PRM2

Summary

PRM2 (protamine 2, HGNC:9448) is a protein-coding gene on chromosome 16p13.13, encoding Protamine-2 (P04554). Protamines substitute for histones in the chromatin of sperm during the haploid phase of spermatogenesis.

Protamines substitute for histones in the chromatin of sperm during the haploid phase of spermatogenesis, and are the major DNA-binding proteins in the nucleus of sperm in many vertebrates. They package the sperm DNA into a highly condensed complex in a volume less than 5% of a somatic cell nucleus. Many mammalian species have only one protamine (protamine 1); however, a few species, including human and mouse, have two. This gene encodes protamine 2, which is cleaved to give rise to a family of protamine 2 peptides. Alternatively spliced transcript variants have also been found for this gene.

Source: NCBI Gene 5620 — RefSeq curated summary.

At a glance

• GWAS associations: 11
• Clinical variants (ClinVar): 38 total
• MANE Select transcript: NM_002762

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9448
Approved symbol	PRM2
Name	protamine 2
Location	16p13.13
Locus type	gene with protein product
Status	Approved
Aliases	CT94.2
Ensembl gene	ENSG00000122304
Ensembl biotype	protein_coding
OMIM	182890
Entrez	5620

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000241808, ENST00000435245

RefSeq mRNA: 5 — MANE Select: NM_002762 NM_001286356, NM_001286357, NM_001286358, NM_001286359, NM_002762

CCDS: CCDS42118, CCDS66944

Canonical transcript exons

ENST00000241808 — 2 exons

Exon	Start	End
ENSE00000829662	11275639	11275937
ENSE00003904001	11276100	11276480

Expression profiles

Bgee: expression breadth ubiquitous, 140 present calls, max score 99.92.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 21.5862 / max 19910.4401, expressed in 13 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
156250	21.5146	13
156248	0.0471	3
156249	0.0134	2
156247	0.0111	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right testis	UBERON:0004534	99.92	gold quality
adult organism	UBERON:0007023	99.79	gold quality
male germ cell	CL:0000015	99.42	gold quality
left testis	UBERON:0004533	99.41	gold quality
sperm	CL:0000019	99.40	gold quality
testis	UBERON:0000473	96.60	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	94.66	gold quality
metanephros cortex	UBERON:0010533	78.10	gold quality
caput epididymis	UBERON:0004358	77.00	gold quality
right coronary artery	UBERON:0001625	76.37	gold quality
cauda epididymis	UBERON:0004360	74.70	gold quality
ectocervix	UBERON:0012249	72.01	gold quality
right uterine tube	UBERON:0001302	70.63	gold quality
endocervix	UBERON:0000458	70.26	gold quality
corpus epididymis	UBERON:0004359	68.81	gold quality
right lobe of liver	UBERON:0001114	67.55	gold quality
right lung	UBERON:0002167	67.40	gold quality
adenohypophysis	UBERON:0002196	66.02	gold quality
right ovary	UBERON:0002118	62.05	gold quality
metanephros	UBERON:0000081	61.71	gold quality
right hemisphere of cerebellum	UBERON:0014890	61.28	gold quality
left adrenal gland	UBERON:0001234	61.14	gold quality
mucosa of transverse colon	UBERON:0004991	61.10	gold quality
body of stomach	UBERON:0001161	61.07	gold quality
coronary artery	UBERON:0001621	60.93	gold quality
left coronary artery	UBERON:0001626	60.83	gold quality
body of pancreas	UBERON:0001150	60.82	gold quality
right adrenal gland	UBERON:0001233	60.63	gold quality
lower esophagus mucosa	UBERON:0035834	59.76	gold quality
lower esophagus	UBERON:0013473	59.58	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-GEOD-134144	yes	121072.70
E-GEOD-124263	yes	56280.72
E-HCAD-38	yes	46998.09
E-ANND-3	no	0.46

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): DMRT3, NR6A1

miRNA regulators (miRDB)

9 targeting PRM2, 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-6721-5P	99.93	68.92	2981
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-3164	99.02	68.39	1071
HSA-MIR-6820-3P	99.02	68.50	1035
HSA-MIR-6846-5P	98.81	65.86	1121
HSA-MIR-6848-5P	98.81	65.49	1126
HSA-MIR-4518	98.12	66.82	1030
HSA-MIR-4736	97.96	65.89	1287
HSA-MIR-1266-5P	97.71	66.92	1052

