PRDM9

Summary

PRDM9 (PR/SET domain 9, HGNC:13994) is a protein-coding gene on chromosome 5p14.2, encoding Histone-lysine N-methyltransferase PRDM9 (Q9NQV7). Histone methyltransferase that sequentially mono-, di-, and tri-methylates both ‘Lys-4’ (H3K4) and ‘Lys-36’ (H3K36) of histone H3 to produce respectively trimethylated ‘Lys-4’ (H3K4me3) and trimethylated ‘Lys-36’ (H3K36me3) histone H3 and plays a key role in meiotic prophase by….

The protein encoded by this gene is a zinc finger protein with histone methyltransferase activity that catalyzes histone H3 lysine 4 trimethylation (H3K4me3) during meiotic prophase. This protein contains multiple domains, including a Kruppel-associated box (KRAB) domain, an SSX repression domain (SSXRD), a PRD1-BF1 and RIZ homologous region, a subclass of SET (PR/SET) domain, and a tandem array of C2H2 zinc fingers. The zinc finger array recognizes a short sequence motif, leading to local H3K4me3, and meiotic recombination hotspot activity. The observed allelic variation alters the DNA-binding sequence specificity of the protein, resulting in distinct meiotic recombination hotspots amongst individuals and populations. Multiple alternate alleles of this gene have been described.

Source: NCBI Gene 56979 — RefSeq curated summary.

At a glance

• Gene–disease (curated): primary ovarian failure (Strong, GenCC)
• GWAS associations: 10
• Clinical variants (ClinVar): 178 total — 3 pathogenic
• Regional missense constraint (gnomAD): 1 of 5 regions constrained (≈2% of expected missense variation)
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.04 (unconstrained)
• MANE Select transcript: NM_020227

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13994
Approved symbol	PRDM9
Name	PR/SET domain 9
Location	5p14.2
Locus type	gene with protein product
Status	Approved
Aliases	PFM6, ZNF899, KMT8B, Meisetz
Ensembl gene	ENSG00000164256
Ensembl biotype	protein_coding
OMIM	609760
Entrez	56979

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

MANE Select: ENST00000296682

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1, TSL 4: 1, TSL 5: 1

ENST00000296682, ENST00000502755, ENST00000635252

RefSeq mRNA: 2 — MANE Select: NM_020227 NM_001376900, NM_020227

CCDS: CCDS43307

Canonical transcript exons

ENST00000296682 — 11 exons

Exon	Start	End
ENSE00001082836	23526233	23528093
ENSE00001082838	23524334	23524527
ENSE00001539964	23507609	23507712
ENSE00001600268	23522304	23522405
ENSE00001693488	23521023	23521179
ENSE00001694470	23509470	23509593
ENSE00001720652	23523291	23523358
ENSE00001742641	23517881	23517930
ENSE00001804383	23522614	23522885
ENSE00002713340	23508950	23509102
ENSE00003790838	23509920	23510027

Expression profiles

Bgee: expression breadth broad, 70 present calls, max score 80.01.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.2601 / max 66.0171, expressed in 63 samples.

Highest expression (Bgee): male germ line stem cell (sensu Vertebrata) in testis, diaphragm, primordial germ cell in gonad, buccal mucosa cell, superficial temporal artery.

Genetic regulation across tissues (GTEx eQTL / sQTL)

PRDM9 is not an eGene in any GTEx v10 tissue: no tissue shows a variant significantly associated with its expression or splicing (q < 0.05).

FANTOM5 promoters

1 alternative TSS:

Promoter ID	TPM avg	Samples expressed
55908	0.2601	63

Top tissues by expression

showing 100 of 220 tissues 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	80.01	gold quality
diaphragm	UBERON:0001103	75.48	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	73.51	gold quality
buccal mucosa cell	CL:0002336	69.29	silver quality
superficial temporal artery	UBERON:0001614	67.92	gold quality
upper arm skin	UBERON:0004263	67.06	gold quality
right testis	UBERON:0004534	66.76	gold quality
left testis	UBERON:0004533	65.57	gold quality
testis	UBERON:0000473	64.58	gold quality
sural nerve	UBERON:0015488	60.59	gold quality
trabecular bone tissue	UBERON:0002483	59.58	gold quality
mucosa of urinary bladder	UBERON:0001259	59.35	gold quality
gluteal muscle	UBERON:0002000	58.57	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	58.45	gold quality
jejunal mucosa	UBERON:0000399	57.58	gold quality
lower lobe of lung	UBERON:0008949	57.33	silver quality
corpus callosum	UBERON:0002336	57.07	gold quality
periodontal ligament	UBERON:0008266	56.62	gold quality
decidua	UBERON:0002450	56.55	gold quality
mucosa of sigmoid colon	UBERON:0004993	56.53	gold quality
vastus lateralis	UBERON:0001379	55.81	gold quality
oral cavity	UBERON:0000167	55.51	gold quality
quadriceps femoris	UBERON:0001377	55.50	gold quality
tibia	UBERON:0000979	54.77	gold quality
myocardium	UBERON:0002349	54.36	gold quality
mononuclear cell	CL:0000842	53.84	gold quality
colonic mucosa	UBERON:0000317	53.76	gold quality
monocyte	CL:0000576	53.69	gold quality
hair follicle	UBERON:0002073	53.39	gold quality
leukocyte	CL:0000738	52.59	gold quality
granulocyte	CL:0000094	51.76	gold quality
adrenal tissue	UBERON:0018303	51.26	gold quality
parietal pleura	UBERON:0002400	51.11	gold quality
pleura	UBERON:0000977	51.01	gold quality
visceral pleura	UBERON:0002401	50.70	gold quality
adult organism	UBERON:0007023	50.48	gold quality
jejunum	UBERON:0002115	49.69	gold quality
Brodmann (1909) area 46	UBERON:0006483	49.57	gold quality
blood vessel layer	UBERON:0004797	49.29	gold quality
cervix squamous epithelium	UBERON:0006922	49.20	gold quality
olfactory bulb	UBERON:0002264	48.92	gold quality
choroid plexus epithelium	UBERON:0003911	48.89	gold quality
epithelial cell of pancreas	CL:0000083	48.83	gold quality
type B pancreatic cell	CL:0000169	48.83	gold quality
cervix epithelium	UBERON:0004801	48.83	gold quality
cardiac muscle of right atrium	UBERON:0003379	48.55	gold quality
CA1 field of hippocampus	UBERON:0003881	48.50	gold quality
oviduct epithelium	UBERON:0004804	48.42	gold quality
left ventricle myocardium	UBERON:0006566	48.24	gold quality
orbitofrontal cortex	UBERON:0004167	48.20	gold quality
tongue squamous epithelium	UBERON:0006919	47.92	gold quality
nasal cavity epithelium	UBERON:0005384	47.70	gold quality
thymus	UBERON:0002370	47.42	gold quality
deltoid	UBERON:0001476	47.39	gold quality
kidney epithelium	UBERON:0004819	47.02	gold quality
triceps brachii	UBERON:0001509	47.01	gold quality
renal glomerulus	UBERON:0000074	46.99	gold quality
metanephric glomerulus	UBERON:0004736	46.96	gold quality
nephron tubule	UBERON:0001231	46.88	gold quality
pancreatic ductal cell	CL:0002079	46.32	silver quality
skeletal muscle tissue	UBERON:0001134	46.05	gold quality
bone marrow	UBERON:0002371	45.92	silver quality
layer of synovial tissue	UBERON:0007616	45.76	gold quality
muscle tissue	UBERON:0002385	45.61	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	45.35	gold quality
metanephros	UBERON:0000081	45.27	gold quality
inferior olivary complex	UBERON:0002127	45.14	gold quality
palpebral conjunctiva	UBERON:0001812	44.95	gold quality
calcaneal tendon	UBERON:0003701	44.23	gold quality
pharyngeal mucosa	UBERON:0000355	43.94	gold quality
duodenum	UBERON:0002114	43.90	gold quality
tibialis anterior	UBERON:0001385	43.43	silver quality
squamous epithelium	UBERON:0006914	43.42	gold quality
cortex of kidney	UBERON:0001225	43.33	silver quality
bronchus	UBERON:0002185	42.92	gold quality
epithelium of bronchus	UBERON:0002031	42.91	gold quality
gingiva	UBERON:0001828	42.90	gold quality
epithelium of esophagus	UBERON:0001976	42.87	gold quality
placenta	UBERON:0001987	42.68	silver quality
amniotic fluid	UBERON:0000173	42.67	gold quality
tendon	UBERON:0000043	42.60	silver quality
secondary oocyte	CL:0000655	42.57	gold quality
blood	UBERON:0000178	42.54	gold quality
medulla oblongata	UBERON:0001896	42.45	gold quality
kidney	UBERON:0002113	42.33	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	42.14	gold quality
substantia nigra pars compacta	UBERON:0001965	42.06	gold quality
embryo	UBERON:0000922	42.05	gold quality
cartilage tissue	UBERON:0002418	42.04	gold quality
biceps brachii	UBERON:0001507	41.74	gold quality
superior vestibular nucleus	UBERON:0007227	41.67	gold quality
epithelium of mammary gland	UBERON:0003244	41.66	gold quality
ventral tegmental area	UBERON:0002691	41.62	gold quality
trachea	UBERON:0003126	41.02	gold quality
mucosa of paranasal sinus	UBERON:0005030	40.98	gold quality
right uterine tube	UBERON:0001302	40.91	silver quality
Brodmann (1909) area 23	UBERON:0013554	40.74	gold quality
mammalian vulva	UBERON:0000997	40.61	gold quality
dorsal plus ventral thalamus	UBERON:0001897	40.56	gold quality
epithelium of nasopharynx	UBERON:0001951	40.45	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.93
E-GEOD-99795	no	7.51

