PIWIL2

Summary

PIWIL2 (piwi like RNA-mediated gene silencing 2, HGNC:17644) is a protein-coding gene on chromosome 8p21.3, encoding Piwi-like protein 2 (Q8TC59). Endoribonuclease that plays a central role during spermatogenesis by repressing transposable elements and preventing their mobilization, which is essential for the germline integrity.

PIWIL2 belongs to the Argonaute family of proteins, which function in development and maintenance of germline stem cells (Sasaki et al., 2003 [PubMed 12906857]).

Source: NCBI Gene 55124 — RefSeq curated summary.

At a glance

• Gene–disease (curated): male infertility with azoospermia or oligozoospermia due to single gene mutation (Strong, GenCC)
• GWAS associations: 1
• Clinical variants (ClinVar): 171 total
• MANE Select transcript: NM_018068

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17644
Approved symbol	PIWIL2
Name	piwi like RNA-mediated gene silencing 2
Location	8p21.3
Locus type	gene with protein product
Status	Approved
Aliases	HILI, FLJ10351, Mili, CT80
Ensembl gene	ENSG00000197181
Ensembl biotype	protein_coding
OMIM	610312
Entrez	55124

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 8 protein_coding, 1 retained_intron

ENST00000356766, ENST00000454009, ENST00000519884, ENST00000521356, ENST00000611073, ENST00000868093, ENST00000912221, ENST00000912222, ENST00000970486

RefSeq mRNA: 3 — MANE Select: NM_018068 NM_001135721, NM_001330480, NM_018068

CCDS: CCDS6029, CCDS83261

Canonical transcript exons

ENST00000356766 — 23 exons

Exon	Start	End
ENSE00001159321	22352959	22353212
ENSE00001159332	22316245	22316333
ENSE00001159337	22315029	22315145
ENSE00001159343	22314328	22314429
ENSE00001159349	22311112	22311300
ENSE00001159354	22309961	22310074
ENSE00001159357	22307933	22308073
ENSE00001159362	22305927	22306016
ENSE00001159366	22304784	22304868
ENSE00001159371	22304021	22304209
ENSE00001159374	22290233	22290346
ENSE00001159380	22289847	22289927
ENSE00001159388	22288542	22288666
ENSE00001159396	22287528	22287645
ENSE00001159403	22284162	22284272
ENSE00001159409	22283034	22283240
ENSE00001159416	22281377	22281515
ENSE00001159422	22281120	22281207
ENSE00001284012	22318170	22318275
ENSE00001319022	22275316	22275398
ENSE00001391932	22279341	22279584
ENSE00001948649	22355349	22357568
ENSE00003599961	22354271	22354378

Expression profiles

Bgee: expression breadth ubiquitous, 183 present calls, max score 94.31.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.2954 / max 46.4618, expressed in 118 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
87748	0.1349	47
87747	0.1124	42
87750	0.0242	10
205108	0.0133	4
87749	0.0106	5

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	94.31	gold quality
secondary oocyte	CL:0000655	93.27	gold quality
buccal mucosa cell	CL:0002336	93.16	gold quality
jejunal mucosa	UBERON:0000399	91.02	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	90.94	gold quality
oocyte	CL:0000023	85.04	gold quality
testis	UBERON:0000473	84.20	gold quality
right testis	UBERON:0004534	83.97	gold quality
left testis	UBERON:0004533	83.10	gold quality
duodenum	UBERON:0002114	79.66	gold quality
cartilage tissue	UBERON:0002418	77.56	silver quality
pancreatic ductal cell	CL:0002079	77.09	silver quality
adult organism	UBERON:0007023	75.95	gold quality
jejunum	UBERON:0002115	74.77	gold quality
mucosa of paranasal sinus	UBERON:0005030	73.56	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	71.21	gold quality
male germ cell	CL:0000015	71.06	silver quality
body of pancreas	UBERON:0001150	71.05	gold quality
tibialis anterior	UBERON:0001385	70.80	silver quality
sperm	CL:0000019	70.65	silver quality
deltoid	UBERON:0001476	70.13	silver quality
calcaneal tendon	UBERON:0003701	69.80	gold quality
rectum	UBERON:0001052	69.01	gold quality
gastrocnemius	UBERON:0001388	68.70	gold quality
muscle of leg	UBERON:0001383	68.49	gold quality
olfactory bulb	UBERON:0002264	68.34	gold quality
type B pancreatic cell	CL:0000169	68.19	gold quality
muscle organ	UBERON:0001630	68.05	gold quality
left ventricle myocardium	UBERON:0006566	67.91	gold quality
epithelial cell of pancreas	CL:0000083	67.85	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.04
E-GEOD-81608	no	18.29
E-MTAB-6379	no	2.19

