ZCWPW1

gene
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Also known as FLJ10057DKFZp434N0510ZCW1

Summary

ZCWPW1 (zinc finger CW-type and PWWP domain containing 1, HGNC:23486) is a protein-coding gene on chromosome 7q22.1, encoding Zinc finger CW-type PWWP domain protein 1 (Q9H0M4). Dual histone methylation reader specific for PRDM9-catalyzed histone marks (H3K4me3 and H3K36me3).

Enables histone reader activity; methyl-CpG binding activity; and methylated histone binding activity. Predicted to be involved in meiosis I; positive regulation of DNA metabolic process; and spermatogenesis. Predicted to act upstream of or within homologous chromosome pairing at meiosis. Predicted to be located in XY body. Predicted to be active in nucleus.

Source: NCBI Gene 55063 — RefSeq curated summary.

At a glance

  • GWAS associations: 15
  • Clinical variants (ClinVar): 111 total — 1 pathogenic
  • Druggable target: yes
  • MANE Select transcript: NM_001386010

Identifiers

Gene identifiers

FieldValue
HGNC IDHGNC:23486
Approved symbolZCWPW1
Namezinc finger CW-type and PWWP domain containing 1
Location7q22.1
Locus typegene with protein product
StatusApproved
AliasesFLJ10057, DKFZp434N0510, ZCW1
Ensembl geneENSG00000078487
Ensembl biotypeprotein_coding
OMIM618900
Entrez55063

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 23 protein_coding, 3 retained_intron

ENST00000360951, ENST00000398027, ENST00000464510, ENST00000471336, ENST00000472716, ENST00000479315, ENST00000490089, ENST00000490721, ENST00000684423, ENST00000857285, ENST00000857286, ENST00000857287, ENST00000857288, ENST00000857289, ENST00000857291, ENST00000857292, ENST00000857293, ENST00000857294, ENST00000857295, ENST00000857296, ENST00000857297, ENST00000857298, ENST00000857299, ENST00000958741, ENST00000958742, ENST00000958743

RefSeq mRNA: 18 — MANE Select: NM_001386010 NM_001258008, NM_001386008, NM_001386009, NM_001386010, NM_001386011, NM_001386012, NM_001386013, NM_001386015, NM_001386016, NM_001386017, NM_001386018, NM_001386019, NM_001386020, NM_001386021, NM_001386022, NM_001386023, NM_001388066, NM_017984

CCDS: CCDS43623, CCDS59067, CCDS94155

Canonical transcript exons

ENST00000684423 — 18 exons

ExonStartEnd
ENSE00001180416100402516100402576
ENSE00001350580100425030100425136
ENSE00001481569100401889100402041
ENSE00003469144100409428100409544
ENSE00003471064100417066100417183
ENSE00003476155100404178100404244
ENSE00003489214100415975100416097
ENSE00003538394100403694100403785
ENSE00003557354100416305100416456
ENSE00003601557100406694100406798
ENSE00003614669100419111100419189
ENSE00003617005100405013100405093
ENSE00003633351100419630100419883
ENSE00003660056100420622100420678
ENSE00003681962100407228100407303
ENSE00003684545100408539100408659
ENSE00003918846100400872100401336
ENSE00003920013100428568100428703

Expression profiles

Bgee: expression breadth ubiquitous, 189 present calls, max score 96.85.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 3.9216 / max 113.2223, expressed in 1398 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter IDTPM avgSamples expressed
851921.7659960
851930.9887352
851890.6366268
851910.4733222
851900.057114

