TXNDC12

Summary

TXNDC12 (thioredoxin domain containing 12, HGNC:24626) is a protein-coding gene on chromosome 1p32.3, encoding Thioredoxin domain-containing protein 12 (O95881). Protein-disulfide reductase of the endoplasmic reticulum that promotes disulfide bond formation in client proteins through its thiol-disulfide oxidase activity.

This gene encodes a member of the thioredoxin superfamily. Members of this family are characterized by a conserved active motif called the thioredoxin fold that catalyzes disulfide bond formation and isomerization. This protein localizes to the endoplasmic reticulum and has a single atypical active motif. The encoded protein is mainly involved in catalyzing native disulfide bond formation and displays activity similar to protein-disulfide isomerases. This protein may play a role in defense against endoplasmic reticulum stress. Alternate splicing results in both coding and non-coding variants.

Source: NCBI Gene 51060 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 27 total
• MANE Select transcript: NM_015913

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24626
Approved symbol	TXNDC12
Name	thioredoxin domain containing 12
Location	1p32.3
Locus type	gene with protein product
Status	Approved
Aliases	TLP19, ERP18, ERP19, hAG-1, AGR1, PDIA16
Ensembl gene	ENSG00000117862
Ensembl biotype	protein_coding
OMIM	609448
Entrez	51060

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 6 protein_coding, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000371626, ENST00000469458, ENST00000471493, ENST00000472624, ENST00000610127, ENST00000715260, ENST00000871920, ENST00000915667, ENST00000915668

RefSeq mRNA: 1 — MANE Select: NM_015913 NM_015913

CCDS: CCDS561

Canonical transcript exons

ENST00000371626 — 7 exons

Exon	Start	End
ENSE00001455699	52020131	52021012
ENSE00003568562	52023491	52023574
ENSE00003594156	52027275	52027348
ENSE00003667524	52024510	52024579
ENSE00003692973	52028578	52028630
ENSE00003703230	52041537	52041597
ENSE00003709855	52055000	52055191

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 96.72.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 52.8018 / max 460.1766, expressed in 1826 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
12347	50.7921	1826
12354	1.6338	832
12352	0.1902	78
12353	0.1856	80

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	96.72	gold quality
leukocyte	CL:0000738	96.70	gold quality
rectum	UBERON:0001052	96.52	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	96.37	gold quality
stromal cell of endometrium	CL:0002255	96.35	gold quality
body of pancreas	UBERON:0001150	96.28	gold quality
islet of Langerhans	UBERON:0000006	96.09	gold quality
pancreas	UBERON:0001264	95.91	gold quality
ventricular zone	UBERON:0003053	95.74	gold quality
placenta	UBERON:0001987	95.61	gold quality
gall bladder	UBERON:0002110	95.53	gold quality
endometrium	UBERON:0001295	95.42	gold quality
adrenal tissue	UBERON:0018303	95.05	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	95.02	gold quality
granulocyte	CL:0000094	95.00	gold quality
lymph node	UBERON:0000029	94.84	gold quality
smooth muscle tissue	UBERON:0001135	94.78	gold quality
vermiform appendix	UBERON:0001154	94.76	gold quality
fallopian tube	UBERON:0003889	94.69	gold quality
duodenum	UBERON:0002114	94.46	gold quality
blood	UBERON:0000178	94.21	gold quality
bone marrow cell	CL:0002092	94.13	gold quality
omental fat pad	UBERON:0010414	94.11	gold quality
right ovary	UBERON:0002118	94.09	gold quality
saliva-secreting gland	UBERON:0001044	94.02	gold quality
mucosa of transverse colon	UBERON:0004991	94.02	gold quality
tonsil	UBERON:0002372	93.95	gold quality
left adrenal gland	UBERON:0001234	93.91	gold quality
ovary	UBERON:0000992	93.87	gold quality
minor salivary gland	UBERON:0001830	93.84	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	11.87

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

57 targeting TXNDC12, 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-4262	100.00	73.26	3931
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-30B-3P	99.70	65.76	2325
HSA-MIR-3689A-3P	99.70	65.73	2306
HSA-MIR-3689B-3P	99.70	65.71	2311
HSA-MIR-3689C	99.70	65.71	2311
HSA-MIR-6779-5P	99.70	65.76	2363
HSA-MIR-4502	99.65	66.99	1021
HSA-MIR-561-3P	99.64	70.90	3647
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-24-3P	99.59	69.97	1934
HSA-MIR-2053	99.57	69.15	1635
HSA-MIR-7106-5P	99.53	67.47	3574
HSA-MIR-199A-5P	99.51	69.71	1107
HSA-MIR-199B-5P	99.51	69.74	1098
HSA-MIR-5584-5P	99.49	68.22	2814
HSA-MIR-766-5P	99.47	67.91	2225
HSA-MIR-582-5P	99.47	70.79	2635
HSA-MIR-516A-3P	99.46	67.96	1378
HSA-MIR-516B-3P	99.46	67.96	1378

