUFAB1	psi-mi:“MI:0914”(association)	0.640
AGR2	UBQLN1	psi-mi:“MI:0915”(physical association)	0.560
UBQLN1	AGR2	psi-mi:“MI:0915”(physical association)	0.560
AGR2		psi-mi:“MI:0915”(physical association)	0.560
AGR2	SED1	psi-mi:“MI:0915”(physical association)	0.560
AGR2	SGT2	psi-mi:“MI:0915”(physical association)	0.560
AGR2	BSC1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (1211): AGR2 (Affinity Capture-MS), AGR2 (Two-hybrid), AGR2 (Two-hybrid), AGR2 (Two-hybrid), UBQLN1 (Two-hybrid), NUP62CL (Two-hybrid), CATSPER1 (Two-hybrid), AGR2 (Two-hybrid), AGR2 (Affinity Capture-MS), AGR2 (Two-hybrid), AGR2 (Affinity Capture-MS), AGR2 (Two-hybrid), AGR2 (Two-hybrid), AGR2 (Two-hybrid), AGR2 (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.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 101 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
SUMOylation of RNA binding proteins	5	18.3×	4e-03
SUMOylation of chromatin organization proteins	5	12.2×	7e-03
SUMOylation of DNA damage response and repair proteins	5	11.3×	7e-03

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	6
Uncertain significance	28
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (9)

Variant ID	HGVS	Classification
148160	GRCh38/hg38 7p21.2-21.1(chr7:16121516-20607899)x1	Pathogenic
2443887	NM_006408.4(AGR2):c.330+1G>T	Pathogenic
2443888	NM_006408.4(AGR2):c.428G>A (p.Gly143Glu)	Pathogenic
2443885	NM_006408.4(AGR2):c.211C>A (p.Pro71Thr)	Likely pathogenic
2443886	NM_006408.4(AGR2):c.349C>T (p.His117Tyr)	Likely pathogenic
2664703	NM_006408.4(AGR2):c.256+2T>C	Likely pathogenic
3384114	NM_006408.4(AGR2):c.104del (p.Asp35fs)	Likely pathogenic
4087694	NM_006408.4(AGR2):c.257-1G>C	Likely pathogenic
4087695	NM_006408.4(AGR2):c.162G>A (p.Trp54Ter)	Likely pathogenic

SpliceAI

1037 predictions. Top by Δscore:

Variant	Effect	Δscore
7:16792956:CA:C	acceptor_gain	1.0000
7:16792958:C:CC	acceptor_gain	1.0000
7:16794935:CA:C	donor_gain	1.0000
7:16799742:A:AC	donor_gain	1.0000
7:16799742:ACAAC:A	donor_gain	1.0000
7:16799743:C:CC	donor_gain	1.0000
7:16799743:CA:C	donor_gain	1.0000
7:16799743:CAA:C	donor_gain	1.0000
7:16799743:CAACC:C	donor_gain	1.0000
7:16799813:TAAAG:T	acceptor_gain	1.0000
7:16799817:GC:G	acceptor_loss	1.0000
7:16799818:C:CA	acceptor_loss	1.0000
7:16799818:C:CC	acceptor_gain	1.0000
7:16801206:T:C	acceptor_gain	1.0000
7:16792955:GCA:G	acceptor_gain	0.9900
7:16792956:CAC:C	acceptor_gain	0.9900
7:16794934:A:AC	donor_gain	0.9900
7:16794935:C:CC	donor_gain	0.9900
7:16797622:T:TA	donor_gain	0.9900
7:16797641:AAT:A	donor_gain	0.9900
7:16799738:ACTT:A	donor_loss	0.9900
7:16799739:CT:C	donor_loss	0.9900
7:16799740:TT:T	donor_loss	0.9900
7:16799741:T:TG	donor_loss	0.9900
7:16799814:AAAG:A	acceptor_gain	0.9900
7:16799815:AAG:A	acceptor_gain	0.9900
7:16799816:AG:A	acceptor_gain	0.9900
7:16799816:AGCT:A	acceptor_gain	0.9900
7:16799817:GCTAT:G	acceptor_gain	0.9900
7:16801204:C:CC	acceptor_gain	0.9900

AlphaMissense

1135 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:16797648:G:T	P126H	1.000
7:16797655:A:G	Y124H	1.000
7:16801166:A:G	C81R	1.000
7:16801342:C:G	A61P	1.000
7:16801361:C:A	W54C	1.000
7:16801361:C:G	W54C	1.000
7:16801363:A:G	W54R	1.000
7:16801363:A:T	W54R	1.000
7:16801379:C:A	W48C	1.000
7:16801379:C:G	W48C	1.000
7:16792957:A:G	L160S	0.999
7:16794971:C:G	R148P	0.999
7:16794986:C:T	G143E	0.999
7:16794987:C:G	G143R	0.999
7:16794987:C:T	G143R	0.999
7:16795000:T:A	R138S	0.999
7:16795000:T:G	R138S	0.999
7:16795001:C:G	R138T	0.999
7:16795004:A:T	V137D	0.999
7:16797633:A:T	V131D	0.999
7:16797636:A:C	F130C	0.999
7:16797636:A:G	F130S	0.999
7:16797644:C:A	R127S	0.999
7:16797644:C:G	R127S	0.999
7:16797645:C:A	R127M	0.999
7:16797645:C:G	R127T	0.999
7:16797648:G:C	P126R	0.999
7:16797649:G:A	P126S	0.999
7:16797649:G:T	P126T	0.999
7:16797651:A:T	V125D	0.999