Top tissues by expression

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

TissueAnatomy IDExpression scoreQuality
right testisUBERON:000453496.85gold quality
left testisUBERON:000453396.76gold quality
testisUBERON:000047394.87gold quality
male germ line stem cell (sensu Vertebrata) in testisCL:0000089 ∩ UBERON:000047392.74gold quality
primordial germ cell in gonadCL:0000670 ∩ UBERON:000099192.70gold quality
sural nerveUBERON:001548888.74gold quality
C1 segment of cervical spinal cordUBERON:000646986.48gold quality
cerebellar hemisphereUBERON:000224586.44gold quality
cerebellar cortexUBERON:000212986.42gold quality
right hemisphere of cerebellumUBERON:001489085.94gold quality
cerebellumUBERON:000203785.36gold quality
spinal cordUBERON:000224085.36gold quality
calcaneal tendonUBERON:000370184.53gold quality
monocyteCL:000057684.19gold quality
mononuclear cellCL:000084284.04gold quality
apex of heartUBERON:000209883.74gold quality
leukocyteCL:000073883.58gold quality
vena cavaUBERON:000408783.27gold quality
tendonUBERON:000004383.20gold quality
cerebellar vermisUBERON:000472082.67gold quality
tendon of biceps brachiiUBERON:000818882.09silver quality
olfactory segment of nasal mucosaUBERON:000538682.02gold quality
right uterine tubeUBERON:000130281.89gold quality
type B pancreatic cellCL:000016981.31gold quality
olfactory bulbUBERON:000226481.27gold quality
skeletal muscle tissue of rectus abdominisUBERON:000451180.96gold quality
right lobe of liverUBERON:000111480.62gold quality
substantia nigraUBERON:000203880.53gold quality
granulocyteCL:000009480.52gold quality
inferior vagus X ganglionUBERON:000536380.51silver quality

Single-cell (SCXA)

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

ExperimentMarker?Max mean expression
E-GEOD-124263yes2615.78
E-MTAB-9543yes1303.12
E-GEOD-134144yes29.07
E-ANND-3no4.53

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

8 targeting ZCWPW1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNAMax scoreAvg scoremiRNA target_count
HSA-MIR-315498.9466.551455
HSA-MIR-6760-5P98.8766.731515
HSA-MIR-4477A98.8369.752952
HSA-MIR-58398.7167.441791
HSA-MIR-6878-5P98.4967.912142
HSA-MIR-4662A-5P98.4867.181007
HSA-MIR-103B95.5166.85441
HSA-MIR-3130-3P94.9866.97574

Literature-anchored findings (GeneRIF, showing 7)

  • Of those 394 variants, 34 showed strong evidence of regulatory function (RegulomeDB score <3), and only 3 of them were genome-wide significant SNPs (ZCWPW1/rs1476679, CLU/rs1532278 and ABCA7/rs3764650). (PMID:24743338)
  • PILRB and GATS expression levels, within the ZCWPW1 locus, were associated with Alzheimer’s disease status. (PMID:26919393)
  • rs1476679 polymorphism in ZCWPW1 is associated with late-onset Alzheimer’s disease. (PMID:26958812)
  • ZCWPW1 is recruited to recombination hotspots by PRDM9 and is essential for meiotic double strand break repair. (PMID:32744506)
  • PRDM9 losses in vertebrates are coupled to those of paralogs ZCWPW1 and ZCWPW2. (PMID:35217607)
  • The histone modification reader ZCWPW1 promotes double-strand break repair by regulating cross-talk of histone modifications and chromatin accessibility at meiotic hotspots. (PMID:36068616)
  • A loss-of-function variant in ZCWPW1 causes human male infertility with sperm head defect and high DNA fragmentation. (PMID:38310235)

Cross-species orthologs

2 orthologs

OrganismSymbolGene ID
mus_musculusZcwpw1ENSMUSG00000037108
rattus_norvegicusZcwpw1ENSRNOG00000052199

Paralogs (1): ZCWPW2 (ENSG00000206559)

Protein

Protein identifiers

Zinc finger CW-type PWWP domain protein 1Q9H0M4 (reviewed: Q9H0M4)

All UniProt accessions (5): Q9H0M4, A0A0S2Z5N7, A0A804HK41, C9JUV7, H7C4V9

UniProt curated annotations — full annotation on UniProt →

Function. Dual histone methylation reader specific for PRDM9-catalyzed histone marks (H3K4me3 and H3K36me3). Facilitates the repair of PRDM9-induced meiotic double-strand breaks (DSBs). Essential for male fertility and spermatogenesis. Required for meiosis prophase I progression in male but not in female germ cells.