HPA expression

RNA tissue specificity: Group enriched

24 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM
Testis	tissue	3.4
Choroid plexus	tissue	2.2
Medulla oblongata	tissue	2.0
Pons	tissue	1.9
Basal ganglia	tissue	1.8
Thalamus	tissue	1.8
Hypothalamus	tissue	1.8
Cerebellum	tissue	1.7
Cerebral cortex	tissue	1.6
Amygdala	tissue	1.6
Hippocampal formation	tissue	1.6
Epididymis	tissue	1.5
Nucleus accumbens	tissue	1.5
Midbrain	tissue	1.5
Putamen	tissue	1.4
Substantia nigra	tissue	1.3
Locus coeruleus	tissue	1.3
Spinal cord	tissue	1.3
Hippocampus	tissue	1.3
Retrosplenial cortex	tissue	1.2
Occipital cortex	tissue	1.2
Postcentral gyrus	tissue	0.9
Skin 1	tissue	0.2
Bone marrow	tissue	0.1

Brain sub-regions (HPA Brain Atlas): detected in 184; highest nTPM — Angular gyrus (white matter) (2.6), White matter (2.6), Corpus callosum, splenium (white matter) (2.5), Parieto-temporal junction (white matter) (2.5), Temporal white matter (2.5).

Regulation

Is transcription factor: yes

JASPAR motifs

Motif	Name	Family
MA1723.1	PRDM9	Factors with multiple dispersed zinc fingers
MA1723.2	PRDM9	Factors with multiple dispersed zinc fingers

JASPAR matrix evidence (PMIDs): PMID:29072575

miRNA regulators (miRDB)

Targeting PRDM9 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 44 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-329-3P	99.91	66.56	1234
HSA-MIR-362-3P	99.91	66.38	1267
HSA-MIR-3941	99.86	70.54	2735
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-4276	99.56	67.66	2514
HSA-MIR-143-3P	99.49	69.05	1457
HSA-MIR-4770	99.49	69.09	1451
HSA-MIR-3612	99.45	66.02	1333
HSA-MIR-650	99.45	65.77	1309
HSA-MIR-5695	99.41	67.48	1047
HSA-MIR-548B-3P	99.38	67.26	1000
HSA-MIR-4784	99.15	67.41	1733
HSA-MIR-3160-3P	99.07	64.78	955
HSA-MIR-511-5P	98.97	70.94	2268
HSA-MIR-3150B-3P	98.81	67.21	1728
HSA-MIR-2467-3P	98.65	67.18	1969
HSA-MIR-6830-3P	98.62	68.07	1760
HSA-MIR-603	98.58	68.28	1603
HSA-MIR-4768-3P	98.16	66.02	2330
HSA-MIR-6072	98.00	66.47	804
HSA-MIR-637	97.91	64.05	1517
HSA-MIR-4294	97.86	65.72	1110
HSA-MIR-3936	97.64	64.47	732

Functional genomics

gnomAD constraint: pLI 1.27e-13, LOEUF 1.04, missense Z 1.49 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000296682 splits into 5 regions with different missense tolerance; 1 is missense-constrained (≈2% of the expected missense variation). Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
5:23,509,034–23,526,865	662 / 711.9	0.93	no
5:23,526,866–23,526,991	27 / 50.0	0.54	no
5:23,526,992–23,527,033	0 / 19.0	0.00	yes (p 1.3e-05)
5:23,527,034–23,527,601	92 / 185.7	0.50	no
5:23,527,602–23,527,770	86 / 73.6	1.17	no

Literature-anchored findings (GeneRIF, showing 35)

