TXNDC8

Summary

TXNDC8 (thioredoxin domain containing 8, HGNC:31454) is a protein-coding gene on chromosome 9q31.3, encoding Thioredoxin domain-containing protein 8 (Q6A555). May be required for post-translational modifications of proteins required for acrosomal biogenesis.

Involved in spermatogenesis. Located in Golgi apparatus. Biomarker of male infertility.

Source: NCBI Gene 255220 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 19 total
• MANE Select transcript: NM_001424031

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:31454
Approved symbol	TXNDC8
Name	thioredoxin domain containing 8
Location	9q31.3
Locus type	gene with protein product
Status	Approved
Aliases	bA427L11.2, TRX6, SPTRX-3
Ensembl gene	ENSG00000204193
Ensembl biotype	protein_coding
OMIM	617789
Entrez	255220

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 6 protein_coding

ENST00000374507, ENST00000374510, ENST00000374511, ENST00000423740, ENST00000713575, ENST00000713585

RefSeq mRNA: 5 — MANE Select: NM_001424031 NM_001003936, NM_001286946, NM_001286947, NM_001364963, NM_001424031

CCDS: CCDS35104, CCDS69639, CCDS75872

Canonical transcript exons

ENST00000374511 — 6 exons

Exon	Start	End
ENSE00001463687	110337773	110337863
ENSE00001463690	110303476	110303583
ENSE00001463694	110329232	110329291
ENSE00003238857	110326175	110326240
ENSE00003334422	110334216	110334320
ENSE00004020373	110304467	110304532

Expression profiles

Bgee: expression breadth broad, 48 present calls, max score 88.25.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0116 / max 12.1793, expressed in 3 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
101924	0.0116	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left testis	UBERON:0004533	88.25	gold quality
right testis	UBERON:0004534	87.90	gold quality
testis	UBERON:0000473	84.12	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	66.79	gold quality
buccal mucosa cell	CL:0002336	64.26	gold quality
endothelial cell	CL:0000115	57.19	gold quality
upper leg skin	UBERON:0004262	52.58	silver quality
olfactory segment of nasal mucosa	UBERON:0005386	51.16	gold quality
nasal cavity mucosa	UBERON:0001826	45.71	gold quality
endometrium	UBERON:0001295	45.63	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	43.37	gold quality
secondary oocyte	CL:0000655	42.57	gold quality
vastus lateralis	UBERON:0001379	41.41	gold quality
quadriceps femoris	UBERON:0001377	41.37	gold quality
superficial temporal artery	UBERON:0001614	41.33	gold quality
palpebral conjunctiva	UBERON:0001812	41.10	gold quality
mucosa of paranasal sinus	UBERON:0005030	40.98	gold quality
amniotic fluid	UBERON:0000173	40.69	gold quality
jejunal mucosa	UBERON:0000399	40.59	gold quality
biceps brachii	UBERON:0001507	40.57	gold quality
epithelium of nasopharynx	UBERON:0001951	40.45	gold quality
myocardium	UBERON:0002349	40.45	gold quality
gingival epithelium	UBERON:0001949	40.43	gold quality
lower lobe of lung	UBERON:0008949	40.34	silver quality
germinal epithelium of ovary	UBERON:0001304	40.33	gold quality
esophagus squamous epithelium	UBERON:0006920	40.29	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	40.27	gold quality
jejunum	UBERON:0002115	40.18	gold quality
cartilage tissue	UBERON:0002418	40.06	gold quality
mammary duct	UBERON:0001765	39.98	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.57

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 3)

• SPTRX3 is a novel Golgi apparatus-associated thioredoxin, and has a role in aberrant spermatogenesis (PMID:15181017)
• Data indicate that the elevated semen content of SPTRX3/TXNDC8 from assisted reproductive therapy (ART) couples coincided with reduced incidence of pregnancy by in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI). (PMID:23734172)
• Sperm content of TXNDC8 reflects sperm chromatin structure, pregnancy establishment, and incidence of multiple births after ART. (PMID:32851881)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
mus_musculus	Txndc8	ENSMUSG00000038709
rattus_norvegicus	Txndc8	ENSRNOG00000029073
drosophila_melanogaster	CG14221	FBGN0031042

Paralogs (4): TXNL1 (ENSG00000091164), TXN2 (ENSG00000100348), TXN (ENSG00000136810), TXNDC2 (ENSG00000168454)

Protein

Protein identifiers

Thioredoxin domain-containing protein 8 — Q6A555 (reviewed: Q6A555)

Alternative names: Spermatid-specific thioredoxin-3, Thioredoxin-6

All UniProt accessions (5): A0AAA9YHJ3, A0AAA9YHL0, A9Z1W9, B7ZME0, Q6A555

UniProt curated annotations — full annotation on UniProt →

Function. May be required for post-translational modifications of proteins required for acrosomal biogenesis. May act by reducing disulfide bonds within the sperm.