Literature-anchored findings (GeneRIF, showing 8)

• putative physiological role for endoplasmic reticulum thioredoxin superfamily member p18(ERp18) in native disulfide bond formation is discussed (PMID:12761212)
• ERp16 mediates disulfide bond formation in the ER and plays an important role in cellular defense against prolonged ER stress (PMID:18628206)
• the solution structure of oxidized ERp18 as determined using NMR spectroscopy (PMID:19361226)
• ERp18 shows specificity towards a component of the complement cascade, pentraxin-related protein PTX3. (PMID:19887585)
• We conclude that ERp19 contributes to tumorigenicity and metastasis of gastric cancer (PMID:25940440)
• Data demonstrate that ERp18 monitors ATF6a endoplasmic reticulum quality control to ensure optimal processing following trafficking to the Golgi. (PMID:31368601)
• TXNDC12 promotes EMT and metastasis of hepatocellular carcinoma cells via activation of beta-catenin. (PMID:31570854)
• Clinical Value of TXNDC12 Combined With IDH and 1p19q as Biomarkers for Prognosis of Glioma. (PMID:34629960)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	txndc12	ENSDARG00000038980
mus_musculus	Txndc12	ENSMUSG00000028567
rattus_norvegicus	Txndc12	ENSRNOG00000008090
caenorhabditis_elegans		WBGENE00013263
caenorhabditis_elegans		WBGENE00018656

Paralogs (2): AGR2 (ENSG00000106541), AGR3 (ENSG00000173467)

Protein

Protein identifiers

Thioredoxin domain-containing protein 12 — O95881 (reviewed: O95881)

Alternative names: Endoplasmic reticulum resident protein 18, Endoplasmic reticulum resident protein 19, Thioredoxin-like protein p19, hTLP19

All UniProt accessions (3): O95881, V9GY50, V9GYV4

UniProt curated annotations — full annotation on UniProt →

Function. Protein-disulfide reductase of the endoplasmic reticulum that promotes disulfide bond formation in client proteins through its thiol-disulfide oxidase activity.

Subcellular location. Endoplasmic reticulum lumen.

Tissue specificity. Widely expressed.

RefSeq proteins (1): NP_056997* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR013766	Thioredoxin_domain	Domain
IPR017937	Thioredoxin_CS	Conserved_site
IPR036249	Thioredoxin-like_sf	Homologous_superfamily
IPR037462	ERp19	Family
IPR051099	AGR/TXD	Family

Pfam: PF13899

Catalyzed reactions (Rhea), 1 shown:

• [protein]-disulfide + 2 glutathione = [protein]-dithiol + glutathione disulfide (RHEA:21064)

UniProt features (21 total): helix 7, strand 4, turn 2, mutagenesis site 2, signal peptide 1, chain 1, domain 1, short sequence motif 1, disulfide bond 1, sequence conflict 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
1SEN	X-RAY DIFFRACTION	1.2
2K8V	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O95881-F1	87.59	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.

Disulfide bonds (1): 66–69

Mutagenesis-validated functional residues (2):

Position	Phenotype
66	loss of protein-disulfide reductase (glutathione) activity. loss of the formation of disulfide bonds in substrate.
69	loss of protein-disulfide reductase (glutathione) activity. loss of the formation of disulfide bonds in substrate.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 185 (showing top): GOBP_NEGATIVE_REGULATION_OF_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, MODULE_93, FREAC2_01, TGCGCANK_UNKNOWN, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, CGGAARNGGCNG_UNKNOWN, AP4_Q6, FOXO4_01, USF_C, CAGCTG_AP4_Q5, YY1_Q6, GGCNKCCATNK_UNKNOWN, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, GOBP_NEGATIVE_REGULATION_OF_INTRINSIC_APOPTOTIC_SIGNALING_PATHWAY, MYOD_01

GO Biological Process (1): negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway (GO:1902236)

GO Molecular Function (4): protein-disulfide reductase activity (GO:0015035), protein-disulfide reductase (glutathione) activity (GO:0019153), protein binding (GO:0005515), oxidoreductase activity (GO:0016491)

GO Cellular Component (2): endoplasmic reticulum (GO:0005783), endoplasmic reticulum lumen (GO:0005788)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress	1
regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway	1
negative regulation of response to endoplasmic reticulum stress	1
negative regulation of intrinsic apoptotic signaling pathway	1
disulfide oxidoreductase activity	1
catalytic activity, acting on a protein	1
protein-disulfide reductase activity	1
oxidoreductase activity, acting on a sulfur group of donors, disulfide as acceptor	1
binding	1
catalytic activity	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
endoplasmic reticulum	1
intracellular organelle lumen	1

