ZCWPW2

Summary

ZCWPW2 (zinc finger CW-type and PWWP domain containing 2, HGNC:23574) is a protein-coding gene on chromosome 3p24.1, encoding Zinc finger CW-type PWWP domain protein 2 (Q504Y3). Histone methylation reader which binds to non-methylated (H3K4me0), monomethylated (H3K4me1), dimethylated (H3K4me2) and trimethylated (H3K4me3) ‘Lys-4’ on histone H3.

Enables methylated histone binding activity. Predicted to be active in nucleus.

Source: NCBI Gene 152098 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 77 total
• MANE Select transcript: NM_001040432

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23574
Approved symbol	ZCWPW2
Name	zinc finger CW-type and PWWP domain containing 2
Location	3p24.1
Locus type	gene with protein product
Status	Approved
Aliases	ZCW2
Ensembl gene	ENSG00000206559
Ensembl biotype	protein_coding
OMIM	621188
Entrez	152098

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 11 protein_coding

ENST00000383768, ENST00000419130, ENST00000420223, ENST00000428875, ENST00000457897, ENST00000888968, ENST00000888969, ENST00000888970, ENST00000888971, ENST00000888972, ENST00000920408

RefSeq mRNA: 3 — MANE Select: NM_001040432 NM_001040432, NM_001324169, NM_001324170

CCDS: CCDS33723

Canonical transcript exons

ENST00000383768 — 10 exons

Exon	Start	End
ENSE00001336158	28348721	28349203
ENSE00001498559	28520992	28521116
ENSE00001498560	28515554	28515621
ENSE00001498561	28514064	28514122
ENSE00001498562	28492127	28492173
ENSE00001498563	28478814	28478931
ENSE00001498564	28435110	28435269
ENSE00001498565	28413056	28413400
ENSE00001498566	28390498	28390617
ENSE00003841787	28524527	28526358

Expression profiles

Bgee: expression breadth ubiquitous, 163 present calls, max score 86.31.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 3.7845 / max 208.2473, expressed in 1219 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
35786	2.8761	858
202711	0.9084	473

Top tissues by expression

249 total, 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	86.31	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	81.81	gold quality
sperm	CL:0000019	80.84	gold quality
left testis	UBERON:0004533	77.79	gold quality
right testis	UBERON:0004534	77.24	gold quality
testis	UBERON:0000473	76.91	gold quality
muscle of leg	UBERON:0001383	74.57	gold quality
gastrocnemius	UBERON:0001388	74.48	gold quality
hindlimb stylopod muscle	UBERON:0004252	74.16	gold quality
popliteal artery	UBERON:0002250	71.07	gold quality
tibial artery	UBERON:0007610	71.07	gold quality
stromal cell of endometrium	CL:0002255	69.81	gold quality
calcaneal tendon	UBERON:0003701	69.50	gold quality
aorta	UBERON:0000947	69.26	gold quality
mucosa of stomach	UBERON:0001199	68.95	gold quality
monocyte	CL:0000576	68.84	gold quality
descending thoracic aorta	UBERON:0002345	68.73	gold quality
right atrium auricular region	UBERON:0006631	68.69	gold quality
leukocyte	CL:0000738	68.39	gold quality
islet of Langerhans	UBERON:0000006	67.97	gold quality
left coronary artery	UBERON:0001626	67.54	gold quality
right coronary artery	UBERON:0001625	67.45	gold quality
cardiac atrium	UBERON:0002081	67.45	gold quality
muscle layer of sigmoid colon	UBERON:0035805	67.45	gold quality
thoracic aorta	UBERON:0001515	67.25	gold quality
ascending aorta	UBERON:0001496	67.14	gold quality
gall bladder	UBERON:0002110	67.13	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	67.06	gold quality
lower esophagus muscularis layer	UBERON:0035833	66.96	gold quality
lower esophagus	UBERON:0013473	66.95	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	5.16

