PIWIL1

Summary

PIWIL1 (piwi like RNA-mediated gene silencing 1, HGNC:9007) is a protein-coding gene on chromosome 12q24.33, encoding Piwi-like protein 1 (Q96J94). Endoribonuclease that plays a central role in postnatal germ cells by repressing transposable elements and preventing their mobilization, which is essential for the germline integrity.

This gene encodes a member of the PIWI subfamily of Argonaute proteins, evolutionarily conserved proteins containing both PAZ and Piwi motifs that play important roles in stem cell self-renewal, RNA silencing, and translational regulation in diverse organisms. The encoded protein may play a role as an intrinsic regulator of the self-renewal capacity of germline and hematopoietic stem cells. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 9271 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 166 total — 1 likely-pathogenic
• MANE Select transcript: NM_004764

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9007
Approved symbol	PIWIL1
Name	piwi like RNA-mediated gene silencing 1
Location	12q24.33
Locus type	gene with protein product
Status	Approved
Aliases	PIWI, HIWI, CT80.1
Ensembl gene	ENSG00000125207
Ensembl biotype	protein_coding
OMIM	605571
Entrez	9271

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 6 protein_coding, 1 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000245255, ENST00000535956, ENST00000539400, ENST00000539995, ENST00000540672, ENST00000541480, ENST00000542723, ENST00000546060

RefSeq mRNA: 2 — MANE Select: NM_004764 NM_001190971, NM_004764

CCDS: CCDS9268

Canonical transcript exons

ENST00000245255 — 21 exons

Exon	Start	End
ENSE00000757496	130354888	130355005
ENSE00000757497	130355553	130355667
ENSE00000757498	130356918	130357105
ENSE00000757499	130357481	130357553
ENSE00000757500	130361180	130361380
ENSE00000757501	130361498	130361601
ENSE00000757502	130362766	130362836
ENSE00000757503	130362991	130363144
ENSE00000757505	130371176	130371323
ENSE00000853549	130354537	130354663
ENSE00001002610	130349856	130349967
ENSE00001002612	130349239	130349436
ENSE00001002621	130345753	130345878
ENSE00001002623	130342580	130342669
ENSE00001002624	130342990	130343101
ENSE00001226828	130371482	130372637
ENSE00002310852	130337887	130338146
ENSE00003563286	130367133	130367258
ENSE00003675743	130346370	130346584
ENSE00003726760	130348103	130348183
ENSE00003732100	130346941	130347062

Expression profiles

Bgee: expression breadth broad, 89 present calls, max score 94.50.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.5445 / max 308.9932, expressed in 32 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
128729	0.2450	7
128724	0.1037	15
128725	0.0685	13
128726	0.0507	13
128727	0.0364	9
128734	0.0201	4
128728	0.0200	7

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right testis	UBERON:0004534	94.50	gold quality
left testis	UBERON:0004533	94.36	gold quality
testis	UBERON:0000473	93.61	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	89.21	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.07	gold quality
metanephros cortex	UBERON:0010533	61.39	gold quality
adenohypophysis	UBERON:0002196	58.25	gold quality
pituitary gland	UBERON:0000007	56.77	gold quality
right lobe of thyroid gland	UBERON:0001119	52.12	gold quality
right uterine tube	UBERON:0001302	51.59	gold quality
endocervix	UBERON:0000458	51.49	gold quality
cortex of kidney	UBERON:0001225	50.99	gold quality
spleen	UBERON:0002106	50.84	gold quality
superior frontal gyrus	UBERON:0002661	48.96	gold quality
thyroid gland	UBERON:0002046	48.87	gold quality
fallopian tube	UBERON:0003889	47.62	gold quality
adult mammalian kidney	UBERON:0000082	47.56	gold quality
kidney	UBERON:0002113	47.49	gold quality
left lobe of thyroid gland	UBERON:0001120	46.99	gold quality
endometrium	UBERON:0001295	46.62	gold quality
colonic epithelium	UBERON:0000397	46.02	gold quality
rectum	UBERON:0001052	45.42	gold quality
left uterine tube	UBERON:0001303	45.30	gold quality
adrenal tissue	UBERON:0018303	44.15	gold quality
duodenum	UBERON:0002114	41.93	gold quality
mucosa of transverse colon	UBERON:0004991	41.54	silver quality
right adrenal gland	UBERON:0001233	41.28	gold quality
left adrenal gland cortex	UBERON:0035825	40.93	gold quality
adrenal gland	UBERON:0002369	40.58	gold quality
right coronary artery	UBERON:0001625	40.12	silver quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.72

