TXNDC2

Summary

TXNDC2 (thioredoxin domain containing 2, HGNC:16470) is a protein-coding gene on chromosome 18p11.31-p11.2, encoding Thioredoxin domain-containing protein 2 (Q86VQ3). Probably plays a regulatory role in sperm development.

Enables thioredoxin-disulfide reductase (NADPH) activity. Predicted to be involved in cell redox homeostasis and spermatogenesis. Predicted to act upstream of or within cellular response to reactive oxygen species and flagellated sperm motility. Located in cytoplasm.

Source: NCBI Gene 84203 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 101 total
• MANE Select transcript: NM_032243

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16470
Approved symbol	TXNDC2
Name	thioredoxin domain containing 2
Location	18p11.31-p11.2
Locus type	gene with protein product
Status	Approved
Aliases	SPTRX1
Ensembl gene	ENSG00000168454
Ensembl biotype	protein_coding
OMIM	617790
Entrez	84203

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 4 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000306084, ENST00000357775, ENST00000426718, ENST00000536353, ENST00000584255

RefSeq mRNA: 2 — MANE Select: NM_032243 NM_001098529, NM_032243

CCDS: CCDS11846, CCDS42414

Canonical transcript exons

ENST00000357775 — 2 exons

Exon	Start	End
ENSE00001408932	9885973	9886080
ENSE00002734356	9886589	9889275

Expression profiles

Bgee: expression breadth broad, 100 present calls, max score 95.86.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.2358 / max 233.2109, expressed in 14 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
169386	0.1852	12
169387	0.0199	3
169385	0.0150	6
169384	0.0094	3
208494	0.0063	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left testis	UBERON:0004533	95.86	gold quality
right testis	UBERON:0004534	95.57	gold quality
sperm	CL:0000019	95.37	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	93.09	gold quality
testis	UBERON:0000473	92.69	gold quality
adult organism	UBERON:0007023	81.28	gold quality
kidney epithelium	UBERON:0004819	75.92	gold quality
cardiac muscle of right atrium	UBERON:0003379	74.81	gold quality
nasal cavity epithelium	UBERON:0005384	74.42	gold quality
left ventricle myocardium	UBERON:0006566	74.24	gold quality
upper arm skin	UBERON:0004263	74.07	gold quality
epithelial cell of pancreas	CL:0000083	70.62	gold quality
myocardium	UBERON:0002349	68.42	gold quality
vastus lateralis	UBERON:0001379	67.74	gold quality
quadriceps femoris	UBERON:0001377	67.36	gold quality
epithelium of nasopharynx	UBERON:0001951	67.26	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	66.97	gold quality
mucosa of paranasal sinus	UBERON:0005030	66.14	gold quality
parotid gland	UBERON:0001831	65.05	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	64.25	gold quality
cerebellar vermis	UBERON:0004720	63.48	gold quality
superficial temporal artery	UBERON:0001614	63.26	gold quality
vena cava	UBERON:0004087	62.92	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	62.24	gold quality
tendon of biceps brachii	UBERON:0008188	62.08	gold quality
biceps brachii	UBERON:0001507	61.62	gold quality
lateral nuclear group of thalamus	UBERON:0002736	61.41	gold quality
epithelium of mammary gland	UBERON:0003244	61.07	gold quality
mammary duct	UBERON:0001765	60.92	gold quality
layer of synovial tissue	UBERON:0007616	60.37	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.28

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 5)

• sperm specific expression, together with chromosomal assignment to a position as a potential locus for flagellar anomalies and male infertility phenotypes, suggests that it might be a novel component of the human sperm axonemal organization. (PMID:11737268)
• spermatid-specific thioredoxin-1 (Sptrx-1) is a two-domain protein with oxidizing activity (PMID:12387870)
• The patients with advanced-stagemalignant pleural mesothelioma (MPM) showed higher levels of TRX than those with early-stage MPM. (PMID:21375472)
• Testis-Specific Thioredoxins TXNDC2, TXNDC3, and TXNDC6 Are Expressed in Both Testicular and Systemic DLBCL and Correlate with Clinical Disease Presentation. (PMID:33603952)
• TXNDC2 joint molecular marker is associated with testis pathology and is an accurate predictor of sperm retrieval. (PMID:34158577)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
mus_musculus	Txndc2	ENSMUSG00000050612
rattus_norvegicus	Txndc2	ENSRNOG00000027916
drosophila_melanogaster	CG14221	FBGN0031042

Paralogs (4): TXNL1 (ENSG00000091164), TXN2 (ENSG00000100348), TXN (ENSG00000136810), TXNDC8 (ENSG00000204193)

Protein

Protein identifiers

Thioredoxin domain-containing protein 2 — Q86VQ3 (reviewed: Q86VQ3)

Alternative names: Spermatid-specific thioredoxin-1

All UniProt accessions (4): Q86VQ3, A0A140VJY8, F5H6S7, J3QSG5

UniProt curated annotations — full annotation on UniProt →

Function. Probably plays a regulatory role in sperm development. May participate in regulation of fibrous sheath (FS) assembly by supporting the formation of disulfide bonds during sperm tail morphogenesis. May also be required to rectify incorrect disulfide pairing and generate suitable pairs between the FS constituents. Can reduce disulfide bonds in vitro in the presence of NADP and thioredoxin reductase.