Subcellular location. Cytoplasm. Golgi apparatus.

Tissue specificity. Testis-specific. Only expressed during spermiogenesis, prominently in the Golgi apparatus of pachytene spermatocytes and round and elongated spermatids, with a transient localization in the developing acrosome of round spermatids (at protein level).

Miscellaneous. Increased levels, possibly caused by overexpression, are observed in morphologically abnormal spermatozoa from infertile men, suggesting that it may be used as a marker of aberrant spermatogenesis.

Similarity. Belongs to the thioredoxin family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q6A555-1	1	yes
Q6A555-2	2

RefSeq proteins (5): NP_001003936, NP_001273875, NP_001273876, NP_001351892, NP_001410960* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR013766	Thioredoxin_domain	Domain
IPR036249	Thioredoxin-like_sf	Homologous_superfamily

Pfam: PF00085

UniProt features (5 total): chain 1, domain 1, disulfide bond 1, splice variant 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6A555-F1	84.87	0.71

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): 32–35

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 47 (showing top): GOCC_SECRETORY_GRANULE, GOBP_MALE_GAMETE_GENERATION, GOBP_DEVELOPMENTAL_PROCESS_INVOLVED_IN_REPRODUCTION, GOCC_SECRETORY_VESICLE, GOCC_ACROSOMAL_VESICLE, GOMF_DISULFIDE_OXIDOREDUCTASE_ACTIVITY, MIKKELSEN_MEF_LCP_WITH_H3K27ME3, ZWANG_TRANSIENTLY_UP_BY_2ND_EGF_PULSE_ONLY, SUPT16H_TARGET_GENES, UBN1_TARGET_GENES, MIR3121_3P, MIR577, MIR3180_5P, MIR3182, MIR335_5P

GO Biological Process (2): spermatogenesis (GO:0007283), cell differentiation (GO:0030154)

GO Molecular Function (0):

GO Cellular Component (5): acrosomal vesicle (GO:0001669), cytoplasm (GO:0005737), Golgi apparatus (GO:0005794), extracellular exosome (GO:0070062), endomembrane system (GO:0012505)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
developmental process involved in reproduction	1
male gamete generation	1
cellular developmental process	1
secretory granule	1
intracellular anatomical structure	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
extracellular vesicle	1
vacuole	1
plasma membrane	1

Protein interactions and networks

STRING

1772 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TXNDC8	NME8	Q8N427	530
TXNDC8	NME9	Q86XW9	507
TXNDC8	CATSPERB	Q9H7T0	501
TXNDC8	SEPTIN12	Q8IYM1	489
TXNDC8	DRC4	O95995	453
TXNDC8	ENTPD6	O75354	449
TXNDC8	GLRX	P35754	430
TXNDC8	EEPD1	Q7L9B9	423
TXNDC8	CATSPERG	Q6ZRH7	420
TXNDC8	ODF1	Q14990	402
TXNDC8	TEX53	A0A1B0GU33	400
TXNDC8	TXNIP	Q9H3M7	387
TXNDC8	SPA17	Q15506	383
TXNDC8	AADACL2	Q6P093	375
TXNDC8	TXN2	Q99757	374

IntAct

2 interactions, top by confidence:

A	B	Type	Score
TXNDC8	S100P	psi-mi:“MI:0914”(association)	0.350

BioGRID (6): ANKRD13A (Affinity Capture-MS), POTEKP (Affinity Capture-MS), PCBP4 (Affinity Capture-MS), S100P (Affinity Capture-MS), TXNDC8 (Affinity Capture-MS), TXNDC8 (Affinity Capture-MS)

ESM2 similar proteins: C0HJG9, P08515, P09210, P09488, P15964, P18380, P27013, P27583, P35661, P46434, P46439, P48774, P49261, P50581, P51781, P68253, P68464, P68465, P82810, P83325, P85842, P86195, P86214, P86215, P86252, P86265, P86699, P93292, Q08863, Q10092, Q1ZXB9, Q5BG51, Q69AB2, Q6A555, Q6AXY0, Q7REH6, Q7RTV2, Q84TK0, Q8IWF7, Q96VH2

Diamond homologs: A2YIW7, D4B2L8, G4NFB7, O14463, O17486, O22022, O22779, O48897, O64394, O64654, O81332, O94504, O96952, O97508, O97680, P05307, P07237, P08628, P08629, P09856, P0AGG4, P0AGG5, P0AGG6, P0AGG7, P10599, P10639, P11232, P17967, P21609, P21610, P22217, P22803, P29448, P29449, P29450, P29451, P40557, P50413, P55059, P82460