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

20 targeting PIWIL2, 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-4531	99.99	69.70	3181
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-1976	99.74	65.48	1127
HSA-MIR-5584-5P	99.49	68.22	2814
HSA-MIR-12131	99.48	68.72	1673
HSA-MIR-103A-1-5P	99.39	67.78	1545
HSA-MIR-103A-2-5P	99.39	67.72	1577
HSA-MIR-504-3P	99.30	67.18	1745
HSA-MIR-593-3P	99.22	67.28	1327
HSA-MIR-3922-5P	98.77	66.53	1059
HSA-MIR-2276-3P	98.76	67.75	1384
HSA-MIR-3689A-5P	98.35	70.12	1049
HSA-MIR-3689B-5P	98.35	70.12	1049
HSA-MIR-3689E	98.35	70.12	1049
HSA-MIR-3689F	98.35	70.08	1052
HSA-MIR-1267	98.24	69.05	837
HSA-MIR-3977	98.00	68.17	1500
HSA-MIR-5681A	97.99	67.17	1658
HSA-MIR-431-5P	96.16	66.50	652
HSA-MIR-4435	95.90	65.47	1201

Literature-anchored findings (GeneRIF, showing 40)

• Stem-cell protein Piwil2 is widely expressed in tumors and inhibits apoptosis through activation of Stat3/Bcl-XL pathway. (PMID:16377660)
• our study indicates that PIWIL2 does not play a role in carcinogenesis of human bladder carcinoma (PMID:19683485)
• Findings define Piwil2 and its effector signaling pathways as key factors in the proliferation and survival of breast cancer stem cells. (PMID:20460541)
• piwil2 is expressed in various stages of breast cancers and has the potential to be used a novel biomarker. (PMID:20490325)
• The study demonstrated that HILI along with piRNAs plays a role in LINE1 suppression in Hela cancer cell line. (PMID:20846497)
• Piwil2 may play a role in the invasion and metastasis of papillary thyroid carcinoma. (PMID:21575418)
• a new role for Piwil2 in DNA repair (PMID:22110608)
• Piwil2 plays a role in anti-apoptosis in tumor cells possessing P53 as a positive regulator of STAT3 signaling pathway. (PMID:22303479)
• we identified a significant association between the expression of Piwi-like 2 and 4 mRNAs and the tumor-specific survival of soft tissue sarcoma patients. (PMID:22748119)
• a critical negative regulation level of TGF-beta signaling mediated by HILI (human PIWIL2) by its ability to interact with Hsp90 and promote TbetaR degradation (PMID:22848678)
• Piwil2 moderates the proliferation and metastasis potential of colon cancer. (PMID:23104504)
• DNA methylation, at least that affecting PIWIL2/TDRD1, has a role in the control of gene expression in spermatogenesis and its imbalance contributes to an unsuccessful germ cell development that might explain a group of male infertility disorders. (PMID:23112866)
• expression of AURKC, OIP5, PIWIL2 and TAF7L differed between patients with Acute myeloid leukemia, myelodysplastic syndrome and healthy controls in a gender-dependent manner (PMID:23292864)
• High Piwil2 expression is associated with breast cancer. (PMID:23992744)
• Data suggest that the epitopes could be used as novel candidates to the immunotherapy of HLA-A2 positive patients with tumors expressing PL2L60, the spliced fragment of PIWIL2. (PMID:24077852)
• Our study identifies surrogate DNA methylation markers for idiopathic infertility in peripheral blood and suggests that allele-specific DNA methylation differences at regulatory sites of genes are associated with disturbed spermatogenesis. (PMID:24524831)
• This study revealed critical negative regulation of TGF-beta signalling by PIWIL2 in HepG2 tumour cells. (PMID:25040173)
• Study indicates that Piwil2 plays a role in Fas-mediated apoptosis and can affect p53 phosphorylation in tumor cells, revealing a novel mechanism of Piwil2 in apoptosis, and supports that Piwil2 plays an active role in tumorigenesis. (PMID:25113562)
• PIWIL2 modulates tumor cell proliferation and F-actin filaments by interacting with NME2 and regulating c-Myc expression. (PMID:25193865)
• Results show that both PIWIL2 protein isoforms are expressed in testicular germ cell lines but in the tumors, the short protein and mRNA are predominant and highly expressed in undifferentiated tumors. (PMID:25384072)