Subcellular location. Cytoplasm.

Tissue specificity. Testis-specific. Only expressed during spermiogenesis, prominently in round and elongating spermatids.

Isoforms (3)

UniProt ID	Names	Canonical?
Q86VQ3-1	1	yes
Q86VQ3-2	2
Q86VQ3-3	3

RefSeq proteins (2): NP_001091999, NP_115619* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR013766	Thioredoxin_domain	Domain
IPR036249	Thioredoxin-like_sf	Homologous_superfamily

Pfam: PF00085

UniProt features (43 total): repeat 22, sequence variant 6, compositionally biased region 5, region of interest 3, modified residue 2, splice variant 2, chain 1, domain 1, disulfide bond 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q86VQ3-F1	52.65	0.20

Functional residue map

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

Post-translational modifications (2): 362, 392

Disulfide bonds (1): 480–483

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 0 (showing top):

GO Biological Process (4): spermatogenesis (GO:0007283), cell differentiation (GO:0030154), cell redox homeostasis (GO:0045454), cellular oxidant detoxification (GO:0098869)

GO Molecular Function (2): thioredoxin-disulfide reductase (NADPH) activity (GO:0004791), protein binding (GO:0005515)

GO Cellular Component (1): cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
developmental process involved in reproduction	1
male gamete generation	1
cellular developmental process	1
cellular homeostasis	1
cellular detoxification	1
antioxidant activity	1
protein-disulfide reductase [NAD(P)H] activity	1
binding	1
intracellular anatomical structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1873 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TXNDC2	NME8	Q8N427	639
TXNDC2	NME9	Q86XW9	522
TXNDC2	NXN	Q6DKJ4	487
TXNDC2	NXNL2	Q5VZ03	475
TXNDC2	SPACA3	Q8IXA5	457
TXNDC2	ACRBP	Q8NEB7	452
TXNDC2	ZPBP2	Q6X784	443
TXNDC2	AKAIN1	P0CW23	431
TXNDC2	TXNIP	Q9H3M7	430
TXNDC2	LRRC30	A6NM36	412
TXNDC2	TXNRD3	Q86VQ6	393
TXNDC2	AKAP3	O75969	384
TXNDC2	TSSK3	Q96PN8	383
TXNDC2	TNP1	P09430	380
TXNDC2	GLRX	P35754	368

IntAct

7 interactions, top by confidence:

A	B	Type	Score
DDIT3	TXNDC2	psi-mi:“MI:0915”(physical association)	0.560
APOA1	CNMD	psi-mi:“MI:0914”(association)	0.350
TXNDC2	H2AZ1	psi-mi:“MI:0914”(association)	0.350
TXNDC2	S100A2	psi-mi:“MI:0914”(association)	0.350
TXNDC2	DDIT3	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (18): DDIT3 (Two-hybrid), TXNDC2 (Reconstituted Complex), SSRP1 (Affinity Capture-MS), PPM1J (Affinity Capture-MS), VPS53 (Affinity Capture-MS), SUPT16H (Affinity Capture-MS), PIBF1 (Affinity Capture-MS), H2AFZ (Affinity Capture-MS), VPS54 (Affinity Capture-MS), S100A2 (Affinity Capture-MS), SLC25A15 (Affinity Capture-MS), TRMT2A (Affinity Capture-MS), SLC25A31 (Affinity Capture-MS), AURKB (Affinity Capture-MS), LMO7 (Affinity Capture-MS)

ESM2 similar proteins: A0A087WUL8, A0A0J9YWL9, A0A0J9YY54, A0A0U1RQI7, A6NJ88, A6QL64, B4DH59, D3ZVV1, E9Q6E9, F1LWT0, O04492, O88799, P0DKJ7, P0DKJ8, P0DKL2, P0DPF3, P18583, P53353, Q08AG5, Q0P6D6, Q2EG98, Q3BBV2, Q4ZJZ1, Q5HY64, Q5JPF3, Q5QGU6, Q5TAG4, Q5TI25, Q5XHX6, Q6P3W6, Q6P902, Q6XPR3, Q6ZQX7, Q86T75, Q86VE3, Q86VQ3, Q8N2N9, Q8N660, Q8N693, Q96EQ9

Diamond homologs: A2YIW7, C9K7C5, G4NFB7, O14463, O17486, O64394, O64432, O64764, O65049, O84544, O94504, O96952, O97508, O97680, P07591, P08628, P08629, P0A0K4, P0A0K5, P0A0K6, P0A4L1, P0A4L2, P10472, P10599, P10639, P11232, P12243, P14949, P22217, P22803, P29429, P29448, P29449, P29451, P34723, P37395, P42115, P47938, P48384, P50413