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	18
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

773 predictions. Top by Δscore:

Variant	Effect	Δscore
9:110321572:A:C	donor_gain	1.0000
9:110337430:T:TA	donor_gain	1.0000
9:110333873:T:C	donor_gain	0.9900
9:110334214:A:AC	donor_gain	0.9900
9:110334215:C:CC	donor_gain	0.9900
9:110337435:A:AC	donor_gain	0.9900
9:110337436:C:CC	donor_gain	0.9900
9:110337438:T:TA	donor_gain	0.9900
9:110326168:AACAT:A	donor_loss	0.9800
9:110326169:ACATA:A	donor_loss	0.9800
9:110326170:CATAC:C	donor_loss	0.9800
9:110326171:ATAC:A	donor_loss	0.9800
9:110326172:TA:T	donor_loss	0.9800
9:110326173:A:AT	donor_loss	0.9800
9:110334207:TGTAC:T	donor_loss	0.9800
9:110334208:GTAC:G	donor_loss	0.9800
9:110334209:TAC:T	donor_loss	0.9800
9:110334210:ACT:A	donor_loss	0.9800
9:110334211:CTCAC:C	donor_loss	0.9800
9:110334212:TCA:T	donor_loss	0.9800
9:110334213:CACAT:C	donor_loss	0.9800
9:110334214:A:T	donor_loss	0.9800
9:110334215:C:CG	donor_loss	0.9800
9:110334215:CAT:C	donor_gain	0.9800
9:110334233:T:TA	donor_gain	0.9800
9:110334317:CATT:C	acceptor_gain	0.9800
9:110334319:TT:T	acceptor_gain	0.9800
9:110334321:C:CC	acceptor_gain	0.9800
9:110337435:ACTT:A	donor_gain	0.9800
9:110337436:CTTC:C	donor_gain	0.9800

AlphaMissense

857 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:110334264:A:C	F27L	0.970
9:110334264:A:T	F27L	0.970
9:110334266:A:G	F27L	0.970
9:110326199:A:C	F77L	0.938
9:110326199:A:T	F77L	0.938
9:110326201:A:G	F77L	0.938
9:110326190:G:C	F80L	0.920
9:110326190:G:T	F80L	0.920
9:110326192:A:G	F80L	0.920
9:110329259:A:C	F54L	0.913
9:110329259:A:T	F54L	0.913
9:110329261:A:G	F54L	0.913
9:110334265:A:G	F27S	0.873
9:110334219:G:C	F42L	0.870
9:110334219:G:T	F42L	0.870
9:110334221:A:G	F42L	0.870
9:110334271:A:T	V25D	0.844
9:110329257:G:T	A55D	0.822
9:110303572:A:C	F111L	0.805
9:110303572:A:T	F111L	0.805
9:110303574:A:G	F111L	0.805
9:110334303:A:C	F14L	0.804
9:110334303:A:T	F14L	0.804
9:110334305:A:G	F14L	0.804
9:110329258:C:G	A55P	0.801
9:110334274:A:T	V24E	0.796
9:110334265:A:C	F27C	0.779
9:110326191:A:G	F80S	0.773
9:110326200:A:G	F77S	0.746
9:110334313:A:G	F11S	0.742

dbSNP variants (sampled 300 via entrez): RS1000048448 (9:110300857 A>C), RS1000180351 (9:110318974 A>G), RS1000279504 (9:110307347 A>G), RS1000297334 (9:110337352 C>A,T), RS1000406783 (9:110313480 C>G), RS1000440093 (9:110309430 T>A,C), RS1000512528 (9:110320651 T>C), RS1000560077 (9:110320827 C>T), RS1000626020 (9:110312010 G>A), RS1000633740 (9:110323602 G>A,C), RS1000657148 (9:110312254 T>G), RS1000662225 (9:110324659 A>G), RS1000662307 (9:110303125 G>C), RS1000688951 (9:110325901 G>T), RS1000773536 (9:110317897 T>A,C)

Disease associations

OMIM: gene MIM:617789 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST004865_42	Itch intensity from mosquito bite adjusted by bite size	3.000000e-07
GCST008273_6	Post-bronchodilator FEV1 x air pollution (NO2) interaction in childhood asthma	7.000000e-06

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0008377	mosquito bite reaction itch intensity measurement
EFO:0008378	mosquito bite reaction size measurement
EFO:0004314	forced expiratory volume
EFO:0007908	traffic air pollution measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

2 total (human), top 2 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Tobacco Smoke Pollution	decreases expression	1
Aflatoxin B1	decreases methylation	1

Clinical trials (associated diseases)

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