Literature-anchored findings (GeneRIF, showing 32)

• analyse the presence of DAZ, RBMY1, USP9Y, protamine-2, SRY and actin messenger RNA (mRNA) in testicular cells of men suffering from idiopathic azoospermia. (PMID:11869379)
• significantly enhanced evolutionary rates in the hominid lineage (PMID:12524352)
• single nucleotide polymorphisms in this gene in fertile and infertile males (PMID:12569175)
• Altered protamine P1/P2 ratio effects fertilization rate and embryo quality which subsequently may affect implantation and pregnancy outcome. (PMID:15670415)
• levels of pre-P2 may provide clues into pathogenesis of infertility. increased proportion of pre-P2 in some men with increased P1/P2 ratio suggests involvement of pre-P2 processing & link between deficient protamine processing & decreased DNA integrity. (PMID:16632464)
• A number of SNPs are present in the testis-specific nuclear protein genes. (PMID:16989827)
• The P1/P2 ratio has a significant relationship to sperm fertilization ability. (PMID:17011555)
• Novel polycythemia vera (PV)-associated tumor antigen PV13 (protamine 2) elicits IgG antibody reactions in a subset of PV patients but not in healthy donors, suggesting that it is an authentic tumor antigens. (PMID:17113348)
• The PRM2 contributes not only to successful fertilization, but may has an important impact in development of preimplantation embryos. (PMID:18292840)
• A reduction in contents of PRM2 transcript in spermatozoa may be linked with asthenozoospermia. (PMID:18292846)
• Decreased pre-P2/P2 and P1/P2 ratios are related to a poor pregnancy outcome, but not with the proportion of embryos obtained after assisted reproduction. (PMID:18314125)
• Histones localized to the posterior ring region (i.e. the sperm nuclear annulus), whereas PRM1 and PRM2 appeared to be dispersed throughout the entire nucleus. (PMID:18478156)
• The CCNA1, CCNB1, CCNB2, PRM1, and PRM2 messenger RNA transcript ratios were significantly decreased in patients with spermatogenic disorders. Transcript ratios in patients with successful sperm retrieval were higher than with failed sperm retrieval. (PMID:18692784)
• Mutations in the protamine locus may be an infrequent cause of male infertility. (PMID:19602509)
• identified and we report for the first time five novel rare haplotypes encompassing the protamine 1 and 2 genes (PMID:21029114)
• Data suggest that Casp4, Casp 6 and TNFSF10 are differentially expressed in potentially fertile and subfertile men and represent useful biomarkers for predicting male fertility in combination with P1 and P2. (PMID:21317160)
• Single nuclotide polymorphisms in PRM2 gene is associated with male infertility. (PMID:22104739)
• significant correlation has been found between protamine 1 and 2 transcripts/proteins and: sperm concentration, progressive sperm motility, sperm fertilization ability as well as embryo quality (PMID:22472940)
• Data indicate changed ecpression levels of PRM2, HSP90 and WNT5A in male of couples experiencing idiopathic recurrent miscarriages. (PMID:23271023)
• the quantity of PRM1, PRM2, and TNP2 transcripts and the PRM1/PRM2 mRNA ratio affect spermiogenesis, sperm morphology (PMID:25536093)
• The expressed human protamine2 in two fast-growing cell systems, E. coli and HeLa cells. The protamine2 expression significantly attenuated cell proliferation when compared with control cells. (PMID:25649960)
• PRM2 gene expression was significantly decreased in immature sperm extracted from the fertile and infertile groups. Caspase 9 activity was significantly increased in immature sperm extracted from both groups. (PMID:26392304)
• Bacterial infections have significant negative effects on sperm chromatin condensation and protamine P1/P2 ratio. (PMID:28736810)
• Protamine-1 and protamine-2 mRNA levels as well as the protamine mRNA ratio and all routine semen parameters revealed significant differences between recurrent miscarriage couples and healthy volunteers. Values of protamine-1 and protamine-2 mRNAs were significantly higher and the protamine mRNA ratio was significantly lower in couples with recurrent miscarriage. (PMID:28854581)
• Authors examined, for the first time in a Turkish population, the association between protamine gene alleles (PRM1 c.-190C>A, PRM1 c.197G>T, and PRM2 c.248C>T), and YBX2 (c.187T>C and c.1095 + 16A>G) and male infertility. (PMID:29227750)
• Polymorphisms of sperm protamine genes and CMA3 staining in infertile men with varicocele. (PMID:30482464)
• Correlation Between Protamine-2 and miRNA-122 in Sperm from Heroin-addicted Men: A Case-Control Study. (PMID:32748386)
• Evaluation of the association between polymorphisms of PRM1 and PRM2 and the risk of male infertility: a systematic review, meta-analysis, and meta-regression. (PMID:33057064)
• Protamine 1/Protamine 2 mRNA ratio in nonobstructive azoospermic patients. (PMID:33427330)
• Tobacco smoking and its impact on the expression level of sperm nuclear protein genes: H2BFWT, TNP1, TNP2, PRM1 and PRM2. (PMID:33440036)
• Spermatozoa retrieval in azoospermia and expression profile of JMJD1A, TNP2, and PRM2 in a subset of the Karachi population. (PMID:34235877)
• Impact of tobacco smoking in association with H2BFWT, PRM1 and PRM2 genes variants on male infertility. (PMID:36217675)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Prm2	ENSMUSG00000038015
rattus_norvegicus	Prm2	ENSRNOG00000002539