• Piwil 2 expression is correlated with disease-specific and progression-free survival of chemotherapy-treated bladder cancer patients (PMID:25998509)
• Our results indicate a reciprocal regulation between HIWI, HILI and some CSCs markers in colorectal cancer (PMID:26026091)
• Univariate analysis demonstrated that high PIWIL2 expression was associated with shorter survival time after radical resection. (PMID:26125915)
• PIWIL2 has a role in promoting progression of non-small cell lung cancer by inducing CDK2 and Cyclin A expression (PMID:26373553)
• Knockdown of Piwil2 gene in SiHa cells inhibited cell growth and invasion, and downregulated matrix metalloproteinase-9 (MMP-9) compared to scrambled shRNA transfected cells (PMID:26775345)
• MMP9 and PIWIL2 expression levels in cancerous tissues were significantly higher than the adjacent normal tissues (PMID:27215085)
• this study demonstrates that Piwil2, reactivated by the human papillomavirus oncoproteins E6 and E7, plays an essential role in the transformation of cervical epithelial cells to tumor-initiating cells via epigenetics-based cell reprogramming (PMID:27602489)
• PIWIL2 and PIWIL4 genes expression in synovial fibroblasts of the rheumatoid arthritis patients (PMID:27893851)
• Results revealed that Piwil2 exhibits 100% positive expression in the cell nucleus, with the intensity higher than in the cytoplasm. Along with nuclear location of PIWIL4, PIWIL2 expression is associated with worse prognosis of hepatocellular carcinoma. (PMID:27894076)
• Data show that the PIWIL2 protein transfected fibroblast cells grew into tumorous masses within 5 weeks of subcutaneous injection into adult nude mice. (PMID:28103575)
• report demonstrated that human Piwil proteins, especially Hili, not only bind to select tRNA species, including rare tRNAs, but also inhibit HIV replication (PMID:28331090)
• Our results showed that HILI suppresses microtubule polymerization and promotes cell proliferation, migration and invasion via TBCB for the first time, revealing a novel mechanism for HILI in tumorigenesis. (PMID:28393858)
• High expression of PIWIL2 is associated with glioma. (PMID:28534979)
• this study shows that an unusual intragenic promoter of PIWIL2 contributes to aberrant activation of oncogenic PL2L60 (PMID:28545024)
• PIWILIKE 1 and PIWILIKE 2 mRNA expression exhibited a significant association with impaired sperm characteristics and may be a useful candidate for the evaluation of the impact of PIWILIKE 1-4 mRNA expression on male infertility. (PMID:29286006)
• n vitro experiments demonstrated a possible role of the PIWIL2/HILI short isoform in repressing TEs, which could provide a growth advantage for testicular germ cell tumors through securing their genome integrity. (PMID:29301509)
• Protein expression levels of PIWIL2 was significantly up-regulated in both papillary and micropapillary thyroid cancers (p<0.01). Moreover, consistent with protein expression levels, mRNA expression levels of PIWIL2 was elevated in both papillary and micropapillary thyroid cancer tissues. (PMID:29369786)
• PIWIL2 interacts with HDAC3 and promotes the stability and phosphorylation of HDAC3. PIWIL2 can play a role in HDAC3-mediated epigenetic regulation on cancer cell proliferation and apoptosis. (PMID:29555935)
• A statistically significantly higher level of PIWIL1 and PIWIL2 was found in IDC compared to mastopathy samples (p</=0.0001). Increased expression of PIWIL1 was correlated with increased PIWIL2 expression in breast cancer tissue. (PMID:29599319)
• Data show that piR-FTH1 (ferritin heavy chain 1) knocks down the Fth1 mRNA via the HIWI2 and HILI mediated mechanism. (PMID:30102404)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	piwil2	ENSDARG00000062601
mus_musculus	Piwil2	ENSMUSG00000033644
rattus_norvegicus	Piwil2	ENSRNOG00000009871
drosophila_melanogaster	AGO3	FBGN0250816

Paralogs (3): PIWIL1 (ENSG00000125207), PIWIL4 (ENSG00000134627), PIWIL3 (ENSG00000184571)

Protein

Protein identifiers

Piwi-like protein 2 — Q8TC59 (reviewed: Q8TC59)