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NFYA, USF1

Literature-anchored findings (GeneRIF, showing 40)

• specifically expressed in both normal and malignant spermatogenic cells in a maturation stage-dependent pattern, in which it might function in germ cell proliferation (PMID:12037681)
• results suggest that hiwi may be involved in the development of gastric cancer and is a potential target for cancer therapy (PMID:16287078)
• High-level expression of Hiwi mRNA identifies soft-tissue sarcoma patients at high risk of tumor-related death. (PMID:16953229)
• alterations in mRNA expression of Hiwi can increase the risk of tumour-related death in male ductal pancreatic carcinoma patients (PMID:18781170)
• The expression of HIWI in the cytoplasm of esophageal cancer cells is significantly associated with higher histological grade, clinical stage and poorer clinical outcome (PMID:19995427)
• These results suggest that hiwi plays an important role in the oncogenesis and is a potential target for cancer angiogenesis (PMID:20204292)
• We report the first analysis of PSCA, PIWIL1, and TBX2 expression in EAC. Our findings suggest that PSCA and TBX2 might be candidate targets for cancer therapy. (PMID:20502058)
• The result of this study suggested that Hiwi may be a critical factor in glioma progression and could be used as a potential molecular marker for pathological diagnosis and prognosis evaluation for malignant gliomas. (PMID:21138738)
• HIWI expression is significantly higher in HCC tissue than in adjacent normal hepatic tissue. (PMID:21327579)
• The human piwi-like 1 PAZ domain is a typical OB fold and specifically recognizes the 2nt 3 0 -OH end of the single-stranded RNA and buries the two 3 0 -terminal nucleotides in the hydrophobic cleft. (PMID:21465557)
• Colorectal cancer patients with positive HIWI expression in adjacent non-cancerous tissue had statistically lower overall survival (OS) and disease free survival (DFS) compared with negative patients. (PMID:21933617)
• HIWI may play a key role in hepatocellular carcinoma (HCC) proliferation and metastasis and can be a potential prognostic factor for HCC after curative resection (PMID:21989785)
• In this review, the current state of knowledge on the structure, biogenesis and function of piRNA and their interactions with Piwi proteins is presented. (PMID:22235650)
• A subgroup of more aggressive tumors can be identified by evaluating Hiwi level in lymph node metastatic cancer. (PMID:22261620)
• Hiwi-associated DNA hyper-methylation with subsequent genetic and epigenetic changes favors a tumorigenic state (PMID:22438986)
• Findings suggest the role of RASSF1C/PIWIL1 proteins in initiation and progression of lung cancer. (PMID:22591718)
• Expression of PIWIL1 was an independent prognostic factor in gastric cancer. (PMID:22670175)
• Polymorphism in PIWIL1 gene is associated with HBV-related hepatocellular carcinoma (PMID:23868705)
• associations were determined between the Piwi-like family member expression levels and clinicopathological parameters of ccRCC, suggesting a potential role for these genes/proteins in ccRCC diagnostics and tumorigenesis (PMID:24509249)
• 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)
• A important role of HIWI and DPPA2 in tumorigenesis and also in lymph node metastasis of tumor cells. (PMID:24532429)
• detection of mitochondrial Piwi by colocalization using anti-Piwil1 and mitochondria organelle-specific protein antibodies in cancer cell lines (PMID:24602614)
• IGFBP-5 may be a negative modulator of RASSF1C/ PIWIL1 growth-promoting activities. (PMID:25007054)
• Results show that HIWI is highly expressed in high-grade squamous intraepithelial lesions and cervical cancer tissues suggesting its participation in the carcinogenesis of cervical cancer. (PMID:25119492)
• These findings suggest that HIWI is an oncogene involved in the progression of glioma. (PMID:25269862)
• Overexpression of hiwi promotes growth of breast cancer cells. (PMID:25292027)
• Evidence of an active PIWI-interacting small non-coding RNAs pathway in BC suggests that these small non-coding RNAs do exert transcriptional and post-transcriptional gene regulatory actions also in cancer cells. (PMID:25313140)
• Hiwi downregulation mediated by shRNA reduce the proliferation and migration of HCC cells. (PMID:25370791)
• Among patients with high let-7a expression, those with medium HIWI had an increased risk of death compared to those with low HIWI (HR = 2.62, 95% CI: 1.30-5.30). (PMID:25630839)
• Overexpression of Hiwi significantly suppressed cell proliferation and cell migration and induced apoptosis in K562 cells. (PMID:25701408)
• Hiwi upregulation enhanced chemosensitivity of Chronic Myeloid Leukemia cells to daunomycin, suppressed cell proliferation and promoted apoptosis. (PMID:25701955)
• PIWIL1 expression emerged as an independent prognostic marker in non-small cell lung cancer. (PMID:25742785)
• Our results indicate a reciprocal regulation between HIWI, HILI and some CSCs markers in colorectal cancer (PMID:26026091)
• results suggested that Piwil1 caused the loss of PTEN expression through DNMT1-mediated PTEN hypermethylation (PMID:26056945)
• Our study reveals a novel mechanism for PIWIL1 in tumorigenesis. (PMID:26317901)
• HIWI promotes the activity of breast cancer cells while depression of HIWI may induce apoptosis of breast cancer cells. (PMID:26847393)
• PIWIL3 and PIWIL4 genes showed prognostic relevance. 306 gene targets exhibited reciprocal relationship with piRNA expression (PMID:27177224)
• In blood serum, piR-823 is up-regulated, but with unsatisfactory analytical performance. Preliminary data indicate the promising diagnostic utility of urinary piR-823 in patients with RCC (PMID:27919963)
• Findings identify Piwi as a factor in human infertility and reveal its role in regulating the histone-to-protamine exchange during spermiogenesis. (PMID:28552346)
• Expression of PIWIL1 in the cancer tissue was higher than that in the corresponding adjacent tissue. High PIWIL1 expression suggests a poor prognosis for colorectal cancer patients. (PMID:28634417)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	piwil1	ENSDARG00000041699
mus_musculus	Piwil1	ENSMUSG00000029423
rattus_norvegicus	Piwil1	ENSRNOG00000000934
drosophila_melanogaster	aub	FBGN0000146
drosophila_melanogaster	piwi	FBGN0004872
caenorhabditis_elegans	prg-1	WBGENE00004178