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

69 targeting ZCWPW2, 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-9-5P	100.00	72.28	2361
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-374B-5P	99.90	69.98	2734
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-345-3P	99.89	70.23	1421
HSA-MIR-944	99.82	70.85	3042
HSA-MIR-4495	99.82	72.08	3080
HSA-MIR-4799-5P	99.82	70.60	2663
HSA-MIR-202-5P	99.78	67.65	991
HSA-MIR-4517	99.76	69.19	1867
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-6885-3P	99.75	70.36	3187
HSA-MIR-518A-5P	99.70	69.01	2209
HSA-MIR-527	99.70	69.01	2209
HSA-MIR-5580-3P	99.70	69.41	2052
HSA-MIR-670-5P	99.67	69.94	1565
HSA-MIR-29B-2-5P	99.67	68.98	1726
HSA-MIR-7-5P	99.67	70.53	1809
HSA-MIR-4470	99.66	69.35	1767
HSA-MIR-425-5P	99.59	67.67	900

Literature-anchored findings (GeneRIF, showing 1)

• PRDM9 losses in vertebrates are coupled to those of paralogs ZCWPW1 and ZCWPW2. (PMID:35217607)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Zcwpw2	ENSMUSG00000032443
rattus_norvegicus	Zcwpw2	ENSRNOG00000053820

Paralogs (1): ZCWPW1 (ENSG00000078487)

Protein

Protein identifiers

Zinc finger CW-type PWWP domain protein 2 — Q504Y3 (reviewed: Q504Y3)

All UniProt accessions (5): C9JFK0, H7C087, H7C0K4, H7C0L9, Q504Y3

UniProt curated annotations — full annotation on UniProt →

Function. Histone methylation reader which binds to non-methylated (H3K4me0), monomethylated (H3K4me1), dimethylated (H3K4me2) and trimethylated (H3K4me3) ‘Lys-4’ on histone H3. The order of binding preference is H3K4me3 > H3K4me2 > H3K4me1 > H3K4me0.

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

RefSeq proteins (3): NP_001035522, NP_001311098, NP_001311099 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000313	PWWP_dom	Domain
IPR011124	Znf_CW	Domain
IPR042778	ZCWPW1/ZCWPW2	Family

Pfam: PF00855, PF07496

UniProt features (22 total): mutagenesis site 8, binding site 4, strand 2, helix 2, chain 1, domain 1, turn 1, zinc finger region 1, region of interest 1, sequence variant 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
4Z0O	X-RAY DIFFRACTION	1.57
4Z0R	X-RAY DIFFRACTION	1.75
4O62	X-RAY DIFFRACTION	1.78

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q504Y3-F1	72.85	0.34

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): 33; 38; 60; 71

Mutagenesis-validated functional residues (8):

Position	Phenotype
30	significantly reduced histone h3k4me3 binding.
30	loss of histone h3k4me3 binding; when associated with f-41.
30	loss of histone h3k4me3 binding.
41	significantly reduced histone h3k4me3 binding. loss of histone h3k4me3 binding; when associated with l-30 or m-30.
78	little effect on histone h3k4me3 binding.
30	reduced histone h3k4me3 binding.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 53 (showing top): MARTIN_NFKB_TARGETS_DN, BRUINS_UVC_RESPONSE_LATE, chr3p24, PEDRIOLI_MIR31_TARGETS_UP, ZWANG_TRANSIENTLY_UP_BY_2ND_EGF_PULSE_ONLY, GSE13522_CTRL_VS_T_CRUZI_Y_STRAIN_INF_SKIN_IFNG_KO_DN, FOXD2_TARGET_GENES, FOXJ2_TARGET_GENES, HES4_TARGET_GENES, SALL4_TARGET_GENES, MIR153_5P, MIR4495, MIR944, MIR6885_3P, MIR9_5P

GO Biological Process (1): chromatin organization (GO:0006325)