Alternative names: Cancer/testis antigen 80

All UniProt accessions (2): Q8TC59, W0HK13

UniProt curated annotations — full annotation on UniProt →

Function. Endoribonuclease that plays a central role during spermatogenesis by repressing transposable elements and preventing their mobilization, which is essential for the germline integrity. Plays an essential role in meiotic differentiation of spermatocytes, germ cell differentiation and in self-renewal of spermatogonial stem cells. Acts via the piRNA metabolic process, which mediates the repression of transposable elements during meiosis by forming complexes composed of piRNAs and Piwi proteins and govern the methylation and subsequent repression of transposons. During piRNA biosynthesis, plays a key role in the piRNA amplification loop, also named ping-pong amplification cycle, by acting as a ‘slicer-competent’ piRNA endoribonuclease that cleaves primary piRNAs, which are then loaded onto ‘slicer-incompetent’ PIWIL4. PIWIL2 slicing produces a pre-miRNA intermediate, which is then processed in mature piRNAs, and as well as a 16 nucleotide by-product that is degraded. Required for PIWIL4/MIWI2 nuclear localization and association with secondary piRNAs antisense. Besides their function in transposable elements repression, piRNAs are probably involved in other processes during meiosis such as translation regulation. Indirectly modulates expression of genes such as PDGFRB, SLC2A1, ITGA6, GJA7, THY1, CD9 and STRA8. When overexpressed, acts as an oncogene by inhibition of apoptosis and promotion of proliferation in tumors. Represses circadian rhythms by promoting the stability and activity of core clock components BMAL1 and CLOCK by inhibiting GSK3B-mediated phosphorylation and ubiquitination-dependent degradation of these proteins.

Subunit / interactions. Interacts with DDX4, MAEL, EIF3A, EIF4E, EIF4G, PRMT5 and WDR77. Associates with EIF4E- and EIF4G-containing m7G cap-binding complexes. Interacts (when methylated on arginine residues) with TDRD1 and TDRKH/TDRD2. Interacts with TDRD12. Component of the PET complex, at least composed of EXD1, PIWIL2, TDRD12 and piRNAs. Interacts with MOV10L1. Interacts with GPAT2. Interacts with TEX19. Interacts with GSK3B. Interacts (via PIWI domain) with BMAL1 and CLOCK. Interacts with TEX15.

Subcellular location. Cytoplasm.

Tissue specificity. Expressed in adult testis and in most tumors.

Post-translational modifications. Arginine methylation by PRMT5 is required for the interaction with Tudor domain-containing protein TDRD1 and subsequent localization to the meiotic nuage, also named P granule.

Similarity. Belongs to the argonaute family. Piwi subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8TC59-1	1	yes
Q8TC59-2	2

RefSeq proteins (3): NP_001129193, NP_001317409, NP_060538* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003100	PAZ_dom	Domain
IPR003165	Piwi	Domain
IPR012337	RNaseH-like_sf	Homologous_superfamily
IPR014811	ArgoL1	Domain
IPR036085	PAZ_dom_sf	Homologous_superfamily
IPR036397	RNaseH_sf	Homologous_superfamily

Pfam: PF02170, PF02171, PF08699, PF23278

UniProt features (94 total): strand 40, helix 23, modified residue 11, sequence conflict 6, active site 4, turn 3, domain 2, region of interest 2, chain 1, splice variant 1, compositionally biased region 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
3QIR	X-RAY DIFFRACTION	2.45
3O7X	X-RAY DIFFRACTION	2.92
7YFX	ELECTRON MICROSCOPY	3.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8TC59-F1	78.20	0.56

Functional residue map

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

Catalytic / active sites (4): 745; 783; 815; 948

Post-translational modifications (11): 47, 76, 76, 97, 97, 102, 102, 146, 158, 165, 551

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-5601884	PIWI-interacting RNA (piRNA) biogenesis

MSigDB gene sets: 178 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_DN, GOBP_CIRCADIAN_RHYTHM, GOBP_CYTOPLASMIC_TRANSLATION, GOBP_POSITIVE_REGULATION_OF_REPRODUCTIVE_PROCESS, GOMF_ENDONUCLEASE_ACTIVITY, GOMF_RNA_NUCLEASE_ACTIVITY, GOBP_REGULATION_OF_MRNA_CATABOLIC_PROCESS, GOBP_REGULATION_OF_NUCLEAR_DIVISION, GOMF_NUCLEASE_ACTIVITY, GOBP_REGULATION_OF_MEIOTIC_NUCLEAR_DIVISION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_OOGENESIS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, KEGG_DORSO_VENTRAL_AXIS_FORMATION, GOBP_MALE_GAMETE_GENERATION