• Evolutionary analysis suggests that human PRDM7 and PRDM9 genes, a pair of close paralogs corresponding to a single mouse gene Prdm9, were generated by a recent gene duplication event after the divergence of the ancestors of human and mouse. (PMID:18231586)
• Results show a possible association between PRDM9 and azoospermia by meiotic arrest. (PMID:18941885)
• Our results suggest that mutations in PRDM9 may cause idiopathic infertility in human males. (PMID:19168450)
• Human coding polymorphism and interspecies evolutionary changes in the PRDM9 gene, was analyzed. (PMID:20041164)
• sequence of exon 12 of PRDM9; human populations exhibit two predominant alleles and multiple minor alleles of Prdm9 (PMID:20044538)
• results provide a molecular basis for the distribution of meiotic recombination in mammals in which the binding of PRDM9 to specific DNA sequences targets the initiation of recombination at specific locations in the genome (PMID:20044539)
• findings implicate the PRDM9 gene in meiotic recombination; involvement of PRDM9, which causes histone H3 lysine 4 trimethylation, implies that there is a common mechanism for recombination hotspots in eukaryotes (PMID:20044541)
• PRDM9 variation strongly influences recombination hot-spot activity and meiotic instability. (PMID:20818382)
• Each African-enhanced hotspot is activated by a distinct spectrum of PRDM9 variants, despite the fact that all are predicted to bind the same motif. This differential activation points to complex interactions between the zinc-finger array and hotspots. (PMID:21750151)
• discussion of role of PRDM9 in meiotic recombination hotspots; consideration of the structure of the PRDM9 protein [REVIEW] (PMID:22162947)
• observed a increased frequency of PRDM9 variants in parents who transmitted de novo 7q11.23 deletions to their offspring. These data suggest that certain PRDM9 alleles may be associated with an increased susceptibility to recurrent 7q11.23 microdeletions (PMID:22643917)
• We identified PRDM9 as being associated with unusual recombination patterns and discovered a substantial excess of rare allelic forms of PRDM9 in two independent acute lymphoblastic leukemia cohorts. (PMID:23222848)
• Recombination regulator PRDM9 influences the instability of its own coding sequence in humans. (PMID:23267059)
• Overexpression of PRDM9 in HEK293 cells also resulted in a significant increase in trimethylated H3K36 and H3K4 further confirming our in vitro observations (PMID:24634223)
• Results confirm an association between rare variant PRDM9 alleic forms and childhood ALL (PMID:24754746)
• Alignment of Neandertal and Denisovan sequences suggests that PRDM9 in archaic hominins was closely related to present-day human alleles that are rare and specific to African populations. (PMID:25001002)
• This depletion of PRDM9 genomic targets is expected to decrease fitness, and thereby to favor new PRDM9 alleles binding different motifs (PMID:25393762)
• PRDM9 protein variants form functional heteromeric complexes which can bind hotspots sequences. When a heteromeric complex binds at a hotspot of one PRDM9 variant, the other PRDM9 variant, which would otherwise not bind, methylates hotspot nucleosomes (PMID:26368021)
• Allele C was found to bind a C-specific hot spot with higher affinity than allele A bound A-specific hot spots (PMID:26833727)
• subspecies-specific degradation of PRDM9 binding sites by meiotic drive, which steadily increases asymmetric PRDM9 binding, has impacts beyond simply changing hotspot positions, and strongly support a direct involvement in hybrid infertility (PMID:26840484)
• The article outlines the role of PRDM9 in fertility. (PMID:27045445)
• These results support the hypothesis that ow-copy repeats 22 variations influences 22q11.2 non-allelic homologous recombination events, however further studies are needed to confirm this association and clarify the contribution of pseudogenes and rare PDRM9 alleles to non-allelic homologous recombination susceptibility for DiGeorge/velocardiofacial syndrome. (PMID:28059126)
• The most common genetic variant of PRDM9 is allele A (PRDM9a) which contains 13 Cys2-His2 zinc fingers (ZF); the second-most common variant among African populations is allele C (PRDM9c), which contains 14 Cys2-His2 ZF. Data suggest that Ser764 in ZF9 allows PRDM9c to accommodate a variable base, whereas PRDM9a Arg764 recognizes a conserved guanine. (PMID:28801461)
• Finally, the authors demonstrate that, in addition to binding DNA, PRDM9’s zinc fingers also mediate its multimerization, and they show that a pair of highly diverged alleles preferentially form homo-multimers. (PMID:29072575)
• PRDM9 influences the possibility of genetic exchange by determining the locations of meiotic recombination hotspots in most mammals. (Review) (PMID:29366606)
• PRDM9 activity leads to the erosion of its own binding sites and the rapid evolution of its DNA-binding domain. PRDM9 may also contribute to reproductive isolation, as it is involved in hybrid sterility potentially due to a reduction of its activity in specific heterozygous contexts. [Review] (PMID:30161134)
• Recent findings have highlighted an unexpected molecular control of the distribution of meiotic double-strand breaks (DSBs) in mammals by a rapidly evolving gene in trans, PR-domain-containing 9 (PRDM9), and specific DNA sequence motifs in cis (PMID:30311566)
• PRDM9 expression in tumors is significantly higher than in healthy neighboring tissues. Aberrant expression of PRDM9 is associated with genomic instability in cancers. (PMID:30341163)
• ZCWPW1 is recruited to recombination hotspots by PRDM9 and is essential for meiotic double strand break repair. (PMID:32744506)
• Pathogenic variants of meiotic double strand break (DSB) formation genes PRDM9 and ANKRD31 in premature ovarian insufficiency. (PMID:34257419)
• The KRAB Domain of ZNF10 Guides the Identification of Specific Amino Acids That Transform the Ancestral KRAB-A-Related Domain Present in Human PRDM9 into a Canonical Modern KRAB-A Domain. (PMID:35162997)
• PRDM9 losses in vertebrates are coupled to those of paralogs ZCWPW1 and ZCWPW2. (PMID:35217607)
• Association of Single Nucleotide Polymorphisms in the PYGO2 and PRDM9 Genes with Idiopathic Azoospermia in Iranian Infertile Male Patients. (PMID:36688188)
• FBLN5 was Regulated by PRDM9, and Promoted Senescence and Osteogenic Differentiation of Human Periodontal Ligament Stem Cells. (PMID:37608663)
• Cancer Associated PRDM9: Implications for Linking Genomic Instability and Meiotic Recombination. (PMID:38003713)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Zfp78	ENSMUSG00000055150
rattus_norvegicus	Zfp78	ENSRNOG00000083797

Paralogs (62): ZNF582 (ENSG00000018869), ZNF264 (ENSG00000083844), ZNF343 (ENSG00000088876), ZNF684 (ENSG00000117010), ZNF133 (ENSG00000125846), ZNF557 (ENSG00000130544), ZNF337 (ENSG00000130684), ZNF20 (ENSG00000132010), ZFP37 (ENSG00000136866), ZNF614 (ENSG00000142556), KRABD4 (ENSG00000147121), ZNF599 (ENSG00000153896), ZNF19 (ENSG00000157429), ZNF589 (ENSG00000164048), ZNF180 (ENSG00000167384), ZNF558 (ENSG00000167785), ZNF35 (ENSG00000169981), ZNF778 (ENSG00000170100), ZNF439 (ENSG00000171291), ZNF440 (ENSG00000171295), ZNF556 (ENSG00000172000), ZNF554 (ENSG00000172006), ZNF596 (ENSG00000172748), ZNF80 (ENSG00000174255), ZNF266 (ENSG00000174652), ZNF25 (ENSG00000175395), ZNF77 (ENSG00000175691), ZNF169 (ENSG00000175787), ZNF404 (ENSG00000176222), ZNF491 (ENSG00000177599), ZNF620 (ENSG00000177842), ZNF619 (ENSG00000177873), ZNF875 (ENSG00000181666), ZNF329 (ENSG00000181894), ZFP90 (ENSG00000184939), ZNF566 (ENSG00000186017), ZNF529 (ENSG00000186020), ZNF749 (ENSG00000186230), ZNF555 (ENSG00000186300), ZNF70 (ENSG00000187792), ZFP69B (ENSG00000187801), ZFP69 (ENSG00000187815), ZNF669 (ENSG00000188295), ZNF559 (ENSG00000188321), ZNF177 (ENSG00000188629), ZNF124 (ENSG00000196418), ZNF846 (ENSG00000196605), ZNF705A (ENSG00000196946), ZNF763 (ENSG00000197054), ZNF560 (ENSG00000198028), ZNF248 (ENSG00000198105), ZNF69 (ENSG00000198429), ZNF805 (ENSG00000204524), ZNF425 (ENSG00000204947), ZNF891 (ENSG00000214029), ZNF705D (ENSG00000215343), ZNF705B (ENSG00000215356), ZNF705G (ENSG00000215372), ZNF487 (ENSG00000243660), ZNF674 (ENSG00000251192)

+2 more (showing top 60).

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:2384854) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 25 distinct phenotype terms.

Mouse phenotype (MP)	Records
male infertility	4
decreased testis weight	4
female infertility	3
azoospermia	3
arrest of male meiosis	3
abnormal chromosomal synapsis	3
small ovary	2
abnormal female meiosis	2
decreased oocyte number	2
abnormal ovarian folliculogenesis	1
small testis	1
reduced female fertility	1
abnormal gametogenesis	1
abnormal meiosis	1
abnormal spermiogenesis	1
abnormal germ cell morphology	1
abnormal seminiferous tubule morphology	1
absent ovarian follicles	1
decreased male germ cell number	1
abnormal DNA methylation during gametogenesis	1
abnormal chiasmata formation	1
abnormal female meiosis I arrest	1
abnormal double-strand DNA break repair	1
decreased elongated spermatid number	1
impaired double-strand DNA break repair	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Danio rerio	Q6P2A1	49.7%	Diamond
Caenorhabditis elegans	A0A163UT06	42.2%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
PRDM9-AS1	ncRNA	124901171

Protein

Protein identifiers

Histone-lysine N-methyltransferase PRDM9 — Q9NQV7 (reviewed: Q9NQV7)

Alternative names: PR domain zinc finger protein 9, PR domain-containing protein 9, Protein-lysine N-methyltransferase PRDM9, [histone H3]-lysine36 N-trimethyltransferase PRDM9, [histone H3]-lysine4 N-trimethyltransferase PRDM9, [histone H3]-lysine9 N-trimethyltransferase PRDM9, [histone H4]-N-methyl-L-lysine20 N-methyltransferase PRDM9, [histone H4]-lysine20 N-methyltransferase PRDM9