Subcellular location. Nucleus. Chromosome.

Tissue specificity. Testis.

Domain organisation. The CW-TYPE zinc finger mediates its binding to trimethylated histone H3K4me3.

Isoforms (5)

UniProt IDNamesCanonical?
Q9H0M4-11yes
Q9H0M4-22
Q9H0M4-33
Q9H0M4-44
Q9H0M4-55

RefSeq proteins (18): NP_001244937, NP_001372937, NP_001372938, NP_001372939, NP_001372940, NP_001372941, NP_001372942, NP_001372944, NP_001372945, NP_001372946, NP_001372947, NP_001372948, NP_001372949, NP_001372950, NP_001372951, NP_001372952, NP_001374995, NP_060454 (=MANE)

Domains & families (InterPro)

IDNameType
IPR000313PWWP_domDomain
IPR011124Znf_CWDomain
IPR042778ZCWPW1/ZCWPW2Family

Pfam: PF00855, PF07496

UniProt features (45 total): compositionally biased region 8, splice variant 8, mutagenesis site 7, binding site 4, strand 4, region of interest 3, sequence variant 2, turn 2, helix 2, chain 1, domain 1, modified residue 1, zinc finger region 1, coiled-coil region 1

Structure

Experimental structures (PDB)

2 structures.

PDBMethodResolution (Å)
2E61SOLUTION NMR
2RR4SOLUTION NMR

Predicted structure (AlphaFold)

ModelpLDDTFraction very-high
AF-Q9H0M4-F156.150.23

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 (4): 259; 264; 285; 296

Post-translational modifications (1): 636

Mutagenesis-validated functional residues (7):

PositionPhenotype
256loss of histone h3k4me3 binding; when associated with r-301; l-302 and p-303.
300reduced histone h3k4me3 binding but complete loss of non-methylated histone h3k4 binding.
301loss of histone h3k4me3 binding; when associated with i-256; l-302 and p-303.
302loss of histone h3k4me3 binding; when associated with i-256; r-301 and p-303.
303reduced histone h3k4me3 binding but no effect on non-methylated histone h3k4 binding.
303slightly reduced histone h3k4me3 and non-methylated histone h3k4 binding.
303loss of histone h3k4me3 binding; when associated with i-256; r-301 and l-302.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 149 (showing top): GOBP_MEIOTIC_CHROMOSOME_SEGREGATION, GOBP_REGULATION_OF_DOUBLE_STRAND_BREAK_REPAIR, RNGTGGGC_UNKNOWN, GOBP_CHROMOSOME_ORGANIZATION, GOBP_REGULATION_OF_DNA_RECOMBINATION, TGCGCANK_UNKNOWN, E2F4DP1_01, GOBP_MALE_GAMETE_GENERATION, GGGTGGRR_PAX4_03, GOBP_REGULATION_OF_DNA_REPAIR, AACWWCAANK_UNKNOWN, E2F1DP1_01, E2F1DP2_01, GOBP_ORGANELLE_FISSION, BACH2_01

GO Biological Process (9): meiosis I (GO:0007127), homologous chromosome pairing at meiosis (GO:0007129), spermatogenesis (GO:0007283), cell differentiation (GO:0030154), epigenetic regulation of gene expression (GO:0040029), positive regulation of DNA recombination (GO:0045911), positive regulation of double-strand break repair (GO:2000781), chromatin organization (GO:0006325), double-strand break repair involved in meiotic recombination (GO:1990918)

GO Molecular Function (6): zinc ion binding (GO:0008270), histone H3K4me3 reader activity (GO:0140002), protein binding (GO:0005515), metal ion binding (GO:0046872), histone H3K36me3 reader activity (GO:0140003), histone reader activity (GO:0140566)