GO Molecular Function (4): zinc ion binding (GO:0008270), histone H3K4me3 reader activity (GO:0140002), protein binding (GO:0005515), metal ion binding (GO:0046872)

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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular component organization	1
transition metal ion binding	1
histone H3 reader activity	1
binding	1
cation binding	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1237 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ZCWPW2	SPO11	Q9Y5K1	474
ZCWPW2	PRDM9	Q9NQV7	433
ZCWPW2	NSD2	O96028	415
ZCWPW2	FBXO47	Q5MNV8	381
ZCWPW2	MORC3	Q14149	371
ZCWPW2	TEX15	Q9BXT5	371
ZCWPW2	DHRS4L2	Q6PKH6	370
ZCWPW2	ANKRD31	Q8N7Z5	367
ZCWPW2	ZNF133	P52736	367
ZCWPW2	MEI1	Q5TIA1	358
ZCWPW2	THSD1	Q9NS62	343
ZCWPW2	FMR1NB	Q8N0W7	339
ZCWPW2	CFAP44	Q96MT7	339
ZCWPW2	RPS6KA2	Q15349	314
ZCWPW2	POLR3F	Q9H1D9	312

IntAct

7 interactions, top by confidence:

A	B	Type	Score
HSF2BP	ZCWPW2	psi-mi:“MI:0915”(physical association)	0.560
PBX2	ZCWPW2	psi-mi:“MI:0915”(physical association)	0.560
ZCWPW2	HSF2BP	psi-mi:“MI:0915”(physical association)	0.000
ZCWPW2	PBX2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (5): ZCWPW2 (Affinity Capture-MS), ZCWPW2 (Two-hybrid), ZCWPW2 (Two-hybrid), RBM46 (Cross-Linking-MS (XL-MS)), ZCWPW2 (Reconstituted Complex)

ESM2 similar proteins: A0A163UT06, A0A7H0DN94, A6ZTB4, A7E2Z2, B9RU15, G5EBM1, H9JDT2, O13682, O13881, O17514, O76720, O94324, P04312, P0C9F5, P0C9F6, P21012, P32097, P33071, P38890, P41474, P42124, P47156, P70351, Q08BS4, Q09291, Q10077, Q15910, Q18008, Q18317, Q28D84, Q4R381, Q4V863, Q504Y3, Q5RDS6, Q5UNX9, Q5UQB9, Q5UR71, Q61188, Q84WW6, Q8VZJ1

Diamond homologs: Q08EN7, Q504Y3, Q8TE76, Q2LAE1, Q9H0M4, E1BYJ2, O96028, P52701, P54276, Q6IR42, Q8BMD7, Q8BVE8

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	64
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2088 predictions. Top by Δscore:

Variant	Effect	Δscore
3:28413052:CCAG:C	acceptor_loss	1.0000
3:28413053:CAG:C	acceptor_loss	1.0000
3:28413054:A:AG	acceptor_gain	1.0000
3:28413054:A:C	acceptor_loss	1.0000
3:28413055:G:GG	acceptor_gain	1.0000
3:28413055:GAT:G	acceptor_gain	1.0000
3:28413055:GATT:G	acceptor_gain	1.0000
3:28413055:GATTA:G	acceptor_gain	1.0000
3:28435104:T:TA	acceptor_gain	1.0000
3:28435107:AAGTT:A	acceptor_gain	1.0000
3:28435108:A:G	acceptor_gain	1.0000
3:28435109:GTT:G	acceptor_gain	1.0000
3:28435270:G:GA	donor_loss	1.0000
3:28478801:T:A	acceptor_gain	1.0000
3:28478811:T:G	acceptor_gain	1.0000
3:28478812:A:AG	acceptor_gain	1.0000
3:28478813:G:GA	acceptor_gain	1.0000
3:28478813:GC:G	acceptor_gain	1.0000
3:28478813:GCCA:G	acceptor_gain	1.0000
3:28492172:GG:G	donor_gain	1.0000
3:28492173:GG:G	donor_gain	1.0000
3:28496796:A:AG	acceptor_gain	1.0000
3:28496797:G:GG	acceptor_gain	1.0000
3:28496900:AAAAG:A	donor_loss	1.0000
3:28496901:AAAG:A	donor_loss	1.0000
3:28496902:AA:A	donor_gain	1.0000
3:28496902:AAGTA:A	donor_loss	1.0000
3:28496903:AG:A	donor_loss	1.0000
3:28496904:G:GG	donor_gain	1.0000
3:28496905:T:TC	donor_loss	1.0000