Paralogs (3): PIWIL4 (ENSG00000134627), PIWIL3 (ENSG00000184571), PIWIL2 (ENSG00000197181)

Protein

Protein identifiers

Piwi-like protein 1 — Q96J94 (reviewed: Q96J94)

All UniProt accessions (6): Q96J94, F5GYG0, F5GZL9, F5H2F7, F5H3U6, F5H889

UniProt curated annotations — full annotation on UniProt →

Function. Endoribonuclease that plays a central role in postnatal germ cells by repressing transposable elements and preventing their mobilization, which is essential for the germline integrity. 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 governs the methylation and subsequent repression of transposons. Directly binds methylated piRNAs, a class of 24 to 30 nucleotide RNAs that are generated by a Dicer-independent mechanism and are primarily derived from transposons and other repeated sequence elements. Strongly prefers a uridine in the first position of their guide (g1U preference, also named 1U-bias). Not involved in the piRNA amplification loop, also named ping-pong amplification cycle. Acts as an endoribonuclease that cleaves transposon messenger RNAs. Besides their function in transposable elements repression, piRNAs are probably involved in other processes during meiosis such as translation regulation. Probable component of some RISC complex, which mediates RNA cleavage and translational silencing. Also plays a role in the formation of chromatoid bodies and is required for some miRNAs stability. Required to sequester RNF8 in the cytoplasm until late spermatogenesis; RNF8 being released upon ubiquitination and degradation of PIWIL1. May be a negative developmental regulator.

Subunit / interactions. Interacts (via Piwi domain) with DICER1, suggesting that it forms ribonucleoprotein RISC complexes; this interaction is regulated by HSP90AB1 activity. Interacts with MAEL, KIF17, PABPC1, PRMT5 and WDR77. Interacts (when methylated on arginine residues) with TDRD1, TDRKH/TDRD2, RNF17/TDRD4, TDRD6, TDRD7 and TDRD9. Interacts with CLOCK. Interacts with MOV10L1. Interacts with ANAPC10; interaction oly takes place following piRNA-binding. Interacts with RNF8; leading to sequester RNF8 in the cytoplasm. Interacts with TEX19.