All UniProt accessions (3): Q9NQV7, A0A0U1RQY2, D6RD68

UniProt curated annotations — full annotation on UniProt →

Function. Histone methyltransferase that sequentially mono-, di-, and tri-methylates both ‘Lys-4’ (H3K4) and ‘Lys-36’ (H3K36) of histone H3 to produce respectively trimethylated ‘Lys-4’ (H3K4me3) and trimethylated ‘Lys-36’ (H3K36me3) histone H3 and plays a key role in meiotic prophase by determining hotspot localization thereby promoting meiotic recombination. Can also methylate all four core histones with H3 being the best substrate and the most highly modified. Is also able, on one hand, to mono and di-methylate H4K20 and on other hand to trimethylate H3K9 with the di-methylated H3K9 as the best substrate. During meiotic prophase, binds specific DNA sequences through its zinc finger domains thereby determining hotspot localization where it promotes local H3K4me3 and H3K36me3 enrichment on the same nucleosomes through its histone methyltransferase activity. Thereby promotes double-stranded breaks (DSB) formation, at this subset of PRDM9-binding sites, that initiates meiotic recombination for the proper meiotic progression. During meiotic progression hotspot-bound PRDM9 interacts with several complexes; in early leptonema binds CDYL and EHMT2 followed by EWSR1 and CXXC1 by the end of leptonema. EWSR1 joins PRDM9 with the chromosomal axis through REC8. In this way, controls the DSB repair pathway, pairing of homologous chromosomes and sex body formation. Moreover plays a central role in the transcriptional activation of genes during early meiotic prophase thanks to H3K4me3 and H3K36me3 enrichment that represents a specific tag for epigenetic transcriptional activation. In addition performs automethylation. Acetylation and phosphorylation of histone H3 attenuate or prevent histone H3 methylation.

Subunit / interactions. Homodimer (PubMed:24095733, PubMed:26833727, Ref.10). Interacts with EHMT2 and CDYL; interaction only takes place when PRDM9 is bound to hotspot DNA. Interacts with CXXC1; this interaction does not link PRDM9-activated recombination hotspot sites with DSB machinery and is not required for the hotspot recognition pathway. Forms a complex with EWSR1, REC8, SYCP3 and SYCP1; complex formation is dependent of phosphorylated form of REC8 and requires PRDM9 bound to hotspot DNA; EWSR1 joins PRDM9 with the chromosomal axis through REC8. Interacts with HELLS; the interaction recruits HELLS to meiotic recombination hot spots.

Subcellular location. Nucleus. Chromosome.

Post-translational modifications. Mono-methylated; automethylated. Tri-methylated; automethylated. Mono-methylation is predominant; automethylation is lower and slower than H3 peptide methylation and is in a highest S-adenosyl-L-methionine concentration-dependent. There are two major sites for automethylation at Lys-368 and Lys-374. Lysines can be simultaneously methylated, such as Lys-368(me3)/Lys-372(me1), Lys-368(me1)/Lys-374(me1) and Lys-368(me1)/Lys-372(me1)/Lys-374(me1). Automethylation is an intramolecular (cis) process.

Activity regulation. Inhibited by suramin with an IC(50) of 4.1 uM.

Domain organisation. The C2H2-type zinc fingers determine the hotspot localization through its binding to specific DNA sequences. Variations in their sequence affect affinity towards DNA-binding motif.

Polymorphism. Several alleles exist depending on both the number of zinc finger C2H2 type domains and their identity. Each allele binds to a specific hotspot set. Variations in the zinc finger C2H2 type domains are associated with significant differences in affinity towards DNA-binding motif. The sequence shown is that of allele B.

Similarity. Belongs to the class V-like SAM-binding methyltransferase superfamily.

RefSeq proteins (2): NP_001363829, NP_064612* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001214	SET_dom	Domain
IPR001909	KRAB	Domain
IPR003655	aKRAB	Domain
IPR013087	Zf-C2H2_type	Domain
IPR019041	SSXRD_motif	Conserved_site
IPR036051	KRAB_dom_sf	Homologous_superfamily
IPR036236	Znf_C2H2_sf	Homologous_superfamily
IPR044417	PRDM7_9_PR-SET	Domain
IPR046341	SET_dom_sf	Homologous_superfamily
IPR048414	PDRM9-like_Znf-C2H2	Domain

Pfam: PF00096, PF01352, PF09514, PF21225, PF21549

Enzyme classification (BRENDA)

• EC 2.1.1.359 — [histone H3]-lysine36 N-trimethyltransferase (BRENDA: 13 organisms, 30 substrates, 2 inhibitors, 12 Km, 6 kcat entries)

Substrate kinetics (BRENDA)

7 substrates with measured Km, best-characterized 7. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
S-ADENOSYL-L-METHIONINE	0.0033–0.13	6
CHICKEN NUCLEOSOME	0.0089	1
HISTONE H3(PEPTIDE 21-44)	0.0005	1
RECOMBINANT NUCLEOSOME	0.0081	1
[HISTONE H3]-L-LYSINE36	0.0015	1
[HISTONE H3]-N6,N6-DIMETHYL-L-LYSINE36	0.0025	1
[HISTONE H3]-N6-METHYL-L-LYSINE36	0.0024	1

Catalyzed reactions (Rhea)

• L-lysyl-[protein] + S-adenosyl-L-methionine = N(6)-methyl-L-lysyl-[protein] + S-adenosyl-L-homocysteine + H(+) (RHEA:51736)
• N(6)-methyl-L-lysyl-[protein] + S-adenosyl-L-methionine = N(6),N(6)-dimethyl-L-lysyl-[protein] + S-adenosyl-L-homocysteine + H(+) (RHEA:54196)
• L-lysyl(4)-[histone H3] + 3 S-adenosyl-L-methionine = N(6),N(6),N(6)-trimethyl-L-lysyl(4)-[histone H3] + 3 S-adenosyl-L-homocysteine + 3 H(+) (RHEA:60260)
• L-lysyl(9)-[histone H3] + 3 S-adenosyl-L-methionine = N(6),N(6),N(6)-trimethyl-L-lysyl(9)-[histone H3] + 3 S-adenosyl-L-homocysteine + 3 H(+) (RHEA:60276)
• L-lysyl(36)-[histone H3] + 3 S-adenosyl-L-methionine = N(6),N(6),N(6)-trimethyl-L-lysyl(36)-[histone H3] + 3 S-adenosyl-L-homocysteine + 3 H(+) (RHEA:60324)
• L-lysyl(20)-[histone H4] + S-adenosyl-L-methionine = N(6)-methyl-L-lysyl(20)-[histone H4] + S-adenosyl-L-homocysteine + H(+) (RHEA:60344)
• N(6)-methyl-L-lysyl(20)-[histone H4] + S-adenosyl-L-methionine = N(6),N(6)-dimethyl-L-lysyl(20)-[histone H4] + S-adenosyl-L-homocysteine + H(+) (RHEA:60348)

UniProt features (109 total): binding site 29, strand 17, helix 16, zinc finger region 14, turn 10, sequence variant 5, region of interest 4, modified residue 4, mutagenesis site 3, domain 2, compositionally biased region 2, sequence conflict 2, chain 1

Structure

Experimental structures (PDB)

5 structures by resolution:

PDB	Title	Method	Resolution (Å)
5EI9	Human PRDM9 allele-A ZnF Domain with Associated Recombination Hotspot DNA Sequence I	X-RAY DIFFRACTION	1.92
5EGB	Human PRDM9 allele-A ZnF Domain with Associated Recombination Hotspot DNA Sequence II	X-RAY DIFFRACTION	1.98
5EH2	Human PRDM9 allele-A ZnF Domain with Associated Recombination Hotspot DNA Sequence III	X-RAY DIFFRACTION	2.05
4IJD	Crystal structure of methyltransferase domain of human PR domain-containing protein 9	X-RAY DIFFRACTION	2.15
6NM4	Crystal structure of SAM-bound PRDM9 in complex with MRK-740 inhibitor	X-RAY DIFFRACTION	2.58