dbSNP variants (sampled 300 via entrez): RS1000077862 (7:16796498 T>C,G), RS1000139592 (7:16796759 T>A), RS1001131862 (7:16795542 A>T), RS1001250014 (7:16800255 G>A), RS1001400215 (7:16800307 G>A), RS1001460229 (7:16805578 A>C), RS1001641437 (7:16805396 C>G), RS1001786340 (7:16797432 A>G), RS1001919043 (7:16792167 G>A), RS1002244444 (7:16804377 T>G), RS1002293755 (7:16806713 G>C), RS1002401039 (7:16799226 AT>A,ATT), RS1002589968 (7:16795222 G>A,T), RS1002872220 (7:16804569 C>A,G), RS1003179939 (7:16804017 T>C)

Disease associations

OMIM: gene MIM:606358 | disease phenotypes: MIM:620233

GenCC curated gene-disease

Disease	Classification	Inheritance
respiratory infections, recurrent, and failure to thrive with or without diarrhea	Strong	Autosomal recessive

Mondo (1): respiratory infections, recurrent, and failure to thrive with or without diarrhea (MONDO:0859370)

Orphanet (0):

HPO phenotypes

43 total (30 of 43 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000219	Thin upper lip vermilion
HP:0000403	Recurrent otitis media
HP:0000582	Upslanted palpebral fissure
HP:0001252	Hypotonia
HP:0001254	Lethargy
HP:0001263	Global developmental delay
HP:0001269	Hemiparesis
HP:0001270	Motor delay
HP:0001396	Cholestasis
HP:0001508	Failure to thrive
HP:0001634	Mitral valve prolapse
HP:0001974	Increased total leukocyte count
HP:0002013	Vomiting
HP:0002020	Gastroesophageal reflux
HP:0002028	Chronic diarrhea
HP:0002092	Pulmonary arterial hypertension
HP:0002094	Dyspnea
HP:0002099	Asthma
HP:0002110	Bronchiectasis
HP:0002202	Pleural effusion
HP:0002240	Hepatomegaly
HP:0002783	Recurrent lower respiratory tract infections
HP:0002875	Exertional dyspnea
HP:0003270	Abdominal distention
HP:0003577	Congenital onset
HP:0003593	Infantile onset
HP:0003623	Neonatal onset
HP:0005180	Tricuspid regurgitation
HP:0006530	Abnormal pulmonary interstitial morphology

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST001843_2	Type 2 diabetes (dietary heme iron intake interaction)	6.000000e-06
GCST002007_3	Adverse response to chemotherapy (neutropenia/leucopenia) (cisplatin)	2.000000e-07
GCST004291_5	Residual cognition	8.000000e-07
GCST004573_9	Iron status biomarkers (ferritin levels)	9.000000e-08

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0008355	dietary heme iron intake measurement
EFO:0003925	cognition
EFO:0022597	aging
EFO:0004459	ferritin measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

Clinical evidence (CIViC)

Drug × variant × indication: 1 predictive associations from 1 curated evidence items.

Variant	Therapy	Indication	Effect	Level	CIViC
AGR2 EXPRESSION	Tamoxifen	Breast Cancer	Resistance	CIViC B	EID891

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases expression	8
Estradiol	affects cotreatment, decreases expression, affects binding, increases reaction, increases expression	6
Tetrachlorodibenzodioxin	increases expression, affects binding, increases reaction, affects reaction	5
Cyclosporine	increases expression	3
Arsenic Trioxide	decreases response to substance, increases expression	2
Dihydrotestosterone	affects expression, increases expression	2
Tamoxifen	increases reaction, increases expression, affects response to substance, decreases response to substance, affects binding	2
Tobacco Smoke Pollution	affects expression	2
sotorasib	affects cotreatment, increases expression	1
dicrotophos	decreases expression	1
methyleugenol	increases expression	1
bisphenol A	increases expression	1
glycidyl methacrylate	decreases expression	1
sodium arsenate	decreases expression, increases abundance	1
tris(2-butoxyethyl) phosphate	affects expression	1
beta-lapachone	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	increases expression	1
cobaltous chloride	decreases expression	1
doxifluridine	increases response to substance	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
stearic acid	increases expression	1
1-UFT protocol	increases response to substance	1
bicalutamide	increases expression	1
indolo(3,2-b)carbazole	increases expression	1
S 1 (combination)	increases response to substance	1
perfluoro-n-nonanoic acid	increases expression	1
tanespimycin	increases expression, affects cotreatment	1
perfluorohexanesulfonic acid	increases expression	1
abrine	decreases expression	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D7JT	Ubigene A-549 AGR2 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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