Subcellular location. Cytoplasm.

Tissue specificity. Expressed in spermatocytes and spermatids. Also detected in prostate cancer (at protein level). Detected in most fetal and adult tissues. Expressed in testes, specifically in germline cells; detected in spermatocytes and spermatids during spermatogenesis. Increased expression in testicular tumors originating from embryonic germ cells with retention of germ cells phenotype. No expression in testicular tumors of somatic origin, such as Sertoli cell and Leydig cell tumors. Overexpressed in gastric cancer cells. Isoform 3: Ubiquitously expressed, and specifically in CD34(+) hematopoietic progenitor cells but not in more differentiated cells.

Post-translational modifications. Arginine methylation by PRMT5 is required for the interaction with Tudor domain-containing protein (TDRD1, TDRKH/TDRD2, RNF17/TDRD4, TDRD6, TDRD7 and TDRD9) and subsequent localization to the meiotic nuage, also named P granule. Ubiquitinated by the anaphase promoting complex/cyclosome (APC/C) in late spermatids, leading to its degradation. Ubiquitination only takes place following piRNA-binding in adult testis. Ubiquitination and degradation in late spermatogenesis by APC/C is probably required to release RNF8 from the cytoplasm and promote histone to protamine exchange by RNF8.

Disease relevance. Defects in PIWIL1 may be a cause of a disorder resulting in the absence of sperm (azoospermia) in the semen, leading to male infertility. Male sterility can be caused by defects in ubiquitination and degradation during late spermatogenesis.

Domain organisation. The PAZ domain specifically recognizes binds the 2’-O-methylated 3’-end of piRNAs. The MID region is required for recognition of uridine in the first position of piRNAs (g1U preference, also named 1U-bias). The D-box (destruction box) acts as a recognition signal for association with the APC/C complex, ubiquitination and degradation.

Induction. Down-regulated in CD34(+) hematopoietic cells during differentiation.

Similarity. Belongs to the argonaute family. Piwi subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
Q96J94-1	1	yes
Q96J94-2	2
Q96J94-3	3

RefSeq proteins (2): NP_001177900, NP_004755* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003100	PAZ_dom	Domain
IPR003165	Piwi	Domain
IPR012337	RNaseH-like_sf	Homologous_superfamily
IPR014811	ArgoL1	Domain
IPR031320	GAGE	Domain
IPR036085	PAZ_dom_sf	Homologous_superfamily
IPR036397	RNaseH_sf	Homologous_superfamily

Pfam: PF02170, PF02171, PF05831, PF08699, PF23278

UniProt features (54 total): strand 10, sequence variant 8, modified residue 6, helix 5, active site 4, splice variant 4, sequence conflict 4, region of interest 3, domain 2, mutagenesis site 2, compositionally biased region 2, chain 1, site 1, turn 1, short sequence motif 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
3O7V	X-RAY DIFFRACTION	2.1
6PI7	X-RAY DIFFRACTION	2.8
3O3I	X-RAY DIFFRACTION	2.8
3O6E	X-RAY DIFFRACTION	2.9
2L5C	SOLUTION NMR
2L5D	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96J94-F1	86.25	0.70

Antibody-complex structures (SAbDab): 1 — 6PI7

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 (5): 670; 702; 836; 381 (required for binding 2’-o-methylated 3’-end of pirnas); 632

Post-translational modifications (6): 14, 14, 49, 53, 53, 370

Mutagenesis-validated functional residues (2):

Position	Phenotype
379	impairs binding to 2’-o-methylated 3’-end of pirnas; when associated with y-381.
381	impairs binding to 2’-o-methylated 3’-end of pirnas; when associated with h-379.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