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NQV7-F1	70.19	0.29

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Transferases, Predicted intracellular proteins, Transcription factors, Zinc-coordinating DNA-binding domains

Protein evidence: Evidence at protein level

Antibody reliability (HPA): IH uncertain

Functional residue map

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

Ligand- & substrate-binding residues (29)

Position	Role
205	Zn(2+)
208	Zn(2+)
216	Zn(2+)
219	Zn(2+)
256–258	S-adenosyl-L-methionine
288–294	substrate
291	S-adenosyl-L-methionine
320–321	S-adenosyl-L-methionine
357	substrate
390	Zn(2+)
393	Zn(2+)
406	Zn(2+)
411	Zn(2+)
722	Zn(2+)
725	Zn(2+)
738	Zn(2+)
742	Zn(2+)
750	Zn(2+)
753	Zn(2+)
766	Zn(2+)
770	Zn(2+)
778	Zn(2+)
781	Zn(2+)
794	Zn(2+)
798	Zn(2+)
806	Zn(2+)
809	Zn(2+)
822	Zn(2+)
826	Zn(2+)

Post-translational modifications (4)

Type	Positions
N6,n6,n6-trimethyllysine	368
N6-methyllysine	368, 372, 374

Mutagenesis-validated functional residues (3)

Position	Phenotype
199	increases histone-lysine n-methyltransferase activity; when associated with d-374.
357	loss of histone-lysine n-methyltransferase activity.
374	increases histone-lysine n-methyltransferase activity; when associated with y-199.

Function

Pathways and Gene Ontology

Reactome pathways

1 curated (TAS) of 7; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

7 pathways:

ID	Pathway	Evidence
R-HSA-3214841	PKMTs methylate histone lysines	curated
R-HSA-1640170	Cell Cycle	—
R-HSA-3247509	Chromatin modifying enzymes	—
R-HSA-4839726	Chromatin organization	—
R-HSA-1500620	Meiosis	—
R-HSA-912446	Meiotic recombination	electronic
R-HSA-1474165	Reproduction	—

MSigDB gene sets: 118 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_DN, GOBP_MEIOTIC_CHROMOSOME_SEGREGATION, REACTOME_MEIOTIC_RECOMBINATION, GOBP_CHROMOSOME_ORGANIZATION, GOBP_REGULATION_OF_DNA_RECOMBINATION, GOBP_POSITIVE_REGULATION_OF_REPRODUCTIVE_PROCESS, GOBP_REGULATION_OF_NUCLEAR_DIVISION, GOBP_REGULATION_OF_MEIOTIC_NUCLEAR_DIVISION, TGACCTY_ERR1_Q2, GOBP_MALE_GAMETE_GENERATION, GOBP_POSITIVE_REGULATION_OF_ORGANELLE_ORGANIZATION, GOBP_REGULATION_OF_MEIOTIC_CELL_CYCLE, GOBP_POSITIVE_REGULATION_OF_MEIOTIC_CELL_CYCLE, GOBP_ORGANELLE_FISSION, GOBP_REGULATION_OF_CELL_CYCLE

GO Biological Process (17): meiotic gene conversion (GO:0006311), DNA-templated transcription (GO:0006351), regulation of DNA-templated transcription (GO:0006355), homologous chromosome pairing at meiosis (GO:0007129), female gamete generation (GO:0007292), regulation of gene expression (GO:0010468), positive regulation of reciprocal meiotic recombination (GO:0010845), methylation (GO:0032259), negative regulation of apoptotic process (GO:0043066), male gamete generation (GO:0048232), positive regulation of fertilization (GO:1905516), double-strand break repair involved in meiotic recombination (GO:1990918), chromatin organization (GO:0006325), chromatin remodeling (GO:0006338), homologous recombination (GO:0035825), meiotic cell cycle (GO:0051321), meiosis I cell cycle process (GO:0061982)

GO Molecular Function (19): transcription cis-regulatory region binding (GO:0000976), zinc ion binding (GO:0008270), recombination hotspot binding (GO:0010844), histone H3K4 methyltransferase activity (GO:0042800), protein homodimerization activity (GO:0042803), histone H3K36 methyltransferase activity (GO:0046975), histone H4K20me methyltransferase activity (GO:0140941), histone H4K20 monomethyltransferase activity (GO:0140944), histone H3K9 trimethyltransferase activity (GO:0140949), histone H3K36 trimethyltransferase activity (GO:0140955), histone H3K4 trimethyltransferase activity (GO:0140999), DNA binding (GO:0003677), protein binding (GO:0005515), methyltransferase activity (GO:0008168), protein-lysine N-methyltransferase activity (GO:0016279), transferase activity (GO:0016740), histone methyltransferase activity (GO:0042054), sequence-specific DNA binding (GO:0043565), metal ion binding (GO:0046872)

GO Cellular Component (3): nucleus (GO:0005634), nucleoplasm (GO:0005654), chromosome (GO:0005694)

Reactome top-level categories

5 top-level categories:

Category	Pathways
Chromatin modifying enzymes	1
Meiosis	1
Reproduction	1
Cell Cycle	1
Chromatin organization	1

GO top-level categories

55 GO namespaces:

Category	Terms
gene expression	2
gamete generation	2
reciprocal meiotic recombination	2
meiotic cell cycle process	2
DNA binding	2
protein-lysine N-methyltransferase activity	2
histone H3 methyltransferase activity	2
histone H4K20 methyltransferase activity	2
protein methyltransferase activity	2
gene conversion	1
meiosis I cell cycle process	1
RNA biosynthetic process	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
homologous chromosome segregation	1
chromosome organization involved in meiotic cell cycle	1
regulation of macromolecule biosynthetic process	1
regulation of reciprocal meiotic recombination	1
positive regulation of meiotic nuclear division	1
positive regulation of DNA recombination	1
metabolic process	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
fertilization	1
regulation of fertilization	1
positive regulation of reproductive process	1
double-strand break repair	1
cellular component organization	1
chromatin organization	1
DNA recombination	1
cell cycle	1
sexual reproduction	1
reproductive process	1
meiotic nuclear division	1
transcription regulatory region nucleic acid binding	1
sequence-specific double-stranded DNA binding	1
transition metal ion binding	1
identical protein binding	1
protein dimerization activity	1
histone H3K9 methyltransferase activity	1
histone H3K36 methyltransferase activity	1
histone H3K4 methyltransferase activity	1
nucleic acid binding	1
binding	1
transferase activity, transferring one-carbon groups	1
lysine N-methyltransferase activity	1
catalytic activity	1
histone modifying activity	1
cation binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cellular anatomical structure	1
intracellular membraneless organelle	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 6 of 39 annotations. The rest are phylogenetic / computational / electronic (IEA).

