BPY2

Summary

BPY2 (basic charge Y-linked 2, HGNC:13508) is a protein-coding gene on chromosome Yq11.223, encoding Testis-specific basic protein Y 2 (O14599).

This gene is located in the nonrecombining portion of the Y chromosome, and expressed specifically in testis. The encoded protein interacts with ubiquitin protein ligase E3A and may be involved in male germ cell development and male infertility. Three nearly identical copies of this gene exist on chromosome Y; two copies are part of a palindromic region. This record represents the copy outside of the palidromic region.

Source: NCBI Gene 9083 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 53 total — 29 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 4
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_004678

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13508
Approved symbol	BPY2
Name	basic charge Y-linked 2
Location	Yq11.223
Locus type	gene with protein product
Status	Approved
Aliases	BPY2A, VCY2A
Ensembl gene	ENSG00000183753
Ensembl biotype	protein_coding
OMIM	400013
Entrez	9083

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 3 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000331070, ENST00000382585, ENST00000602732, ENST00000602818

RefSeq mRNA: 1 — MANE Select: NM_004678 NM_004678

CCDS: CCDS14800

Canonical transcript exons

ENST00000331070 — 9 exons

Exon	Start	End
ENSE00001543555	23005144	23005465
ENSE00001626256	22987757	22987893
ENSE00001669186	22984569	22984691
ENSE00001730185	22984263	22984293
ENSE00001792376	22994481	22994598
ENSE00003473409	22998250	22998374
ENSE00003542244	22992303	22992421
ENSE00003677192	22997452	22997557
ENSE00003784145	23004925	23005049

Expression profiles

Bgee: expression breadth broad, 17 present calls, max score 46.43.

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left testis	UBERON:0004533	46.43	gold quality
testis	UBERON:0000473	46.10	gold quality
right testis	UBERON:0004534	44.40	gold quality
colonic epithelium	UBERON:0000397	37.20	gold quality
metanephros cortex	UBERON:0010533	36.97	silver quality
ventricular zone	UBERON:0003053	36.48	gold quality
cortical plate	UBERON:0005343	36.47	gold quality
bone marrow cell	CL:0002092	36.16	gold quality
gall bladder	UBERON:0002110	36.10	gold quality
ganglionic eminence	UBERON:0004023	35.49	gold quality
cortex of kidney	UBERON:0001225	34.56	silver quality
right lobe of liver	UBERON:0001114	33.80	silver quality
skeletal muscle tissue	UBERON:0001134	33.38	gold quality
kidney	UBERON:0002113	32.47	gold quality
hindlimb stylopod muscle	UBERON:0004252	32.15	gold quality
bone marrow	UBERON:0002371	31.74	gold quality
adult mammalian kidney	UBERON:0000082	31.35	gold quality
muscle tissue	UBERON:0002385	31.06	gold quality
sural nerve	UBERON:0015488	30.93	gold quality
stromal cell of endometrium	CL:0002255	29.87	gold quality
islet of Langerhans	UBERON:0000006	29.39	gold quality
prefrontal cortex	UBERON:0000451	29.04	gold quality
skin of abdomen	UBERON:0001416	28.66	gold quality
muscle of leg	UBERON:0001383	28.23	gold quality
duodenum	UBERON:0002114	28.14	gold quality
monocyte	CL:0000576	27.67	gold quality
leukocyte	CL:0000738	27.67	gold quality
gastrocnemius	UBERON:0001388	27.63	gold quality
lymph node	UBERON:0000029	27.57	gold quality
zone of skin	UBERON:0000014	27.45	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