GO Cellular Component (3): nucleus (GO:0005634), chromosome (GO:0005694), XY body (GO:0001741)

GO top-level categories

Rollup of top GO terms by namespace:

CategoryTerms
double-strand break repair2
histone H3 reader activity2
meiotic telophase I1
meiosis I cell cycle process1
meiotic nuclear division1
homologous chromosome segregation1
chromosome organization involved in meiotic cell cycle1
developmental process involved in reproduction1
male gamete generation1
cellular developmental process1
chromatin remodeling1
regulation of gene expression1
regulation of DNA recombination1
DNA recombination1
positive regulation of DNA metabolic process1
positive regulation of DNA repair1
regulation of double-strand break repair1
cellular component organization1
reciprocal meiotic recombination1
meiotic cell cycle process1
transition metal ion binding1
binding1
cation binding1
nucleosome1
histone binding1
chromatin-protein adaptor activity1
intracellular membrane-bounded organelle1
intracellular membraneless organelle1
sex chromosome1
condensed chromatin of inactivated sex chromosome1

Protein interactions and networks

STRING

1437 interactions, top by confidence (×1000):

Protein AProtein BPartner UniProtScore
ZCWPW1SLC24A4Q8NFF2827
ZCWPW1CASS4Q9NQ75800
ZCWPW1NME8Q8N427794
ZCWPW1FERMT2Q96AC1764
ZCWPW1ABCA7Q8IZY2762
ZCWPW1RIN3Q8TB24720
ZCWPW1SORL1Q92673720
ZCWPW1CELF1Q92879720
ZCWPW1MS4A6AQ9H2W1719
ZCWPW1PICALMQ13492718
ZCWPW1CD2APQ9Y5K6713
ZCWPW1HLA-DRB5Q30154698
ZCWPW1INPP5DQ92835692
ZCWPW1BIN1O00499670
ZCWPW1EPHA1P21709661

IntAct

8 interactions, top by confidence:

ABTypeScore
ZCWPW1psi-mi:“MI:0407”(direct interaction)0.440
ZCWPW1H1-2psi-mi:“MI:0915”(physical association)0.400
ZCWPW1PLXDC2psi-mi:“MI:0915”(physical association)0.400
MEF2AREV3Lpsi-mi:“MI:0914”(association)0.350
BMI1MEIS3P1psi-mi:“MI:0914”(association)0.350

BioGRID (11): ZCWPW1 (Affinity Capture-MS), ZCWPW1 (Affinity Capture-MS), MEOX2 (Two-hybrid), L3MBTL3 (Two-hybrid), VAC14 (Two-hybrid), ZCWPW1 (Proximity Label-MS), ZCWPW1 (Negative Genetic), PLXDC2 (Affinity Capture-MS), ZCWPW1 (Cross-Linking-MS (XL-MS)), ZCWPW1 (Cross-Linking-MS (XL-MS)), ZCWPW1 (Cross-Linking-MS (XL-MS))

ESM2 similar proteins: A0A1B0GUA9, A0JNH1, A1L170, A2TJV2, A6H7B4, A6NFA0, A6NGY1, A6X8Z5, A7YY35, B2RQL2, D3Z1D3, M0RD54, P43359, Q05860, Q0VF49, Q1RMX6, Q1RN00, Q2M1Z3, Q32LI3, Q3URK1, Q5EBJ4, Q5M831, Q5RJL0, Q62100, Q640N3, Q64256, Q642A3, Q66H53, Q66LM6, Q68D20, Q68DA7, Q68US1, Q6AXN6, Q6AYA8, Q6IR42, Q711Q0, Q80VY2, Q86UF4, Q8IY42, Q8TDR4