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

MSigDB gene sets: 128 (showing top): GOMF_ENDONUCLEASE_ACTIVITY, GOMF_RNA_NUCLEASE_ACTIVITY, GOBP_REGULATION_OF_MRNA_CATABOLIC_PROCESS, GOMF_NUCLEASE_ACTIVITY, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, KEGG_DORSO_VENTRAL_AXIS_FORMATION, GOBP_MALE_GAMETE_GENERATION, GOBP_TRANSLATION, GOBP_POST_TRANSCRIPTIONAL_REGULATION_OF_GENE_EXPRESSION, GOBP_NEGATIVE_REGULATION_OF_GENE_EXPRESSION_EPIGENETIC, GOMF_RNA_ENDONUCLEASE_ACTIVITY, GOBP_REGULATION_OF_CATABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_CATABOLIC_PROCESS, GOBP_NUCLEUS_ORGANIZATION, GOBP_CELLULAR_PROCESS_INVOLVED_IN_REPRODUCTION_IN_MULTICELLULAR_ORGANISM

GO Biological Process (11): regulation of translation (GO:0006417), spermatogenesis (GO:0007283), spermatid development (GO:0007286), regulatory ncRNA-mediated gene silencing (GO:0031047), piRNA processing (GO:0034587), sperm DNA condensation (GO:0035092), meiotic cell cycle (GO:0051321), primary piRNA processing (GO:0140990), piRNA-mediated gene silencing by mRNA destabilization (GO:0140991), transposable element silencing by piRNA-mediated heterochromatin formation (GO:0141006), cell differentiation (GO:0030154)

GO Molecular Function (13): single-stranded RNA binding (GO:0003727), mRNA binding (GO:0003729), RNA endonuclease activity (GO:0004521), hydrolase activity (GO:0016787), protein kinase binding (GO:0019901), piRNA binding (GO:0034584), metal ion binding (GO:0046872), mRNA cap binding complex binding (GO:0140262), nucleic acid binding (GO:0003676), RNA binding (GO:0003723), nuclease activity (GO:0004518), endonuclease activity (GO:0004519), protein binding (GO:0005515)

GO Cellular Component (5): nucleus (GO:0005634), cytoplasm (GO:0005737), chromatoid body (GO:0033391), P granule (GO:0043186), dense body (GO:0097433)

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
RNA binding	2
binding	2
cellular anatomical structure	2
cytoplasmic ribonucleoprotein granule	2
translation	1
post-transcriptional regulation of gene expression	1
regulation of protein metabolic process	1
developmental process involved in reproduction	1
male gamete generation	1
germ cell development	1
spermatid differentiation	1
negative regulation of gene expression	1
regulatory ncRNA processing	1
chromatin organization	1
spermatid nucleus differentiation	1
cell cycle	1
sexual reproduction	1
reproductive process	1
meiotic nuclear division	1
piRNA processing	1
regulatory ncRNA-mediated post-transcriptional gene silencing	1
mRNA destabilization	1
piRNA-mediated heterochromatin formation	1
transposable element silencing by heterochromatin formation	1
cellular developmental process	1
endonuclease activity	1
RNA nuclease activity	1
catalytic activity	1
kinase binding	1
regulatory RNA binding	1
cation binding	1
protein-containing complex binding	1
nucleic acid binding	1
catalytic activity, acting on a nucleic acid	1
nuclease activity	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
germ plasm	1
cytoplasm	1

Protein interactions and networks

STRING

2224 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PIWIL1	PIR	O00625	971
PIWIL1	TNRC6A	Q8NDV7	955
PIWIL1	TDRD1	Q9BXT4	944
PIWIL1	DICER1	Q9UPY3	939
PIWIL1	TDRD6	O60522	931
PIWIL1	TDRD9	Q8NDG6	907
PIWIL1	SND1	Q7KZF4	894
PIWIL1	MOV10L1	Q9BXT6	883
PIWIL1	GTSF1	Q8WW33	878
PIWIL1	WDR5	P61964	876
PIWIL1	TDRKH	Q9Y2W6	867
PIWIL1	TDRD5	Q8NAT2	859
PIWIL1	PIWIL4	Q7Z3Z4	845
PIWIL1	DROSHA	Q9NRR4	840
PIWIL1	HENMT1	Q5T8I9	825

IntAct

35 interactions, top by confidence:

A	B	Type	Score
SND1	PIWIL1	psi-mi:“MI:0407”(direct interaction)	0.620
PIWIL1	DNM2	psi-mi:“MI:0915”(physical association)	0.560
PIWIL1	JPH3	psi-mi:“MI:0915”(physical association)	0.560
HTT	PIWIL1	psi-mi:“MI:0915”(physical association)	0.560
ATXN1	PIWIL1	psi-mi:“MI:0915”(physical association)	0.560
DICER1	PIWIL1	psi-mi:“MI:0915”(physical association)	0.500
DICER1	PIWIL1	psi-mi:“MI:0914”(association)	0.500
PIWIL1	TDRKH	psi-mi:“MI:0407”(direct interaction)	0.440
PIWIL1	FKBP5	psi-mi:“MI:0915”(physical association)	0.400
PIWIL1	HSP90AB1	psi-mi:“MI:0915”(physical association)	0.400
HSF2	PIWIL1	psi-mi:“MI:0915”(physical association)	0.400
NUDC	PIWIL1	psi-mi:“MI:0915”(physical association)	0.400
PIWIL1	NUDCD3	psi-mi:“MI:0915”(physical association)	0.400
PIWIL1		psi-mi:“MI:0915”(physical association)	0.400
HSP90AA1	PIWIL1	psi-mi:“MI:0915”(physical association)	0.400
PIWIL1	CACYBP	psi-mi:“MI:0915”(physical association)	0.400
PTGES3	PIWIL1	psi-mi:“MI:0915”(physical association)	0.400
PPP5C	PIWIL1	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (24): STMN1 (Two-hybrid), STMN1 (Reconstituted Complex), STMN1 (Affinity Capture-Western), PIWIL1 (Affinity Capture-Western), TUBA1B (Affinity Capture-Western), TUBB3 (Affinity Capture-Western), PIWIL1 (Affinity Capture-Western), PIWIL1 (Affinity Capture-Western), RNF8 (Affinity Capture-Western), PIWIL1 (Affinity Capture-Western), PIWIL1 (Two-hybrid), TDRKH (Affinity Capture-MS), BAG2 (Affinity Capture-MS), TDRKH (Affinity Capture-MS), PDE6B (Affinity Capture-MS)

ESM2 similar proteins: A2CEI6, A3KPK0, A6N7Y9, A6P7L8, A6QPU5, A7YW45, A8D8P8, A8KBF3, O14744, O76922, O77503, P0C928, P10687, P10894, Q0IIM3, Q3T056, Q4G033, Q4R5M3, Q4V7N2, Q5R606, Q5R698, Q5ZLG4, Q5ZMW0, Q60446, Q61699, Q66HA8, Q6PI48, Q6QME8, Q7Z3Z3, Q7Z3Z4, Q8BIP0, Q8CDG1, Q8CGT6, Q8CIG8, Q8CJF9, Q8CJG0, Q8K394, Q8TC59, Q8UVX0, Q8WV93

Diamond homologs: A2CEI6, A6N7Y9, A6P7L8, A8D8P8, A8KBF3, A9ZSZ2, O76922, Q4G033, Q7PLK0, Q7Z3Z3, Q7Z3Z4, Q8CDG1, Q8CGT6, Q8TC59, Q8UVX0, Q96J94, Q9JMB7, Q9VKM1, O61931, Q2PC95, O48771, P34681, Q0JF58, Q10F39, Q3E984, Q5NBN9, Q6YSJ5, Q75HC2, Q7XTS3, Q7XTS4, Q84VQ0, Q9C793, Q9SDG8, Q9SHF2, Q9SHF3, Q9ZVD5, Q09249, Q21770

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
PIWIL1	up-regulates	APC-c	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 20 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
ESR-mediated signaling	5	45.8×	6e-06

GO biological processes:

GO term	Partners	Fold	FDR
protein folding	7	36.2×	1e-07

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	127
Likely benign	17
Benign	9

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
3024489	NM_004764.5(PIWIL1):c.688C>T (p.Arg230Ter)	Likely pathogenic

SpliceAI

4048 predictions. Top by Δscore:

Variant	Effect	Δscore
12:130338037:G:GT	donor_gain	1.0000
12:130342978:A:AG	acceptor_gain	1.0000
12:130342979:T:G	acceptor_gain	1.0000
12:130343120:G:GT	donor_gain	1.0000
12:130345751:A:G	acceptor_gain	1.0000
12:130347059:GGAG:G	donor_gain	1.0000
12:130347060:GAGG:G	donor_gain	1.0000
12:130348097:TTCTA:T	acceptor_loss	1.0000
12:130348098:TCTA:T	acceptor_loss	1.0000
12:130348099:CTAG:C	acceptor_loss	1.0000
12:130348100:TAGGC:T	acceptor_loss	1.0000
12:130348101:A:AG	acceptor_gain	1.0000
12:130348101:AGG:A	acceptor_loss	1.0000
12:130348102:G:GG	acceptor_gain	1.0000
12:130349331:G:GG	donor_gain	1.0000
12:130349437:G:GG	donor_gain	1.0000
12:130355006:G:GG	donor_gain	1.0000
12:130357549:AGATA:A	donor_gain	1.0000
12:130357550:GATA:G	donor_gain	1.0000
12:130357550:GATAG:G	donor_gain	1.0000
12:130357551:ATA:A	donor_gain	1.0000
12:130357552:TA:T	donor_gain	1.0000
12:130357552:TAG:T	donor_loss	1.0000
12:130357553:AG:A	donor_loss	1.0000
12:130357554:G:A	donor_loss	1.0000
12:130357554:G:GG	donor_gain	1.0000
12:130357555:TAAG:T	donor_loss	1.0000
12:130357556:AA:A	donor_loss	1.0000
12:130357557:AGTA:A	donor_loss	1.0000
12:130361381:G:GG	donor_gain	1.0000

AlphaMissense

5647 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:130349427:T:A	V308D	1.000
12:130356999:T:A	W496R	1.000
12:130356999:T:C	W496R	1.000
12:130361347:G:C	K611N	1.000
12:130361347:G:T	K611N	1.000
12:130363051:G:C	R701P	1.000
12:130371302:C:G	C816W	1.000
12:130371498:C:A	P829H	1.000
12:130349412:T:C	L303P	0.999
12:130349879:T:A	V319E	0.999
12:130349917:T:C	F332L	0.999
12:130349919:T:A	F332L	0.999
12:130349919:T:G	F332L	0.999
12:130354577:T:C	L362S	0.999
12:130354643:C:A	P384H	0.999
12:130354651:T:C	C387R	0.999
12:130354652:G:A	C387Y	0.999
12:130354653:C:G	C387W	0.999
12:130356945:T:A	W478R	0.999
12:130356945:T:C	W478R	0.999
12:130357057:T:C	L515P	0.999
12:130361230:A:C	K572N	0.999
12:130361230:A:T	K572N	0.999
12:130361261:A:C	S583R	0.999
12:130361263:T:A	S583R	0.999
12:130361263:T:G	S583R	0.999
12:130361328:C:A	A605D	0.999
12:130361335:G:C	Q607H	0.999
12:130361335:G:T	Q607H	0.999
12:130361345:A:G	K611E	0.999

dbSNP variants (sampled 300 via entrez): RS1000029835 (12:130340701 G>A,C), RS1000113662 (12:130422707 G>A,T), RS1000126664 (12:130423225 G>A,T), RS1000144878 (12:130381826 T>C), RS1000176401 (12:130352488 G>A), RS1000217802 (12:130369064 C>A,T), RS1000288151 (12:130401843 G>A), RS1000308171 (12:130406017 A>C), RS1000334618 (12:130359956 C>A,T), RS1000366250 (12:130389894 T>G), RS1000390113 (12:130402058 T>C,G), RS1000437982 (12:130375497 T>C), RS1000454407 (12:130381693 C>T), RS1000522785 (12:130364276 T>G), RS1000563032 (12:130406076 A>C)

Disease associations

OMIM: gene MIM:605571 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): male infertility (MONDO:0005372)

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST005312_5	Menopause (age at onset)	6.000000e-11
GCST011742_63	Triglyceride levels in HIV infection	7.000000e-07

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004704	age at menopause
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

13 total (human), top 13 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
propionaldehyde	increases expression	1
bisphenol A	decreases expression	1
sodium arsenite	increases expression	1
bisphenol S	decreases methylation	1
(+)-JQ1 compound	decreases expression	1
Benzo(a)pyrene	affects methylation	1
Cadmium	increases abundance, increases expression	1
Tunicamycin	increases expression	1
Valproic Acid	increases methylation	1
Cyclosporine	decreases methylation	1
Aflatoxin B1	decreases methylation	1
Cadmium Chloride	increases abundance, increases expression	1
S-Nitrosoglutathione	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_UK16	AGP01 PIWIL1 KO	Cancer cell line	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