6 experimentally-supported GO terms:

GO term	NS	Evidence
meiotic gene conversion	BP	direct assay
positive regulation of reciprocal meiotic recombination	BP	mutant phenotype
histone H3K36 methyltransferase activity	MF	mutant phenotype
histone H3K4 methyltransferase activity	MF	direct assay
recombination hotspot binding	MF	direct assay
transcription cis-regulatory region binding	MF	mutant phenotype

Protein interactions and networks

STRING

showing 15 of 1,020 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PRDM9	SPO11	Q9Y5K1	796
PRDM9	H3-3A	P06351	768
PRDM9	H3C1	P02295	768
PRDM9	H3-4	Q16695	768
PRDM9	H3-7	Q5TEC6	768
PRDM9	H3-5	Q6NXT2	768
PRDM9	H3C14	Q71DI3	768
PRDM9	RNF212	Q495C1	701
PRDM9	IHO1	Q8IYA8	662
PRDM9	SYCE2	Q6PIF2	658
PRDM9	REC114	Q7Z4M0	652
PRDM9	SYCP3	Q8IZU3	645
PRDM9	SYCP1	Q15431	628
PRDM9	SPATA22	Q8NHS9	625
PRDM9	MEI1	Q5TIA1	623

IntAct

Human interaction partners of PRDM9 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

2 partners by confidence:

Partner	Interaction type	MIscore	Records
CCT6A	physical association	0.400	1
CDC14C	association	0.350	1

BioGRID (10 interactions; top human partners by supporting records): CDC14C (Affinity Capture-MS), CHCHD2 (Affinity Capture-MS), GRHPR (Affinity Capture-MS), PARP6 (Proximity Label-MS), RAD50 (Cross-Linking-MS (XL-MS)), SQSTM1 (Affinity Capture-MS), TIPARP (Proximity Label-MS), USP39 (Cross-Linking-MS (XL-MS)), YBX1 (Affinity Capture-MS)

Disease & clinical

Genetic variants

Variant evidence for PRDM9: 178 ClinVar records (3 pathogenic / likely pathogenic); 10 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	0
Uncertain significance	136
Likely benign	21
Benign	12

Top pathogenic / likely-pathogenic (3)

Showing all 3 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
1120011	NM_020227.4(PRDM9):c.229C>T (p.Arg77Ter)	Pathogenic	criteria provided, single submitter	1
1120012	NM_020227.4(PRDM9):c.638T>G (p.Ile213Ser)	Pathogenic	criteria provided, single submitter	1
1120013	NM_020227.4(PRDM9):c.677A>T (p.Lys226Met)	Pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

Explore PRDM9’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 19 predictions of 689):

Position(s)	Effect	Δscore	Sites
5:23509557	donor_gain	1.0000
5:23509569	donor_gain	1.0000
5:23509918–23509919	acceptor_loss	1.0000	6
5:23510028–23510029	donor_loss	1.0000	5
5:23510041	donor_gain	1.0000
5:23521004	acceptor_gain	1.0000
5:23523281	acceptor_gain	1.0000
5:23524316	acceptor_gain	1.0000
5:23524320	acceptor_gain	1.0000
5:23524325	acceptor_gain	1.0000

AlphaMissense

1,909 missense substitutions predicted likely pathogenic (of 5,904 scored), across 450 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
H738	8	0.982	0.994
H766	8	0.969	0.991
H822	8	0.968	0.991
H710	8	0.967	0.993
F729	8	0.967	0.998
F645	8	0.964	0.998
F813	8	0.962	0.998
H850	8	0.962	0.989
F701	8	0.961	0.998
H794	8	0.960	0.990
H626	8	0.958	0.992
F673	8	0.957	0.997
H714	8	0.955	0.994
H742	8	0.955	0.993
F617	8	0.954	0.997
F785	8	0.951	0.996
H654	8	0.948	0.991
F841	8	0.948	0.996
F757	8	0.947	0.996
H682	8	0.944	0.988

HPA cancer prognostics

RNA cancer specificity: Not detected

Disease associations

OMIM: gene MIM:609760 | disease phenotypes:

GenCC curated gene-disease

1 curated gene-disease records:

Disease	Classification	Inheritance	Records
primary ovarian failure	Strong	Autosomal dominant

Mondo (1): primary ovarian failure (MONDO:0005387)

Orphanet (1): Rare genetic premature ovarian failure (Orphanet:485382)

GWAS associations

10 associations:

Study	Trait	p-value
GCST001168_1	Recombination measurement	2e-246
GCST000848_1	Recombination measurement (females)	1e-100
GCST001168_3	Recombination measurement	2e-52
GCST000845_1	Recombination measurement (males)	1e-50
GCST002911_3	Calcium levels	8e-7
GCST009391_519	Metabolite levels	8e-7
GCST005588_26	Idiopathic dilated cardiomyopathy	3e-6
GCST009391_464	Metabolite levels	9e-6
GCST010725_40	Malaria	9e-6
GCST010725_80	Malaria	9e-6

EFO canonical traits (from GWAS)

6 canonical traits:

EFO ID	Trait name
EFO:0004863	recombination rate
EFO:0005919	recombination measurement
EFO:0004838	calcium measurement
EFO:0009094	idiopathic dilated cardiomyopathy
EFO:0010522	phosphoenolpyruvic acid measurement
EFO:0010496	hippuric acid measurement

MeSH disease descriptors

1 disease descriptors:

Descriptor	Name	Tree numbers
D016649	Primary Ovarian Insufficiency	C12.050.351.500.056.630.750; C12.100.250.056.630.750; C19.391.630.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3588737 (SINGLE PROTEIN)

PharmGKB: 1 entry (CPIC guideline: no)

Binding affinities (BindingDB)

2 measured of 13 human assays (14 total across all organisms); most potent 2 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CHEMBL5187396	IC50	1000 nM
(2R)-7-chloro-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide (Valemetostat)	IC50	1000 nM

ChEMBL bioactivities

10 potent at pChembl≥5 of 10 total, top 5 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.19	Ki	65	nM	CHEMBL4791017
7.10	IC50	80	nM	CHEMBL4791017
7.06	Kd	87	nM	CHEMBL4791017
7.06	IC50	87	nM	CHEMBL4791017
6.10	IC50	800	nM	CHEMBL4791017