Protein interactions and networks

STRING

2075 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TXNDC12	TXN	P10599	756
TXNDC12	ATF6	P18850	729
TXNDC12	P4HB	P07237	724
TXNDC12	TMX4	Q9H1E5	715
TXNDC12	TXNDC5	Q8NBS9	582
TXNDC12	P4HA1	P13674	566
TXNDC12	ERO1A	Q96HE7	550
TXNDC12	PDIA5	Q14554	548
TXNDC12	PDIA4	P13667	523
TXNDC12	ERP27	Q96DN0	516
TXNDC12	PDIA2	Q13087	511
TXNDC12	TMX1	Q9H3N1	489
TXNDC12	CTNNB1	P35222	484
TXNDC12	ERP44	Q9BS26	480
TXNDC12	ERP29	P30040	479

IntAct

65 interactions, top by confidence:

A	B	Type	Score
TXNDC12	SGTB	psi-mi:“MI:0915”(physical association)	0.720
SGTB	TXNDC12	psi-mi:“MI:0915”(physical association)	0.720
KLHL2	TXNDC12	psi-mi:“MI:0915”(physical association)	0.670
TXNDC12	UBQLN1	psi-mi:“MI:0915”(physical association)	0.670
TXNDC12	KLHL2	psi-mi:“MI:0915”(physical association)	0.670
UBQLN1	TXNDC12	psi-mi:“MI:0915”(physical association)	0.670
TM2D3	TXNDC12	psi-mi:“MI:0914”(association)	0.640
SGTA	TXNDC12	psi-mi:“MI:0915”(physical association)	0.560
UBQLN1	TXNDC12	psi-mi:“MI:0915”(physical association)	0.560
TXNDC12	UBQLN1	psi-mi:“MI:0915”(physical association)	0.560
TXNDC12	UBQLN2	psi-mi:“MI:0915”(physical association)	0.560
TXNDC12	CAMLG	psi-mi:“MI:0915”(physical association)	0.560
TXNDC12	DPF2	psi-mi:“MI:0915”(physical association)	0.560
TXNDC12	FKBP7	psi-mi:“MI:0915”(physical association)	0.560
TXNDC12	TUBG1	psi-mi:“MI:0914”(association)	0.530
YTHDC1	TXNDC12	psi-mi:“MI:0915”(physical association)	0.400
GABRQ	TXNDC12	psi-mi:“MI:0915”(physical association)	0.400
TXNDC12	ZDHHC17	psi-mi:“MI:0915”(physical association)	0.370
PRNP	WDR91	psi-mi:“MI:0914”(association)	0.350
CAV1	PPM1G	psi-mi:“MI:0914”(association)	0.350

BioGRID (170): TXNDC12 (Two-hybrid), TXNDC12 (Two-hybrid), TXNDC12 (Two-hybrid), SGTB (Two-hybrid), TXNDC12 (Two-hybrid), IQGAP2 (Co-fractionation), TXNDC12 (Co-fractionation), TXNDC12 (Two-hybrid), TXNDC12 (Proximity Label-MS), TUBGCP4 (Affinity Capture-MS), TUBGCP5 (Affinity Capture-MS), MZT2A (Affinity Capture-MS), TUBGCP6 (Affinity Capture-MS), MZT2B (Affinity Capture-MS), TUBGCP3 (Affinity Capture-MS)

ESM2 similar proteins: H9D1R1, O22263, O48773, O95881, P04785, P05307, P07237, P08003, P09102, P09103, P11598, P13667, P27773, P29828, P30040, P30101, P34329, P38657, P38659, P38660, P38661, P52555, P52588, P57759, P80284, P81623, P81628, Q11067, Q17688, Q29RV1, Q2HWU2, Q43116, Q498E0, Q4VIT4, Q53LQ0, Q5E936, Q5R5B6, Q5RDG4, Q67IX6, Q67UF5

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 52 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
Signaling by high-kinase activity BRAF mutants	5	40.7×	2e-05
MAP2K and MAPK activation	5	36.6×	2e-05
Negative regulation of MAPK pathway	5	34.0×	2e-05
Signaling by moderate kinase activity BRAF mutants	5	32.5×	2e-05
Paradoxical activation of RAF signaling by kinase inactive BRAF	5	32.5×	2e-05
Signaling downstream of RAS mutants	5	32.5×	2e-05
Signaling by BRAF and RAF1 fusions	5	21.9×	9e-05

GO biological processes:

GO term	Partners	Fold	FDR
MAPK cascade	5	17.0×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	14
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1190 predictions. Top by Δscore:

Variant	Effect	Δscore
1:52024504:CCTTA:C	donor_loss	1.0000
1:52024505:CTTAC:C	donor_loss	1.0000
1:52024506:TTACC:T	donor_loss	1.0000
1:52024507:TAC:T	donor_loss	1.0000
1:52024508:AC:A	donor_gain	1.0000
1:52024509:CC:C	donor_gain	1.0000
1:52024578:TCCTA:T	acceptor_loss	1.0000
1:52024579:CC:C	acceptor_loss	1.0000
1:52024580:C:CA	acceptor_loss	1.0000
1:52027349:C:CC	acceptor_gain	1.0000
1:52027366:T:C	acceptor_gain	1.0000
1:52027366:T:TC	acceptor_gain	1.0000
1:52028629:CA:C	acceptor_gain	1.0000
1:52028629:CACT:C	acceptor_gain	1.0000
1:52028631:C:CC	acceptor_gain	1.0000
1:52028632:T:C	acceptor_gain	1.0000
1:52042013:T:TA	donor_gain	1.0000
1:52021010:CAA:C	acceptor_gain	0.9900
1:52021013:C:CC	acceptor_gain	0.9900
1:52023485:CTATA:C	donor_loss	0.9900
1:52023486:TATAC:T	donor_loss	0.9900
1:52023487:ATACC:A	donor_loss	0.9900
1:52023488:TACCT:T	donor_loss	0.9900
1:52023489:ACCT:A	donor_loss	0.9900
1:52023490:C:CT	donor_loss	0.9900
1:52023491:C:A	donor_loss	0.9900
1:52023573:ATC:A	acceptor_loss	0.9900
1:52023576:T:A	acceptor_loss	0.9900
1:52024503:GCCTT:G	donor_loss	0.9900
1:52024508:A:AC	donor_gain	0.9900

AlphaMissense

1142 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:52024524:C:G	R114P	1.000
1:52028583:C:T	C69Y	1.000
1:52028592:C:T	C66Y	1.000
1:52028593:A:G	C66R	1.000
1:52041575:C:A	W40C	1.000
1:52041575:C:G	W40C	1.000
1:52041577:A:G	W40R	1.000
1:52041577:A:T	W40R	1.000
1:52024527:G:C	P113R	0.999
1:52024527:G:T	P113Q	0.999
1:52024528:G:A	P113S	0.999
1:52024533:T:C	Y111C	0.999
1:52024534:A:G	Y111H	0.999
1:52027294:A:G	F89S	0.999
1:52027345:A:G	L72P	0.999
1:52028582:G:C	C69W	0.999
1:52028583:C:A	C69F	0.999
1:52028584:A:G	C69R	0.999
1:52028591:A:C	C66W	0.999
1:52028592:C:A	C66F	0.999
1:52028592:C:G	C66S	0.999
1:52028593:A:T	C66S	0.999
1:52028594:C:A	W65C	0.999
1:52028594:C:G	W65C	0.999
1:52028596:A:G	W65R	0.999
1:52028596:A:T	W65R	0.999
1:52041547:C:G	A50P	0.999
1:52041558:C:T	G46E	0.999
1:52041559:C:A	G46W	0.999
1:52021012:A:T	V147D	0.998

dbSNP variants (sampled 300 via entrez): RS1000100415 (1:52031317 G>A), RS1000135208 (1:52042344 G>A), RS1000169168 (1:52037205 A>C,T), RS1000206401 (1:52056239 G>C), RS1000322937 (1:52056435 C>A,T), RS1000330268 (1:52028016 C>T), RS1000368691 (1:52022046 G>T), RS1000400631 (1:52037707 A>G,T), RS1000530171 (1:52040505 T>A,C), RS1000580553 (1:52054002 G>T), RS1000632194 (1:52047694 G>A), RS1000658128 (1:52057530 T>C), RS1000661636 (1:52047368 G>A), RS1000848428 (1:52044915 C>T), RS1000969069 (1:52033560 G>A)

Disease associations

OMIM: gene MIM:609448 | 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

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases reaction, increases abundance, increases expression	2
sodium arsenite	affects methylation, increases expression	2
Valproic Acid	affects expression, increases expression	2
ginger extract	decreases reaction, increases abundance, increases expression	1
dicrotophos	decreases expression	1
bismuth tripotassium dicitrate	increases expression	1
triphenyl phosphate	affects expression	1
sodium arsenate	decreases expression	1
nickel acetate	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
bisphenol B	increases expression	1
abrine	decreases expression	1
LDN 193189	affects cotreatment, decreases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Temozolomide	decreases expression	1
Sunitinib	increases expression	1
Vorinostat	increases expression	1
Acetaminophen	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Isoniazid	increases expression	1
Ivermectin	decreases expression	1
Lead	increases expression	1
Oils, Volatile	increases abundance, increases expression, decreases reaction	1
Plant Extracts	affects cotreatment, increases expression	1
Rotenone	increases expression	1
Thiram	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Cyclosporine	decreases expression	1

Clinical trials (associated diseases)

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