Protein

Protein identifiers

Protamine-2 — P04554 (reviewed: P04554)

Alternative names: Sperm histone P2, Sperm protamine P2

All UniProt accessions (2): P04554, Q1LZN1

UniProt curated annotations — full annotation on UniProt →

Function. Protamines substitute for histones in the chromatin of sperm during the haploid phase of spermatogenesis. They compact sperm DNA into a highly condensed, stable and inactive complex.

Subunit / interactions. Interacts with TDRP.

Subcellular location. Nucleus. Chromosome.

Tissue specificity. Testis.

Post-translational modifications. Proteolytic processing into mature chains is required for histone eviction during spermatogenesis. Transition proteins (TNP1 and TNP2) are required for processing.

Similarity. Belongs to the protamine P2 family.

Isoforms (2)

UniProt ID	Names	Canonical?
P04554-1	1	yes
P04554-2	2

RefSeq proteins (5): NP_001273285, NP_001273286, NP_001273287, NP_001273288, NP_002753* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000492	PRM2	Family

Pfam: PF00841

UniProt features (18 total): chain 7, compositionally biased region 3, modified residue 3, sequence conflict 2, initiator methionine 1, splice variant 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P04554-F1	54.02	0.00

Functional residue map

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

Post-translational modifications (3): 8, 10, 37

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9821993	Replacement of protamines by nucleosomes in the male pronucleus

MSigDB gene sets: 63 (showing top): RNGTGGGC_UNKNOWN, GOBP_CHROMOSOME_ORGANIZATION, GOBP_MALE_GAMETE_GENERATION, GGGTGGRR_PAX4_03, GOBP_CHROMOSOME_CONDENSATION, GOBP_NUCLEUS_ORGANIZATION, GOBP_CELLULAR_PROCESS_INVOLVED_IN_REPRODUCTION_IN_MULTICELLULAR_ORGANISM, GNF2_CCNA1, MORF_EPHA7, GOBP_DEVELOPMENTAL_PROCESS_INVOLVED_IN_REPRODUCTION, MORF_WNT1, MORF_IL9, GOCC_PROTEIN_DNA_COMPLEX, MORF_FRK, MATZUK_SPERMATID_DIFFERENTIATION

GO Biological Process (6): nucleus organization (GO:0006997), spermatogenesis (GO:0007283), spermatid development (GO:0007286), chromosome condensation (GO:0030261), chromosome organization (GO:0051276), cell differentiation (GO:0030154)

GO Molecular Function (4): DNA binding (GO:0003677), zinc ion binding (GO:0008270), cadmium ion binding (GO:0046870), protein binding (GO:0005515)

GO Cellular Component (5): nucleosome (GO:0000786), male germ cell nucleus (GO:0001673), nucleus (GO:0005634), nucleoplasm (GO:0005654), chromosome (GO:0005694)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Maternal to zygotic transition (MZT)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
organelle organization	2
transition metal ion binding	2
developmental process involved in reproduction	1
male gamete generation	1
germ cell development	1
spermatid differentiation	1
chromosome organization	1
cellular developmental process	1
nucleic acid binding	1
binding	1
chromatin	1
protein-DNA complex	1
germ cell nucleus	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cellular anatomical structure	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