33 targeting BPY2, 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-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-4495	99.82	72.08	3080
HSA-MIR-204-5P	99.79	71.62	2439
HSA-MIR-211-5P	99.79	71.65	2440
HSA-MIR-623	99.76	68.16	1170
HSA-MIR-4446-5P	99.72	69.19	2544
HSA-MIR-4755-5P	99.71	70.34	2716
HSA-MIR-5006-3P	99.71	70.26	2728
HSA-MIR-6126	99.62	68.09	996
HSA-MIR-7159-3P	99.51	70.17	1920
HSA-MIR-657	99.48	66.02	848
HSA-MIR-508-5P	99.41	64.25	1248
HSA-MIR-1276	99.36	68.18	1642
HSA-MIR-4311	99.31	70.47	3041
HSA-MIR-6780B-3P	99.13	67.18	622
HSA-MIR-589-5P	98.72	66.96	927
HSA-MIR-583	98.71	67.44	1791
HSA-MIR-26B-3P	98.71	67.49	1102
HSA-MIR-5011-3P	98.63	64.81	638
HSA-MIR-6776-5P	98.54	67.43	1304
HSA-MIR-6516-5P	98.42	70.19	1551
HSA-MIR-5589-5P	98.34	64.82	1148
HSA-MIR-3130-5P	98.14	66.00	711
HSA-MIR-4482-5P	97.53	65.68	598
HSA-MIR-663B	97.40	62.91	664

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 3)

• VCY2 protein interacts with the HECT domain of ubiquitin-protein ligase E3A (PMID:12207887)
• VCY2 was weakly expressed at the spermatogonia and immunonegative in spermatocytes and round spermatids in testicular biopsy specimens with maturation arrest or hypospermatogenesis. (PMID:12724276)
• genetic association study in Chinese population: Data suggest that combined patterns of copy number abnormality in BPY2 (basic charge Y-linked protein 2) and/or DAZ1 (deleted in azoospermia 1) are associated with spermatogenic impairment/azoospermia. (PMID:24935076)

Cross-species orthologs

0 orthologs

Paralogs (2): BPY2B (ENSG00000183795), BPY2C (ENSG00000185894)

Protein

Protein identifiers

Testis-specific basic protein Y 2 — O14599 (reviewed: O14599)

Alternative names: Basic charge, Y-linked 2, Variably charged protein Y 2

All UniProt accessions (2): O14599, R4GMN0

UniProt curated annotations — full annotation on UniProt →

Subunit / interactions. Interacts with MAP1S. Interacts with UBE3A (via HECT domain).

Tissue specificity. Expressed exclusively in testis. Expressed in ejaculated spermatozoa of germ cell. Expressed in the nuclei of spermatogonia, spermatocytes, and round spermatids, except elongated spermatids (at protein level).

Similarity. Belongs to the VCX/VCY family.

RefSeq proteins (1): NP_004669* (*=MANE)

Domains & families (InterPro)

UniProt features (2 total): chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O14599-F1	41.56	0.00

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 42 (showing top): GOBP_SINGLE_FERTILIZATION, GOBP_MALE_GAMETE_GENERATION, PUJANA_CHEK2_PCC_NETWORK, GOBP_DEVELOPMENTAL_PROCESS_INVOLVED_IN_REPRODUCTION, GOBP_FERTILIZATION, SHEN_SMARCA2_TARGETS_DN, chrYq11, MIR4311, MIR7159_3P, MIR1276, MIR583, MIR6776_5P, MIR7855_5P, MIR5589_5P, MIR6780B_3P

GO Biological Process (2): spermatogenesis (GO:0007283), single fertilization (GO:0007338)

GO Molecular Function (2): HECT domain binding (GO:0032399), protein binding (GO:0005515)

GO Cellular Component (1): nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
developmental process involved in reproduction	1
male gamete generation	1
fertilization	1
protein domain specific binding	1
binding	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

208 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
BPY2	CDY1	Q9Y6F8	964
BPY2	CDY2A	Q9Y6F7	948
BPY2	VCY	O14598	946
BPY2	PRY	O14603	932
BPY2	DAZ1	Q9NQZ3	930
BPY2	DAZ2	Q13117	892
BPY2	RBMY1A1	P0DJD3	855
BPY2	UBE3A	P78355	849
BPY2	E7ERQ6	E7ERQ6	842
BPY2	USP9Y	O00507	821
BPY2	RBMY1D	P0C7P1	800
BPY2	DDX3Y	O15523	799
BPY2	HSFY1	Q96LI6	762
BPY2	UTY	O14607	731
BPY2	TSPY1	P09002	696