PubChem BioAssay actives

11 with measured affinity, of 83 total; 8 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
3-(3,5-dimethoxyphenyl)-5-[1-methyl-9-(2-methyl-4-pyridinyl)-1,4,9-triazaspiro[5.5]undecan-4-yl]-1,2,4-oxadiazole	2146086: Competitive inhibition of PRDM9 (unknown origin) assessed as inhibition constant in presence of varying concentration of SAM and peptide substrate	ki	0.0650	uM
(2S)-2-[[(2S)-6-amino-2-[[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-1-[(2S)-2-[[(2S)-6-amino-2-[[2-[[2-[[(2S,3R)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-5-amino-2-[[(2S)-6-amino-2-[[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-amino-4-methylsulfanylbutanoyl]amino]propanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-hydroxybutanoyl]amino]hexanoyl]amino]-5-oxopentanoyl]amino]-3-hydroxybutanoyl]amino]propanoyl]amino]-5-carbamimidamidopentanoyl]amino]hexanoyl]amino]-3-hydroxypropanoyl]amino]-3-hydroxybutanoyl]amino]acetyl]amino]acetyl]amino]hexanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]-5-carbamimidamidopentanoyl]amino]hexanoyl]amino]-5-oxopentanoyl]amino]-4-methylpentanoyl]amino]propanoyl]amino]-3-hydroxybutanoyl]amino]hexanoyl]amino]propanoic acid	1802826: Radioactivity-Based Assay from Article 10.1074/jbc.M113.523183: “Trimethylation of histone H3 lysine 36 by human methyltransferase PRDM9 protein.”	kd	3.6000	uM
[(5S)-5-[[(2S)-2-[[2-[[2-[[(2S,3R)-2-[[(2S)-2-[[(2S)-1-[(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S,3R)-2-[[(2S)-2-[[(2S)-2-amino-4-methylpentanoyl]amino]propanoyl]amino]-3-hydroxybutanoyl]amino]hexanoyl]amino]propanoyl]amino]propanoyl]amino]-5-carbamimidamidopentanoyl]amino]hexanoyl]amino]-3-hydroxypropanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]-3-hydroxypropanoyl]amino]-3-hydroxybutanoyl]amino]acetyl]amino]acetyl]amino]-3-methylbutanoyl]amino]-6-[[(2S)-6-amino-1-[(2S)-2-[[(2S)-1-[[(2S)-5-carbamimidamido-1-[[(2S)-1-[[(2S)-5-carbamimidamido-1-[(2S)-2-carboxypyrrolidin-1-yl]-1-oxopentan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-1-oxopentan-2-yl]amino]-3-imidazolidin-4-yl-1-oxopropan-2-yl]carbamoyl]pyrrolidin-1-yl]-1-oxohexan-2-yl]amino]-6-oxohexyl]-methylazanium	1802826: Radioactivity-Based Assay from Article 10.1074/jbc.M113.523183: “Trimethylation of histone H3 lysine 36 by human methyltransferase PRDM9 protein.”	kd	4.1000	uM
[(5S)-5-[[(2S)-2-[[2-[[2-[[(2S,3R)-2-[[(2S)-2-[[(2S)-1-[(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S,3R)-2-[[(2S)-2-[[(2S)-2-amino-4-methylpentanoyl]amino]propanoyl]amino]-3-hydroxybutanoyl]amino]hexanoyl]amino]propanoyl]amino]propanoyl]amino]-5-carbamimidamidopentanoyl]amino]hexanoyl]amino]-3-hydroxypropanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]-3-hydroxypropanoyl]amino]-3-hydroxybutanoyl]amino]acetyl]amino]acetyl]amino]-3-methylbutanoyl]amino]-6-[[(2S)-6-amino-1-[(2S)-2-[[(2S)-1-[[(2S)-5-carbamimidamido-1-[[(2S)-1-[[(2S)-5-carbamimidamido-1-[(2S)-2-carboxypyrrolidin-1-yl]-1-oxopentan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-1-oxopentan-2-yl]amino]-3-imidazolidin-4-yl-1-oxopropan-2-yl]carbamoyl]pyrrolidin-1-yl]-1-oxohexan-2-yl]amino]-6-oxohexyl]-dimethylazanium	1802826: Radioactivity-Based Assay from Article 10.1074/jbc.M113.523183: “Trimethylation of histone H3 lysine 36 by human methyltransferase PRDM9 protein.”	kd	4.2000	uM
(2S)-1-[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-1-[(2S)-6-amino-2-[[(2S)-6-amino-2-[[(2S)-2-[[2-[[2-[[(2S,3R)-2-[[(2S)-2-[[(2S)-1-[(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S,3R)-2-[[(2S)-2-[[(2S)-2-amino-4-methylpentanoyl]amino]propanoyl]amino]-3-hydroxybutanoyl]amino]hexanoyl]amino]propanoyl]amino]propanoyl]amino]-5-carbamimidamidopentanoyl]amino]hexanoyl]amino]-3-hydroxypropanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]-3-hydroxypropanoyl]amino]-3-hydroxybutanoyl]amino]acetyl]amino]acetyl]amino]-3-methylbutanoyl]amino]hexanoyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-3-imidazolidin-4-ylpropanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-5-carbamimidamidopentanoyl]pyrrolidine-2-carboxylic acid	1802826: Radioactivity-Based Assay from Article 10.1074/jbc.M113.523183: “Trimethylation of histone H3 lysine 36 by human methyltransferase PRDM9 protein.”	kd	4.6000	uM
[(5S)-6-[[(2S)-5-amino-1-[[(2S,3R)-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-1-[[(2S,3R)-1-[[2-[[2-[[(2S)-6-amino-1-[[(2S)-1-[(2S)-2-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-5-amino-1-[[(2S)-1-[[(2S)-1-[[(2S,3R)-1-[[(2S)-6-amino-1-[[(1S)-1-carboxyethyl]amino]-1-oxohexan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-1-oxopropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-1-oxohexan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]carbamoyl]pyrrolidin-1-yl]-1-oxopropan-2-yl]amino]-1-oxohexan-2-yl]amino]-2-oxoethyl]amino]-2-oxoethyl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-1-oxohexan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-5-[[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-amino-4-methylsulfanylbutanoyl]amino]propanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-hydroxybutanoyl]amino]-6-oxohexyl]-methylazanium	1802826: Radioactivity-Based Assay from Article 10.1074/jbc.M113.523183: “Trimethylation of histone H3 lysine 36 by human methyltransferase PRDM9 protein.”	kd	4.7000	uM
[(5S)-6-[[(2S)-5-amino-1-[[(2S,3R)-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-1-[[(2S,3R)-1-[[2-[[2-[[(2S)-6-amino-1-[[(2S)-1-[(2S)-2-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-5-amino-1-[[(2S)-1-[[(2S)-1-[[(2S,3R)-1-[[(2S)-6-amino-1-[[(1S)-1-carboxyethyl]amino]-1-oxohexan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-1-oxopropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-1-oxohexan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]carbamoyl]pyrrolidin-1-yl]-1-oxopropan-2-yl]amino]-1-oxohexan-2-yl]amino]-2-oxoethyl]amino]-2-oxoethyl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-1-oxohexan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-5-[[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-amino-4-methylsulfanylbutanoyl]amino]propanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-hydroxybutanoyl]amino]-6-oxohexyl]-dimethylazanium	1802826: Radioactivity-Based Assay from Article 10.1074/jbc.M113.523183: “Trimethylation of histone H3 lysine 36 by human methyltransferase PRDM9 protein.”	kd	5.8000	uM
[(5S)-5-[[(2S)-2-[[2-[[2-[[(2S,3R)-2-[[(2S)-2-[[(2S)-1-[(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S,3R)-2-[[(2S)-2-[[(2S)-2-amino-4-methylpentanoyl]amino]propanoyl]amino]-3-hydroxybutanoyl]amino]hexanoyl]amino]propanoyl]amino]propanoyl]amino]-5-carbamimidamidopentanoyl]amino]hexanoyl]amino]-3-hydroxypropanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]-3-hydroxypropanoyl]amino]-3-hydroxybutanoyl]amino]acetyl]amino]acetyl]amino]-3-methylbutanoyl]amino]-6-[[(2S)-6-amino-1-[(2S)-2-[[(2S)-1-[[(2S)-5-carbamimidamido-1-[[(2S)-1-[[(2S)-5-carbamimidamido-1-[(2S)-2-carboxypyrrolidin-1-yl]-1-oxopentan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-1-oxopentan-2-yl]amino]-3-imidazolidin-4-yl-1-oxopropan-2-yl]carbamoyl]pyrrolidin-1-yl]-1-oxohexan-2-yl]amino]-6-oxohexyl]-trimethylazanium	1802826: Radioactivity-Based Assay from Article 10.1074/jbc.M113.523183: “Trimethylation of histone H3 lysine 36 by human methyltransferase PRDM9 protein.”	kd	9.6000	uM

CTD chemical–gene interactions

4 total (human), top 4 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression	2
bisphenol A	increases methylation	1
CGP 52608	affects binding, increases reaction	1
Benzo(a)pyrene	affects methylation, decreases methylation	1

ChEMBL screening assays

60 unique, capped per target: 58 binding, 2 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3592404	Binding	Inhibition of PRDM9 (unknown origin) assessed as incorporation of tritium labeled methyl group from [3H]-SAM to substrate at 1 uM after 1 hr by scintillation proximity assay relative to control	Discovery of A-893, A New Cell-Active Benzoxazinone Inhibitor of Lysine Methyltransferase SMYD2. — *ACS Med Chem Lett*
CHEMBL5723043	Functional	Affinity Biochemical interaction: (inhibition of methyltransferase activity) EUB0000234b PRDM9	Affinity Biochemical Literature for EUbOPEN Chemogenomic Library

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

showing 60 of 75 trials:

NCT	Phase	Status	Title
NCT00417066	Phase 4	COMPLETED	Flexible GnRH Antagonist vs Flare up GnRH Agonist Protocol in Poor Responders
NCT00732693	Phase 4	COMPLETED	Evaluation of Physiologic and Standard Sex Steroid Replacement Regimens in Women With Premature Ovarian Failure
NCT00837616	Phase 4	COMPLETED	Estrogen Dosing in Turner Syndrome: Pharmacology and Metabolism
NCT01853501	Phase 4	UNKNOWN	Effects of ADSC Therapy in Women With POF
NCT02783937	Phase 4	COMPLETED	Filgrastim for Premature Ovarian Insufficiency
NCT03535480	Phase 4	UNKNOWN	Autologous Bone Marrow Stem Cell Ovarian Transplantation to Restore Ovarian Function in Premature Ovarian Failure
NCT00140998	Phase 3	COMPLETED	Estrogen Treatment (Oral vs. Patches) in Turner Syndrome
NCT00001951	Phase 2	COMPLETED	Hormone Replacement in Young Women With Premature Ovarian Failure
NCT00370019	Phase 2	WITHDRAWN	Effects of an Estrogen Replacement Therapy Skin Patch on Ovulation in Women With Premature Ovarian Failure
NCT00429494	Phase 2	COMPLETED	GnRH Analogue for Ovarian Function Preservation in Hematopoietic Stem Cell Transplantation Patients
NCT03816852	Phase 2	SUSPENDED	The Safety and Efficiency Study of Mesenchymal Stem Cell (19#iSCLife®-POI) in Premature Ovarian Insufficiency
NCT04536467	Phase 2	UNKNOWN	Prevention of Chemotherapy-Induced Ovarian Failure With Goserelin in Premenopausal Lymphoma Patients
NCT06117982	Phase 2	COMPLETED	The Impact of Granulocyte Colony Stimulating Factor on Premature Ovarian Insufficiency
NCT02912104	Phase 1	COMPLETED	A Therapeutic Trial of Human Amniotic Epithelial Cells Transplantation for Primary Ovarian Failure
NCT03178695	Phase 1	COMPLETED	Inovium Ovarian Rejuvenation Trials
NCT04815213	Phase 1	ACTIVE_NOT_RECRUITING	The Use of Expandeded Mesenchymal Stromal Cells (MSC) in Premature Ovarian Failure (POF) in Adult Humans
NCT05138367	Phase 1	COMPLETED	Effects of UCA-PSCs in Women With POF
NCT06132542	Phase 1	UNKNOWN	Autologous ADMSC Transplantation in Patients With POI
NCT00948857	Phase 2/3	TERMINATED	Dehydroepiandrosterone (DHEA) Treatment and Premature Ovarian Failure (POF)
NCT04031456	Phase 2/3	RECRUITING	Autologous PRP Infusion May Restore Ovarian Function and May Promote Folliculogenesis in POI Patients
NCT02043743	Phase 1/2	UNKNOWN	Autologous Stem Cells Transplantation in Patients With Idiopathic and Drug Induced Premature Ovarian Failure
NCT02062931	Phase 1/2	UNKNOWN	Autologous Mesenchymal Stem Cells Transplantation In Women With Premature Ovarian Failure
NCT02151890	Phase 1/2	COMPLETED	Pregnancy After Stem Cell Transplantation in Premature Ovarian Failure
NCT02372474	Phase 1/2	COMPLETED	It is a Real The First Baby Of Autologous Stem Cell Therapy in Premature Ovarian Failure
NCT02603744	Phase 1/2	UNKNOWN	Autologous Adipose Derived Mesenchymal Stromal Cells Transplantation in Women With Premature Ovarian Failure (POF)
NCT02644447	Phase 1/2	COMPLETED	Transplantation of HUC-MSCs With Injectable Collagen Scaffold for POF
NCT03069209	Phase 1/2	UNKNOWN	Autologous Bone Marrow-Derived Stem Cell Transplantation in Patients With Premature Ovarian Failure (POF)
NCT03985462	Phase 1/2	WITHDRAWN	Very Small Embryonic-like Stem Cells for Ovary
NCT04009473	Phase 1/2	UNKNOWN	Stem Cell Therapy and Growth Factor Ovarian in Vitro Activation
NCT04071574	Phase 1/2	COMPLETED	Comparative Study on the Efficacy of Ovarian Stimulation Protocols on the Success Rate of ICSI in Female Infertility
NCT04922398	Phase 1/2	UNKNOWN	Ovarian Injection of PRP (Platelet -Rich Plasma) Vs Normal Saline in Premature Ovarian Insufficiency
NCT05462379	Phase 1/2	ACTIVE_NOT_RECRUITING	Autologous Heterotopic Fresh Ovarian Graft in Woman With LACC Eligible for Pelvic Radiotherapy Treatment.
NCT06202547	Phase 1/2	COMPLETED	Intra-ovarian Injection of MSC-EVs in Idiopathic Premature Ovarian Failure
NCT01129947	Early Phase 1	WITHDRAWN	The Use of DHEA in Women With Premature Ovarian Failure
NCT05522634	Early Phase 1	UNKNOWN	A Clinical Study of Chinese Herbal Compound TJAOA101 in the Treatment of Premature Ovarian Insufficiency
NCT07308327	Early Phase 1	ACTIVE_NOT_RECRUITING	The Influence of Gut Microbiota on Ovarian Function: A Single-center, Randomized,Double Blind, Parallel-controlled, Exploratory Clinical Trial
NCT00001275	Not specified	COMPLETED	Ovarian Follicle Function in Patients With Primary Ovarian Failure
NCT00001306	Not specified	COMPLETED	Steroid Therapy in Autoimmune Premature Ovarian Failure
NCT00006156	Not specified	COMPLETED	Feasibility Study for Development of an Early Test for Ovarian Failure
NCT00119925	Not specified	UNKNOWN	‘SPRING’-Study: Subfertility Guidelines: Patient Related Implementation in the Netherlands Among Gynaecologists
NCT00295087	Not specified	COMPLETED	X-Chromosome Inactivation Status and Premature Ovarian Failure
NCT00417157	Not specified	COMPLETED	Modified Natural Cycle Offers a Chance of Pregnancy in Patients With Poor Response and High Basal FSH
NCT00619333	Not specified	UNKNOWN	Inactive FSH in Galactosemia
NCT00780897	Not specified	UNKNOWN	Premature Ovarian Failure (Genetic and Physiopathologic Analysis)
NCT01187524	Not specified	TERMINATED	The Natural History of Reproductive and Overall Health in Girls and Women With a Pre-Mutation in the FMR1 Gene; Creation of a Patient Registry
NCT01411644	Not specified	UNKNOWN	Pheno- & Genotyping POF (WHO III)
NCT02086318	Not specified	UNKNOWN	A New Algorithm to Predict Ovarian Age
NCT02467231	Not specified	ACTIVE_NOT_RECRUITING	Ovarian Reserve After Cancer: Longitudinal Effects
NCT02696889	Not specified	COMPLETED	Rejuvenation of Premature Ovarian Failure With Stem Cells
NCT02779374	Not specified	TERMINATED	Autologous Bone Marrow Transplantation for Premature Ovarian Insufficiency
NCT03207412	Not specified	UNKNOWN	Human Amniotic Epithelial Cells Treatment for Ovarian Insufficiency
NCT03381300	Not specified	ACTIVE_NOT_RECRUITING	Preservation of Ovarian Cortex Tissue in Girls With Turner Syndrome
NCT03412487	Not specified	UNKNOWN	Ovarian Histopathology and Laparoscopic Assessment of Premature Ovarian Failure
NCT03474120	Not specified	UNKNOWN	Prospective Genetic Study in Patients With Ovarian Insufficiency
NCT03480412	Not specified	UNKNOWN	Second Step Protocol in Poor Ovarian Responder (POR)
NCT03840824	Not specified	COMPLETED	Blood Spot Self-administered Test and Assay
NCT03861715	Not specified	UNKNOWN	Single Follicular Dexarelix for LH Suppression During Ovarian Stimulation in Oocyte Donors.
NCT03924648	Not specified	COMPLETED	Endocan Levels in Women With Premature Ovarian Insufficiency
NCT04149028	Not specified	COMPLETED	Platelet Rich Plasma Injection Into Ovary of Patients With Premature Ovarian Insufficiency
NCT04189406	Not specified	UNKNOWN	Turner Syndrome Minipuberty Study

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for PRDM9 across ~30M SureChEMBL compounds — explore on Sugi Predict.