1122 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PRM2	PRM1	P04553	980
PRM2	TNP2	Q05952	980
PRM2	TNP1	P09430	958
PRM2	KLHL10	Q6JEL2	856
PRM2	PRM3	Q9NNZ6	815
PRM2	KDM3A	Q9Y4C1	695
PRM2	SPEM1	Q8N4L4	665
PRM2	CLU	P10909	658
PRM2	SEMG1	P04279	623
PRM2	SYCP3	Q8IZU3	618
PRM2	ODF1	Q14990	601
PRM2	TGM4	P49221	597
PRM2	AKAP4	Q5JQC9	586
PRM2	ADAM2	P78326	580
PRM2	H1-7	Q75WM6	571

IntAct

13 interactions, top by confidence:

A	B	Type	Score
PRM2	KRTAP10-7	psi-mi:“MI:0915”(physical association)	0.560
PRM2	SDCBP2	psi-mi:“MI:0915”(physical association)	0.560
PRM2	KRTAP17-1	psi-mi:“MI:0915”(physical association)	0.560
SEPTIN12	PRM2	psi-mi:“MI:0915”(physical association)	0.370
TFAP2C	PRM2	psi-mi:“MI:0915”(physical association)	0.370
PRM2	IPO5	psi-mi:“MI:0914”(association)	0.350
PRM2	KRTAP10-7	psi-mi:“MI:0915”(physical association)	0.000
PRM2	SDCBP2	psi-mi:“MI:0915”(physical association)	0.000
PRM2	KRTAP17-1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (39): KRTAP10-7 (Two-hybrid), KRTAP10-1 (Two-hybrid), SDCBP2 (Two-hybrid), KRTAP17-1 (Two-hybrid), KRTAP10-7 (Two-hybrid), LSM14B (Affinity Capture-MS), NLE1 (Affinity Capture-MS), CHCHD2 (Affinity Capture-MS), FAF1 (Affinity Capture-MS), PSME3 (Affinity Capture-MS), ZNF444 (Affinity Capture-MS), ZNF496 (Affinity Capture-MS), TSR1 (Affinity Capture-MS), PRRC2A (Affinity Capture-MS), EIF2B1 (Affinity Capture-MS)

ESM2 similar proteins: A0A455ZAR2, A0A7M4DUE8, A6YR34, C0HJY4, C0HJZ0, C0HLB8, D6C4J2, F5HAE6, F7VJQ2, F7VJQ3, O59297, P01069, P01154, P01370, P01540, P04554, P05834, P07978, P0C195, P0C1D0, P0C8X7, P0CI18, P0CV88, P0DJB5, P0DL31, P0DRG7, P0DUC6, P0DUC7, P11760, P14589, P16844, P19564, P19757, P20530, P21959, P23252, P26377, P35312, P35313, P35314

Diamond homologs: P04554, P07978, P35297, P35298, P35299, P35300, P35301, P35312, P35313, P35314, P61253, Q28337, Q91VB3, Q91VE1, Q9GKM0, Q9GKM1, P11248, P19757, P19782

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	27
Likely benign	4
Benign	7

Top pathogenic / likely-pathogenic (0)

SpliceAI

107 predictions. Top by Δscore:

Variant	Effect	Δscore
16:11276112:T:TA	donor_gain	0.9800
16:11276042:C:CA	donor_gain	0.9400
16:11276045:T:TA	donor_gain	0.9400
16:11276051:G:A	donor_gain	0.9400
16:11276109:G:A	donor_gain	0.9200
16:11276121:G:A	donor_gain	0.9200
16:11276101:T:TA	donor_gain	0.9100
16:11276099:CCT:C	donor_gain	0.8600
16:11275936:GCC:G	acceptor_gain	0.8400
16:11276115:T:TA	donor_gain	0.8300
16:11275935:AGCCT:A	acceptor_gain	0.8200
16:11275937:CCTTT:C	acceptor_gain	0.8200
16:11275936:GCCTT:G	acceptor_loss	0.8000
16:11275938:C:CG	acceptor_loss	0.8000
16:11275938:C:CC	acceptor_gain	0.7900
16:11275939:T:C	acceptor_gain	0.7900
16:11276095:CAGA:C	donor_loss	0.7800
16:11276096:AGACC:A	donor_loss	0.7800
16:11276097:GA:G	donor_loss	0.7800
16:11276098:A:AG	donor_loss	0.7800
16:11276099:CCTCT:C	donor_loss	0.7800
16:11276100:C:G	donor_loss	0.7700
16:11275936:GC:G	acceptor_gain	0.7600
16:11275938:CTTTT:C	acceptor_gain	0.7500
16:11275941:T:TC	acceptor_gain	0.7500
16:11275938:C:T	acceptor_gain	0.7400
16:11276094:GCAGA:G	donor_loss	0.7400
16:11276238:CGTAG:C	donor_gain	0.7300
16:11275934:CAGC:C	acceptor_gain	0.7200
16:11275933:GCAGC:G	acceptor_gain	0.7100