GO Biological Process (18): spermatogenesis (GO:0007283), germ-line stem cell population maintenance (GO:0030718), regulatory ncRNA-mediated gene silencing (GO:0031047), piRNA processing (GO:0034587), negative regulation of circadian rhythm (GO:0042754), oogenesis (GO:0048477), rhythmic process (GO:0048511), meiotic cell cycle (GO:0051321), positive regulation of meiosis I (GO:0060903), secondary piRNA processing (GO:0140965), piRNA-mediated gene silencing by mRNA destabilization (GO:0140991), transposable element silencing by heterochromatin formation (GO:0141005), transposable element silencing by piRNA-mediated heterochromatin formation (GO:0141006), transposable element silencing by mRNA destabilization (GO:0141008), transposable element silencing by piRNA-mediated DNA methylation (GO:0141196), positive regulation of cytoplasmic translation (GO:2000767), regulation of translation (GO:0006417), cell differentiation (GO:0030154)

GO Molecular Function (10): mRNA binding (GO:0003729), RNA endonuclease activity (GO:0004521), hydrolase activity (GO:0016787), piRNA binding (GO:0034584), metal ion binding (GO:0046872), nucleic acid binding (GO:0003676), RNA binding (GO:0003723), nuclease activity (GO:0004518), endonuclease activity (GO:0004519), protein binding (GO:0005515)

GO Cellular Component (8): nucleus (GO:0005634), cytoplasm (GO:0005737), perinucleolar chromocenter (GO:0010370), chromatoid body (GO:0033391), P granule (GO:0043186), pi-body (GO:0071546), dense body (GO:0097433), PET complex (GO:1990923)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Gene Silencing by RNA	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
mRNA destabilization	2
transposable element silencing	2
transposable element silencing by heterochromatin formation	2
binding	2
cellular anatomical structure	2
cytoplasmic ribonucleoprotein granule	2
developmental process involved in reproduction	1
male gamete generation	1
stem cell population maintenance	1
negative regulation of gene expression	1
regulatory ncRNA processing	1
circadian rhythm	1
regulation of circadian rhythm	1
negative regulation of biological process	1
germ cell development	1
female gamete generation	1
biological_process	1
cell cycle	1
sexual reproduction	1
reproductive process	1
meiotic nuclear division	1
meiosis I	1
positive regulation of meiotic nuclear division	1
regulation of meiosis I	1
piRNA processing	1
regulatory ncRNA-mediated post-transcriptional gene silencing	1
constitutive heterochromatin formation	1
piRNA-mediated heterochromatin formation	1
gene silencing by piRNA-directed DNA methylation	1
cytoplasmic translation	1
positive regulation of translation	1
regulation of cytoplasmic translation	1
translation	1
post-transcriptional regulation of gene expression	1
regulation of protein metabolic process	1
cellular developmental process	1
RNA binding	1
endonuclease activity	1
RNA nuclease activity	1
catalytic activity	1

Protein interactions and networks

STRING

1210 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PIWIL2	TDRD1	Q9BXT4	991
PIWIL2	PIR	O00625	942
PIWIL2	TDRD9	Q8NDG6	909
PIWIL2	MOV10L1	Q9BXT6	896
PIWIL2	TDRD6	O60522	857
PIWIL2	STAT3	P40763	832
PIWIL2	MAEL	Q96JY0	824
PIWIL2	TDRKH	Q9Y2W6	793
PIWIL2	RNF17	Q9BXT8	785
PIWIL2	DICER1	Q9UPY3	780
PIWIL2	TDRD5	Q8NAT2	779
PIWIL2	TDRD12	Q587J7	776
PIWIL2	TDRD7	Q8NHU6	769
PIWIL2	DAZL	Q92904	731
PIWIL2	ASZ1	Q8WWH4	717

IntAct

10 interactions, top by confidence:

A	B	Type	Score
FKBP5	PIWIL2	psi-mi:“MI:0915”(physical association)	0.400
PIWIL2	HSP90AB1	psi-mi:“MI:0915”(physical association)	0.400
	PIWIL2	psi-mi:“MI:0915”(physical association)	0.400
PIWIL2		psi-mi:“MI:0915”(physical association)	0.400
HSP90AA1	PIWIL2	psi-mi:“MI:0915”(physical association)	0.400
STIP1	PIWIL2	psi-mi:“MI:0915”(physical association)	0.400
PIWIL2	PTGES3	psi-mi:“MI:0915”(physical association)	0.400
AARSD1	PIWIL2	psi-mi:“MI:0915”(physical association)	0.400
PIWIL2	PPP5C	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (27): TBCB (Affinity Capture-Western), PIWIL2 (Affinity Capture-Western), PIWIL2 (Reconstituted Complex), HDAC3 (Affinity Capture-Western), PIWIL2 (Affinity Capture-Western), HDAC3 (Reconstituted Complex), HDAC3 (Co-localization), SIAH2 (Affinity Capture-Western), PIWIL2 (Affinity Capture-Western), CSNK2A2 (Affinity Capture-Western), PIWIL2 (Affinity Capture-Western), PIWIL2 (Affinity Capture-MS), PIWIL2 (Affinity Capture-Western), PIWIL2 (Affinity Capture-MS), PIWIL2 (Affinity Capture-MS)