AlphaMissense

2365 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:28413189:T:A	W41R	0.996
3:28413189:T:C	W41R	0.996
3:28413194:A:C	R42S	0.995
3:28413194:A:T	R42S	0.995
3:28413240:T:A	W58R	0.995
3:28413240:T:C	W58R	0.995
3:28435111:T:A	W112R	0.994
3:28435111:T:C	W112R	0.994
3:28413156:T:A	W30R	0.993
3:28413156:T:C	W30R	0.993
3:28413191:G:C	W41C	0.993
3:28413191:G:T	W41C	0.993
3:28413193:G:C	R42T	0.992
3:28435198:T:C	F141L	0.992
3:28435200:C:A	F141L	0.992
3:28435200:C:G	F141L	0.992
3:28413165:T:C	C33R	0.989
3:28413242:G:C	W58C	0.989
3:28413242:G:T	W58C	0.989
3:28413373:T:A	V102D	0.989
3:28413165:T:A	C33S	0.988
3:28413166:G:C	C33S	0.988
3:28413246:T:C	C60R	0.985
3:28435113:G:C	W112C	0.985
3:28435113:G:T	W112C	0.985
3:28413158:G:C	W30C	0.984
3:28413158:G:T	W30C	0.984
3:28413192:A:G	R42G	0.983
3:28435199:T:C	F141S	0.983
3:28435118:G:A	G114E	0.982

dbSNP variants (sampled 300 via entrez): RS1000007672 (3:28376588 C>G), RS1000050273 (3:28407435 A>G,T), RS1000076633 (3:28481047 A>T), RS1000099845 (3:28411197 C>T), RS1000100240 (3:28498528 G>A), RS1000111824 (3:28393421 A>G), RS1000113836 (3:28437145 C>T), RS1000114026 (3:28371123 C>T), RS1000125709 (3:28396118 A>G), RS1000143958 (3:28455299 G>A,T), RS1000149630 (3:28454552 T>C), RS1000152788 (3:28498242 T>C), RS1000166982 (3:28483745 A>G), RS1000171590 (3:28361264 T>C), RS1000175764 (3:28455729 T>C)

Disease associations

OMIM: gene MIM:621188 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST003901_9	Cognitive decline (age-related)	1.000000e-06
GCST90002388_190	Lymphocyte count	6.000000e-09
GCST90002399_133	Neutrophil percentage of white cells	3.000000e-14
GCST90007005_1	Gut microbiota relative abundance (Eubacterium belonging to family Erysipelotrichaceae)	3.000000e-06

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004587	lymphocyte count
EFO:0007990	neutrophil percentage of leukocytes
EFO:0007874	gut microbiome measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

14 total (human), top 14 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases methylation	2
Aflatoxin B1	decreases methylation, increases methylation	2
sodium arsenite	decreases expression	1
butyraldehyde	decreases expression	1
pentanal	decreases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, decreases expression	1
Sunitinib	increases expression	1
Catechin	affects cotreatment, decreases expression	1
Doxorubicin	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Valproic Acid	decreases methylation	1
Okadaic Acid	decreases expression	1
S-Nitrosoglutathione	increases expression	1
Particulate Matter	increases expression	1

Clinical trials (associated diseases)

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