AlphaMissense

665 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:11276347:G:C	S8R	0.886
16:11276347:G:T	S8R	0.886
16:11276349:T:G	S8R	0.886
16:11276341:G:C	S10R	0.852
16:11276341:G:T	S10R	0.852
16:11276343:T:G	S10R	0.852
16:11276185:C:A	R62S	0.781
16:11276185:C:G	R62S	0.781
16:11276366:A:T	V2D	0.768
16:11276195:G:A	S59F	0.715
16:11276342:C:A	S10I	0.713
16:11276350:C:A	R7S	0.710
16:11276350:C:G	R7S	0.710
16:11276203:T:A	R56S	0.695
16:11276203:T:G	R56S	0.695
16:11276188:C:A	R61S	0.676
16:11276188:C:G	R61S	0.676
16:11276351:C:A	R7M	0.673
16:11276366:A:G	V2A	0.672
16:11276143:C:A	R76S	0.657
16:11276143:C:G	R76S	0.657
16:11276113:C:A	R86S	0.652
16:11276113:C:G	R86S	0.652
16:11275930:T:A	R93S	0.637
16:11275930:T:G	R93S	0.637
16:11276144:C:A	R76M	0.636
16:11276186:C:A	R62M	0.631
16:11276195:G:T	S59Y	0.631
16:11276210:C:A	R54M	0.625
16:11275918:T:A	R97S	0.623

dbSNP variants (sampled 300 via entrez): RS1002888637 (16:11276550 A>C), RS1005852820 (16:11276618 C>A,G), RS1005974861 (16:11275912 G>A,C,T), RS1006171222 (16:11277780 C>T), RS1007372866 (16:11277063 A>G), RS1008091811 (16:11278344 A>C), RS1008122733 (16:11278184 C>T), RS1008628003 (16:11276180 T>C,G), RS1010755441 (16:11275142 A>G), RS1011464047 (16:11275330 A>G), RS1012422042 (16:11276150 C>T), RS1012757575 (16:11276955 C>A,G), RS1013667025 (16:11276699 A>G), RS1014007051 (16:11277701 G>A), RS1014091842 (16:11276396 G>A,T)

Disease associations

OMIM: gene MIM:182890 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST001341_12	Multiple sclerosis	6.000000e-07
GCST001958_14	Bulimia nervosa	2.000000e-06
GCST002793_5	Vein graft stenosis in coronary artery bypass grafting	7.000000e-06
GCST004131_115	Inflammatory bowel disease	1.000000e-06
GCST004132_39	Crohn’s disease	1.000000e-07
GCST005581_11	Primary biliary cirrhosis	7.000000e-15
GCST005581_12	Primary biliary cirrhosis	2.000000e-13
GCST005581_13	Primary biliary cirrhosis	3.000000e-08
GCST005581_35	Primary biliary cirrhosis	6.000000e-20
GCST005581_36	Primary biliary cirrhosis	2.000000e-23
GCST009798_15	Asthma	2.000000e-33

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007051	vein graft stenosis

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

8 total (human), top 8 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
butyraldehyde	increases expression	1
Resveratrol	decreases expression, affects cotreatment	1
Benzo(a)pyrene	increases methylation	1
Cadmium	increases abundance, increases expression	1
Carmustine	decreases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Valproic Acid	increases methylation	1
Cadmium Chloride	increases abundance, increases expression	1

Clinical trials (associated diseases)

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