ESM2 similar proteins: A2CEI6, A3KPK0, A6P7L8, A8D8P8, A8KBF3, A9ZSZ2, O04379, O48771, O76922, O77503, O89040, Q0JF58, Q4G033, Q4KLV6, Q5NBN9, Q5Z5B2, Q5ZLG4, Q5ZMW0, Q69VD5, Q6DCX2, Q6DJB9, Q6EU14, Q6K972, Q6QME8, Q6T5B7, Q6YSJ5, Q6Z4F1, Q7PLK0, Q7XSA2, Q7Y001, Q7Z3Z3, Q7Z3Z4, Q84VQ0, Q851R2, Q8CDG1, Q8CGT6, Q8CJF8, Q8CJF9, Q8CJG0, Q8CJG1

Diamond homologs: A2CEI6, A6N7Y9, A6P7L8, A8D8P8, A8KBF3, A9ZSZ2, O76922, Q4G033, Q7PLK0, Q7Z3Z3, Q7Z3Z4, Q8CDG1, Q8CGT6, Q8TC59, Q8UVX0, Q96J94, Q9JMB7, Q9VKM1, O61931, Q2PC95, Q09249, Q21770, P34681, Q7XTS3

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	144
Likely benign	10
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

3695 predictions. Top by Δscore:

Variant	Effect	Δscore
8:22275396:CAG:C	donor_gain	1.0000
8:22275397:AG:A	donor_gain	1.0000
8:22275398:GG:G	donor_gain	1.0000
8:22275399:G:GG	donor_gain	1.0000
8:22275399:GTGA:G	donor_loss	1.0000
8:22281114:CCACA:C	acceptor_loss	1.0000
8:22281117:CA:C	acceptor_loss	1.0000
8:22281118:A:AG	acceptor_gain	1.0000
8:22281118:AG:A	acceptor_gain	1.0000
8:22281119:G:GA	acceptor_gain	1.0000
8:22281119:GG:G	acceptor_gain	1.0000
8:22281119:GGA:G	acceptor_gain	1.0000
8:22281119:GGAGT:G	acceptor_gain	1.0000
8:22281207:GG:G	donor_loss	1.0000
8:22281208:G:GA	donor_loss	1.0000
8:22283025:A:AG	acceptor_gain	1.0000
8:22283026:C:G	acceptor_gain	1.0000
8:22283027:A:AG	acceptor_gain	1.0000
8:22283028:T:G	acceptor_gain	1.0000
8:22283032:A:AG	acceptor_gain	1.0000
8:22283032:AG:A	acceptor_gain	1.0000
8:22283032:AGGAC:A	acceptor_gain	1.0000
8:22283033:G:A	acceptor_gain	1.0000
8:22283033:G:GA	acceptor_gain	1.0000
8:22283033:GGA:G	acceptor_gain	1.0000
8:22283033:GGAC:G	acceptor_gain	1.0000
8:22283033:GGACG:G	acceptor_gain	1.0000
8:22283236:GAAAA:G	donor_gain	1.0000
8:22283237:A:T	donor_gain	1.0000
8:22283237:AAAA:A	donor_gain	1.0000