IntAct

5 interactions, top by confidence:

A	B	Type	Score
BPY2C	MAP1S	psi-mi:“MI:0915”(physical association)	0.580
MAP1S	BPY2C	psi-mi:“MI:0915”(physical association)	0.580
MAP1S	BPY2C	psi-mi:“MI:0407”(direct interaction)	0.580
BPY2C	PPIA	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (5): UBE3A (Two-hybrid), MAP1S (Two-hybrid), MAP1S (Reconstituted Complex), PPIA (Proximity Label-MS), UBE3A (Affinity Capture-Western)

ESM2 similar proteins: A0A023PXH2, A8MS09, B0L3A2, B6HUQ5, G2TRK6, G2TRL6, G2TRL8, G3V211, O13536, O14599, O30141, P03935, P05678, P0CE96, P0CE97, P0CE98, P19282, P38296, P38476, P39725, P40211, P53132, P53175, P53229, P53342, P75202, P92561, Q02918, Q03864, Q04434, Q07746, Q0Q027, Q10300, Q12174, Q12225, Q12327, Q3E7B9, Q54UZ5, Q65962, Q6B108

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	29
Likely pathogenic	3
Uncertain significance	12
Likely benign	8
Benign	1

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
144388	GRCh38/hg38 Yq11.221-12(chrY:14076802-57165209)x0	Pathogenic
145972	GRCh38/hg38 Yq11.223-11.23(chrY:21927773-26133012)x0	Pathogenic
145999	GRCh38/hg38 Yq11.221-12(chrY:12965721-57212647)x0	Pathogenic
146480	GRCh37/hg19 Yq11.221-12(chrY:16183453-59011762)x2	Pathogenic
146481	GRCh38/hg38 Yq11.222-12(chrY:18664321-26637948)x2	Pathogenic
146622	GRCh38/hg38 Yq11.221-12(chrY:15631816-57211010)x0	Pathogenic
148482	GRCh38/hg38 Yq11.222-12(chrY:18545732-57189762)x0	Pathogenic
149937	GRCh38/hg38 Yq11.221-12(chrY:14062885-57189762)x0	Pathogenic
151214	GRCh38/hg38 Yq11.221-12(chrY:16311571-57190586)x0	Pathogenic
153414	GRCh38/hg38 Yq11.21-12(chrY:10624004-57190586)x0	Pathogenic
154030	GRCh38/hg38 Yq11.221-12(chrY:12702930-26653790)x1	Pathogenic
1676303	GRCh37/hg19 Yq11.21-11.23(chrY:13905421-28799654)	Pathogenic
253557	GRCh37/hg19 Yq11.221-12(chrY:16188682-59349649)x0	Pathogenic
2685222	GRCh37/hg19 Yq11.221-11.23(chrY:18921311-28799937)x0	Pathogenic
3148874	GRCh37/hg19 Yq11.222-11.23(chrY:21035824-28799654)x0	Pathogenic
3148951	GRCh37/hg19 Yq11.223-11.23(chrY:24820716-28420380)x0	Pathogenic
32810	GRCh38/hg38 Yq11.222-12(chrY:18891467-57208726)x0	Pathogenic
394909	GRCh37/hg19 Yq11.221-12(chrY:15415024-59349591)x0	Pathogenic
395225	GRCh37/hg19 Yq11.222-12(chrY:20805226-59336998)x0	Pathogenic
441997	GRCh37/hg19 Yq11.21-12(chrY:13871147-59336737)x0	Pathogenic
443098	GRCh37/hg19 Yq11.223-12(chrY:24073794-59336737)x0	Pathogenic
4796054	GRCh38/hg38 Yq11.222-11.23(chrY:17504022-24095153)x0	Pathogenic
4796071	GRCh38/hg38 Yq11.222-12(chrY:18457002-26653507)x0	Pathogenic
564970	GRCh37/hg19 Yq11.21-12(chrY:13410538-59032808)x0	Pathogenic
57175	GRCh37/hg19 Yq11.21-12(chrY:14698756-59031480)x0	Pathogenic
685271	GRCh37/hg19 Yq11.222-12(chrY:21035530-59336737)x0	Pathogenic
686298	GRCh37/hg19 Yq11.222-11.23(chrY:21039792-28799937)x0	Pathogenic
686904	GRCh37/hg19 Yq11.221-12(chrY:15190336-59343488)x0	Pathogenic
687368	GRCh37/hg19 Yq11.221-12(chrY:16053146-59343488)x2	Pathogenic
155354	GRCh38/hg38 Yq11.21-12(chrY:11680193-26653790)x4	Likely pathogenic