Diamond homologs: A0AHX3, A0L7L5, A2RCQ8, A2RJC8, A3DE67, A4IRL1, A4VSW4, A4VZ51, A4XK62, A6TNX0, A7Z7E7, A8MHU4, A9KR74, B1YJY5, B4U143, B5XI46, B8CX98, B8DI00, B8I1Z8, B9MK78, C0MAV6, C0MEM8, C1L2D7, C5D5Q8, E1BYJ2, O04716, O51125, O74502, O96028, P52701, P54276, P61671, Q02XM1, Q03834, Q03ES2, Q03IU4, Q045P1, Q189Q3, Q18FJ9, Q3IUH3

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

ClassificationCount (floor)
Pathogenic1
Likely pathogenic0
Uncertain significance82
Likely benign9
Benign1

Top pathogenic / likely-pathogenic (1)

Variant IDHGVSClassification
2685254GRCh37/hg19 7q22.1(chr7:99114000-101878272)x1Pathogenic

SpliceAI

2823 predictions. Top by Δscore:

VariantEffectΔscore
7:100403692:A:ACdonor_gain1.0000
7:100403693:C:CTdonor_gain1.0000
7:100403693:CTG:Cdonor_gain1.0000
7:100403707:T:TAdonor_gain1.0000
7:100403710:T:TAdonor_gain1.0000
7:100406794:TTAGA:Tacceptor_gain1.0000
7:100406795:TAGA:Tacceptor_gain1.0000
7:100406797:GA:Gacceptor_gain1.0000
7:100406799:C:CCacceptor_gain1.0000
7:100415987:T:Cdonor_gain1.0000
7:100415991:T:Adonor_gain1.0000
7:100416095:CTT:Cacceptor_gain1.0000
7:100403688:T:Cdonor_gain0.9900
7:100403688:TCTTA:Tdonor_loss0.9900
7:100403689:CTTA:Cdonor_loss0.9900
7:100403690:TTACT:Tdonor_loss0.9900
7:100403691:T:TGdonor_loss0.9900
7:100403692:ACTG:Adonor_loss0.9900
7:100403693:C:Adonor_loss0.9900
7:100403693:CT:Cdonor_gain0.9900
7:100403693:CTGT:Cdonor_gain0.9900
7:100403703:T:Adonor_gain0.9900
7:100403725:T:TAdonor_gain0.9900
7:100403783:AGT:Aacceptor_gain0.9900
7:100403786:C:CCacceptor_gain0.9900
7:100403786:C:CGacceptor_loss0.9900
7:100405024:T:Cdonor_gain0.9900
7:100405089:TTTTT:Tacceptor_gain0.9900
7:100406688:GCTC:Gdonor_loss0.9900
7:100406689:CT:Cdonor_loss0.9900

AlphaMissense

4278 scored. Top likely-pathogenic:

VariantProtein changeam_pathogenicity
7:100406753:A:GW371R0.999
7:100406753:A:TW371R0.999
7:100407302:A:GW331R0.999
7:100407302:A:TW331R0.999
7:100409492:C:AR268S0.999
7:100409492:C:GR268S0.999
7:100409449:A:GW283R0.998
7:100409449:A:TW283R0.998
7:100409493:C:GR268T0.998
7:100409497:A:GW267R0.998
7:100409497:A:TW267R0.998
7:100408564:A:GW322R0.997
7:100408564:A:TW322R0.997
7:100409495:C:AW267C0.997
7:100409495:C:GW267C0.997
7:100409521:A:GC259R0.997
7:100407295:C:TG333D0.996
7:100407300:C:AW331C0.996
7:100407300:C:GW331C0.996
7:100408560:G:TA323D0.996
7:100408561:C:GA323P0.996
7:100408573:A:GS319P0.996
7:100409447:C:AW283C0.996
7:100409447:C:GW283C0.996
7:100406734:A:GL377P0.995
7:100406751:C:AW371C0.995
7:100406751:C:GW371C0.995
7:100406758:C:GR369P0.995
7:100406785:A:TV360E0.995
7:100409443:A:GC285R0.995