AlphaMissense

6414 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:22308041:T:A	W552R	1.000
8:22308041:T:C	W552R	1.000
8:22315125:T:A	W730R	1.000
8:22315125:T:C	W730R	1.000
8:22316263:G:T	G743W	1.000
8:22316323:A:C	S763R	1.000
8:22316325:C:A	S763R	1.000
8:22316325:C:G	S763R	1.000
8:22352975:C:A	P807Q	1.000
8:22352992:T:G	Y813D	1.000
8:22352995:C:A	R814S	1.000
8:22352996:G:C	R814P	1.000
8:22353002:G:A	G816E	1.000
8:22353029:T:A	V825D	1.000
8:22353110:T:A	V852D	1.000
8:22355366:G:A	C928Y	1.000
8:22355367:C:G	C928W	1.000
8:22355405:C:A	P941Q	1.000
8:22355415:C:G	C944W	1.000
8:22284263:T:A	V245E	0.999
8:22284268:T:C	F247L	0.999
8:22284270:C:A	F247L	0.999
8:22284270:C:G	F247L	0.999
8:22287604:T:C	F274L	0.999
8:22287606:T:A	F274L	0.999
8:22287606:T:G	F274L	0.999
8:22287611:G:A	G276E	0.999
8:22287620:T:C	L279P	0.999
8:22287626:T:C	L281P	0.999
8:22288666:G:C	R329P	0.999

dbSNP variants (sampled 300 via entrez): RS1000020345 (8:22273462 C>T), RS1000021462 (8:22307711 A>G), RS1000046516 (8:22312859 T>C), RS1000089179 (8:22278216 T>C), RS1000117142 (8:22326637 T>C), RS1000121759 (8:22326817 T>C,G), RS1000141201 (8:22292373 T>C), RS1000157731 (8:22346020 C>A), RS1000181811 (8:22311592 A>G), RS1000197570 (8:22297555 T>A,C), RS1000202065 (8:22288227 G>A), RS1000212777 (8:22322593 C>A), RS1000259098 (8:22293754 A>G), RS1000333106 (8:22316794 T>C), RS1000333773 (8:22282340 C>T)

Disease associations

OMIM: gene MIM:610312 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
male infertility with azoospermia or oligozoospermia due to single gene mutation	Strong	Autosomal recessive

Mondo (2): male infertility (MONDO:0005372), (MONDO:0018393)

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST001905_1	Hypertriglyceridemia	7.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004530	triglyceride measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D007248	Infertility, Male	C12.100.500.430; C12.100.750.700; C12.200.294.430

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
fluorene-9-bisphenol	decreases expression	1
sotorasib	affects cotreatment, decreases expression	1
propionaldehyde	increases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
dimethylselenide	increases expression, increases oxidation, decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
butyraldehyde	increases expression	1
abrine	increases expression	1
trametinib	affects cotreatment, decreases expression	1
NVP-BKM120	affects cotreatment, decreases expression	1
Air Pollutants	affects methylation, increases abundance	1
Vehicle Emissions	affects methylation, increases abundance	1
Estradiol	affects cotreatment, increases expression	1
Methotrexate	decreases expression	1
Nitrogen Dioxide	affects methylation, increases abundance	1
Sodium Dodecyl Sulfate	increases expression	1
Tetrachlorodibenzodioxin	increases expression	1
Dronabinol	decreases expression	1
Urethane	increases expression	1
Aflatoxin B1	increases methylation	1
Asbestos, Crocidolite	affects methylation	1
Hydroxyl Radical	decreases expression, increases expression, increases oxidation	1
Okadaic Acid	decreases expression	1
Acrylamide	increases expression	1