SpliceAI

1434 predictions. Top by Δscore:

Variant	Effect	Δscore
Y:22997450:A:AG	acceptor_gain	1.0000
Y:22997450:AGT:A	acceptor_gain	1.0000
Y:22997450:AGTG:A	acceptor_gain	1.0000
Y:22997450:AGTGG:A	acceptor_gain	1.0000
Y:22997451:G:GG	acceptor_gain	1.0000
Y:22997451:GT:G	acceptor_gain	1.0000
Y:22997451:GTG:G	acceptor_gain	1.0000
Y:22997451:GTGG:G	acceptor_gain	1.0000
Y:22997451:GTGGG:G	acceptor_gain	1.0000
Y:22987748:T:A	acceptor_gain	0.9900
Y:22987752:A:AG	acceptor_gain	0.9900
Y:22987755:A:AG	acceptor_gain	0.9900
Y:22987756:G:GG	acceptor_gain	0.9900
Y:22988641:A:AG	donor_gain	0.9900
Y:22997448:ATAGT:A	acceptor_gain	0.9900
Y:22997554:CGAGG:C	donor_loss	0.9900
Y:22997555:GAGG:G	donor_loss	0.9900
Y:22997559:TGA:T	donor_loss	0.9900
Y:22997560:G:GT	donor_loss	0.9900
Y:22987749:G:A	acceptor_gain	0.9800
Y:22987756:GT:G	acceptor_gain	0.9800
Y:22997446:CCATA:C	acceptor_loss	0.9800
Y:22997447:CATA:C	acceptor_loss	0.9800
Y:22997448:ATAG:A	acceptor_loss	0.9800
Y:22997449:TA:T	acceptor_loss	0.9800
Y:22997450:A:AC	acceptor_loss	0.9800
Y:22998372:GAT:G	donor_gain	0.9800
Y:22998375:G:GG	donor_gain	0.9800
Y:23003964:C:G	donor_gain	0.9700
Y:22984289:ATATG:A	donor_gain	0.9600

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 66 via entrez): RS1556272623 (Y:22987519 G>GC), RS1556272634 (Y:22995989 A>T), RS1556272644 (Y:22998305 T>C), RS1556272658 (Y:23000982 A>T), RS1603597757 (Y:22986560 C>G), RS1603597758 (Y:22991469 T>A), RS1603597759 (Y:22991776 C>T), RS1603597760 (Y:22991809 G>A), RS1603597761 (Y:22998503 G>T), RS1603597762 (Y:22998505 T>A), RS1603597763 (Y:22998521 T>C), RS1603597764 (Y:22998538 G>T), RS1603597765 (Y:22998540 T>C), RS1603597766 (Y:22998555 G>A), RS1603597767 (Y:22998572 T>G)

Disease associations

OMIM: gene MIM:400013 | disease phenotypes:

GenCC curated gene-disease

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

Orphanet (0):

HPO phenotypes

4 total (4 of 4 shown, HPO-id order):

HPO	Term
HP:0000027	Azoospermia
HP:0001450	Y-linked inheritance
HP:0003251	Male infertility
HP:0011462	Young adult onset

GWAS associations

0 associations (top):

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

3 total (human), top 3 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
CGP 52608	affects binding, increases reaction	1
Isotretinoin	decreases expression	1
Aflatoxin B1	increases methylation	1

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