dbSNP variants (sampled 300 via entrez): RS1000070255 (7:100402528 T>C,G), RS1000135882 (7:100413824 G>C), RS1000215 (7:100406920 T>C), RS1000217 (7:100407147 C>A,G), RS1000271968 (7:100414290 G>A), RS1000333534 (7:100428392 C>T), RS1000339558 (7:100406551 C>A,T), RS1000440512 (7:100421595 T>G), RS1000450244 (7:100421232 C>A,T), RS1000645204 (7:100427491 G>A,C,T), RS1000676116 (7:100427923 C>G), RS1000719121 (7:100415137 G>A), RS1000728752 (7:100408395 T>C), RS1000730700 (7:100407814 G>C), RS1001099584 (7:100420198 T>A)

Disease associations

OMIM: gene MIM:618900 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

15 associations (top):

StudyTraitp-value
GCST002245_15Alzheimer’s disease (late onset)6.000000e-10
GCST004607_155Plateletcrit5.000000e-13
GCST004616_187Platelet distribution width5.000000e-51
GCST007319_16Alzheimer’s disease (late onset)6.000000e-09
GCST007319_32Alzheimer’s disease (late onset)2.000000e-07
GCST007320_103Alzheimer’s disease or family history of Alzheimer’s disease6.000000e-14
GCST007320_71Alzheimer’s disease or family history of Alzheimer’s disease2.000000e-15
GCST007321_32Family history of Alzheimer’s disease2.000000e-10
GCST007321_33Family history of Alzheimer’s disease1.000000e-09
GCST009021_10Alzheimer’s disease2.000000e-06
GCST010002_259Refractive error3.000000e-16
GCST010083_55Hemoglobin levels2.000000e-26
GCST010702_48Subcortical volume (MOSTest)6.000000e-10
GCST010703_289Brain morphology (MOSTest)6.000000e-15
GCST90002404_296Red cell distribution width3.000000e-14

EFO canonical traits (6, from GWAS)

EFO IDTrait name
EFO:0007985platelet crit
EFO:0007984platelet component distribution width
EFO:0009268family history of Alzheimer’s disease
EFO:0004509hemoglobin measurement
EFO:0004346neuroimaging measurement
EFO:0009188Red cell distribution width

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4739863 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

25 total (human), top 25 by PubMed support.

ChemicalActions (top 5)PubMed papers
Benzo(a)pyrenedecreases expression, increases methylation2
Valproic Acidaffects expression, decreases methylation2
Thapsigarginincreases expression2
aristolochic acid Iincreases expression1
triphenyl phosphateaffects expression1
beta-lapachoneincreases expression1
sodium arsenitedecreases expression1
di-n-butylphosphoric acidaffects expression1
perfluorooctane sulfonic acidincreases expression1
ICG 001increases expression1
jinfukangincreases expression1
Sunitinibincreases expression1
Air Pollutantsincreases abundance, increases expression1
Atrazinedecreases expression1
Rotenoneincreases expression1
Seleniumaffects cotreatment, increases expression1
Silicon Dioxidedecreases expression1
Smokedecreases expression1
Tobacco Smoke Pollutionaffects expression1
Tunicamycinincreases expression1
Vitamin Eaffects cotreatment, increases expression1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxidedecreases expression1
Cadmium Chloridedecreases expression1
Copper Sulfateincreases expression1
Particulate Matterincreases abundance, increases expression1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay IDTypeDescriptionSource paper
CHEMBL4736942BindingBinding affinity to ZCWPW1 PWWP1 domain (unknown origin) assessed as aggregation temperature at 400 uM by heating at 25 to 85 degC by differential static light scattering methodDiscovery of Small-Molecule Antagonists of the PWWP Domain of NSD2. — J Med Chem

Clinical trials (associated diseases)

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

No linked Atlas pages yet — the cross-entity mesh grows as the corpus expands.