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	72
Likely benign	26
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

166 predictions. Top by Δscore:

Variant	Effect	Δscore
18:9886581:T:A	acceptor_gain	0.9500
18:9886574:T:G	acceptor_gain	0.9300
18:9886081:G:GG	donor_gain	0.8600
18:9886588:GAAA:G	acceptor_gain	0.8600
18:9886574:T:TA	acceptor_gain	0.8400
18:9886587:A:AG	acceptor_gain	0.8200
18:9886588:G:GG	acceptor_gain	0.8200
18:9886573:AT:A	acceptor_gain	0.7800
18:9886588:GAA:G	acceptor_gain	0.7800
18:9886573:A:AG	acceptor_gain	0.7600
18:9886430:TGA:T	acceptor_gain	0.7500
18:9886431:GAG:G	acceptor_gain	0.7500
18:9886586:CAGAA:C	acceptor_gain	0.7400
18:9886587:AGAAA:A	acceptor_gain	0.7400
18:9886588:GAAAG:G	acceptor_gain	0.7400
18:9886582:G:A	acceptor_gain	0.7300
18:9886429:ATGAG:A	acceptor_gain	0.6900
18:9886432:A:T	acceptor_gain	0.6900
18:9886275:A:AG	donor_gain	0.6800
18:9886583:GTACA:G	acceptor_loss	0.6500
18:9886584:TACA:T	acceptor_loss	0.6500
18:9886585:ACAG:A	acceptor_loss	0.6500
18:9886586:CA:C	acceptor_loss	0.6500
18:9886587:AGA:A	acceptor_loss	0.6500
18:9886582:GGTAC:G	acceptor_loss	0.6200
18:9886004:G:T	donor_gain	0.6000
18:9886256:G:GT	donor_gain	0.5900
18:9886426:T:A	acceptor_gain	0.5900
18:9886588:GA:G	acceptor_gain	0.5900
18:9886280:AATGG:A	donor_loss	0.5600

AlphaMissense

3214 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
18:9887902:T:C	F475L	0.997
18:9887904:C:A	F475L	0.997
18:9887904:C:G	F475L	0.997
18:9887983:T:C	F502L	0.996
18:9887984:T:C	F502S	0.996
18:9887985:C:A	F502L	0.996
18:9887985:C:G	F502L	0.996
18:9887903:T:C	F475S	0.995
18:9888052:T:C	F525L	0.994
18:9888054:T:A	F525L	0.994
18:9888054:T:G	F525L	0.994
18:9887914:T:A	W479R	0.993
18:9887914:T:C	W479R	0.993
18:9888059:T:C	F527S	0.993
18:9887916:G:C	W479C	0.992
18:9887916:G:T	W479C	0.992
18:9888061:T:G	Y528D	0.992
18:9887987:T:C	L503P	0.991
18:9887894:C:A	A472D	0.990
18:9887855:T:C	F459S	0.989
18:9888053:T:C	F525S	0.989
18:9888058:T:C	F527L	0.988
18:9888060:T:A	F527L	0.988
18:9888060:T:G	F527L	0.988
18:9887867:T:C	L463P	0.987
18:9887984:T:G	F502C	0.987
18:9888047:C:A	P523Q	0.987
18:9887891:T:A	V471E	0.984
18:9888046:C:T	P523S	0.984
18:9887897:T:A	V473E	0.983

dbSNP variants (sampled 300 via entrez): RS1000577340 (18:9889558 T>C), RS1001615819 (18:9885407 T>A,C), RS1003690898 (18:9885800 C>T), RS1004037177 (18:9888367 T>C), RS1004072626 (18:9886493 G>A,C,T), RS1004353752 (18:9885113 A>G), RS1004550252 (18:9886816 C>A,T), RS1005818830 (18:9888319 G>A,C,T), RS1006026763 (18:9889444 C>G), RS1006996613 (18:9884804 A>G), RS1007806722 (18:9884556 G>A,T), RS1008561639 (18:9885802 G>A), RS1008590699 (18:9884585 G>A,C), RS1010265961 (18:9885463 C>T), RS1010317744 (18:9889639 T>G)

Disease associations

OMIM: gene MIM:617790 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST001784_15	Pulmonary function (smoking interaction)	3.000000e-07
GCST001784_37	Pulmonary function (smoking interaction)	4.000000e-07
GCST008162_81	Hip circumference	8.000000e-06
GCST009391_487	Metabolite levels	5.000000e-08

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0003892	pulmonary function measurement
EFO:0004713	FEV/FVC ratio
EFO:0005001	phenylalanine measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

9 total (human), top 9 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
CGP 52608	increases reaction, affects binding	1
clothianidin	increases expression	1
Cadmium	decreases expression	1
Nitrogen Dioxide	increases expression	1
Rotenone	increases expression	1
Tretinoin	increases expression	1
Cyclosporine	increases methylation	1
Aflatoxin B1	increases methylation	1
Cadmium Chloride	increases expression	1

Clinical trials (associated diseases)

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