Cellosaurus cell lines

1 cell lines: 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_YR04	HUSTi002-A	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02202382	PHASE4	COMPLETED	Effects of Korean Red Ginseng on Male Infertility
NCT02204826	PHASE4	COMPLETED	Effects of Korean Red Ginseng on Semen Parameters in Male Infertility Patients: a Randomized, Placebo-controlled, Double-blind Clinical Study
NCT03802864	PHASE4	COMPLETED	Post-operative Pain Control of Testicular Sperm Extraction Using Liposomal Bupivacaine
NCT06100432	PHASE4	ACTIVE_NOT_RECRUITING	Effect of Eurycoma Longifolia (DLBS5055) and Multivitamins (Vitamin C+Vitamin E+ β-carotene) for Infertile Males
NCT07523022	PHASE4	ENROLLING_BY_INVITATION	Comparison of the Effect of Gonadotropin and Clomiphene Citrate Treatment on Sperm Parameters and the Outcome of Assisted Reproductive Procedures in Subfertile Men Based on the APHRODITE Groups
NCT00975117	PHASE3	COMPLETED	Spermotrend in the Treatment of Male Infertility
NCT01407432	PHASE3	COMPLETED	Impact of Folates in the Care of the Male Infertility
NCT01895816	PHASE3	COMPLETED	Herbal Tonic Fertile Supplement(ZO2C5)
NCT02605070	PHASE3	TERMINATED	Pilot Study on the Effects of FSH Treatment on the Epigenetic Characteristics of Spermatozoa in Infertile Patients With Severe Oligozoospermia
NCT07402759	PHASE3	ACTIVE_NOT_RECRUITING	Impact of tdrd9 Gene Mutations in the Therapeutic Response to L-carnitine in Oligoasthenozoospermic Men
NCT01880086	PHASE2	COMPLETED	Clomiphene Citrate for the Treatment of Low Testosterone Associated With Chronic Opioid Pain Medication Administration
NCT02061384	PHASE2	COMPLETED	RA-2 13-cis Retinoic Acid (Isotretinoin)
NCT02421887	PHASE2	COMPLETED	Males, Antioxidants, and Infertility Trial
NCT05200663	PHASE2	UNKNOWN	Efficacy Comparison of Tamoxifen and Tamoxifen With Antioxidants on Semen Quality of Male With Idiopathic Infertility
NCT05290558	PHASE2	ACTIVE_NOT_RECRUITING	The Therapeutic Effects of Bu Shen Yi Jing Pill on Semen Quality in Sub Fertile Males: a Randomized Controlled Trial
NCT06091969	PHASE2	NOT_YET_RECRUITING	Supplementation for Male Subfertility
NCT01595308	PHASE1	COMPLETED	A Pilot Study to Evaluate the Effect of Pomegranate Juice on Semen Parameters in Healthy Male Volunteers
NCT02122211	PHASE1	COMPLETED	Choline Dehydrogenase and Sperm Function: Effects of Betaine
NCT02575924	PHASE1	UNKNOWN	Influence of Culture Media on Clinical Outcomes in Poor Responders or Severe Male Infertility
NCT01304927	PHASE2/PHASE3	COMPLETED	Vitamin D Supplementation and Male Infertility: The CBG-study a Randomized Clinical Trial
NCT02349945	PHASE2/PHASE3	COMPLETED	FSH Receptor Polymorphism p.N680S and Efficacy of FSH Therapy
NCT05222841	PHASE2/PHASE3	COMPLETED	The Effectiveness of Spermotrend Food Supplement in the Treatment of Male Infertility
NCT05616598	PHASE2/PHASE3	COMPLETED	Effect of New Oral Treatment for Hepatitis C Virus on Seminal Parameters
NCT02025270	PHASE1/PHASE2	COMPLETED	MSCs For Treatment of Azoospermic Patients
NCT04541459	EARLY_PHASE1	UNKNOWN	Validation of New Devices Against Ambient Electromagnetic Radiation
NCT05792813	EARLY_PHASE1	UNKNOWN	Efficacy and Safety of Linggui Yangyuan Paste in Patients With Male Infertility
NCT06188936	EARLY_PHASE1	COMPLETED	Home Semen Analysis Tests As a Screening Tool for Fertility Patients
NCT00012480	Not specified	COMPLETED	Effect of Environmental Exposures on the Egg Fertilizing Ability of Human Sperm
NCT00044369	Not specified	COMPLETED	Role of the Toxic Metal Cadmium in the Mechanism Producing Infertility With a Varicocele
NCT00119925	Not specified	UNKNOWN	‘SPRING’-Study: Subfertility Guidelines: Patient Related Implementation in the Netherlands Among Gynaecologists
NCT00178516	Not specified	COMPLETED	Vitamin E and Male Infertility
NCT00315029	Not specified	COMPLETED	Patient-Centered Implementation Trial for Single Embryo Transfer
NCT00341120	Not specified	COMPLETED	Genetic Causes of Male Infertility
NCT00481403	Not specified	COMPLETED	Study of Sperm Molecular Factors Implicated in Male Fertility
NCT00548977	Not specified	COMPLETED	Genetic Studies Spermatogenic Failure
NCT00596739	Not specified	COMPLETED	A Study of the Pre- and Post-operative Semen Analyses and Reproductive Hormone Levels of Men Undergoing Weight-reduction Surgery
NCT00756561	Not specified	COMPLETED	HOP-2A - Intratesticular Hormone Levels
NCT00961558	Not specified	TERMINATED	Canadian Varicocelectomy Initiative (CVI): Effects on Male Fertility and Testicular Function of Varicocelectomy
NCT01075334	Not specified	UNKNOWN	Is a Carnitine Based Food Supplement (PorimoreTM) for Infertile Men Superior to Folate and Zinc With Regard to Pregnancy Rates in Intrauterine Insemination Cycles?
NCT01178463	Not specified	UNKNOWN	Spermatogonial Stem Cells in Azoospermic Patients: a Comparison Between Obstructive and Non-obstructive Azoospermia