ZC3HAV1

Summary

ZC3HAV1 (zinc finger CCCH-type containing, antiviral 1, HGNC:23721) is a protein-coding gene on chromosome 7q34, encoding Zinc finger CCCH-type antiviral protein 1 (Q7Z2W4). Antiviral protein which inhibits the replication of viruses by recruiting the cellular RNA degradation machineries to degrade the viral mRNAs.

This gene encodes a CCCH-type zinc finger protein. This antiviral protein inhibits viral replication by recruiting cellular RNA degradation machineries to degrade viral mRNAs. The encoded protein plays an important role in the innate immune response against multiple DNA and RNA viruses, including Ebola virus, HIV and SARS-CoV-2 (which causes COVID-19).

Source: NCBI Gene 56829 — RefSeq curated summary.

At a glance

• GWAS associations: 7
• Clinical variants (ClinVar): 151 total
• Druggable target: yes
• MANE Select transcript: NM_020119

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23721
Approved symbol	ZC3HAV1
Name	zinc finger CCCH-type containing, antiviral 1
Location	7q34
Locus type	gene with protein product
Status	Approved
Aliases	ZAP, FLB6421, FLJ13288, MGC48898, ZC3HDC2, ZC3H2, PARP13, ARTD13
Ensembl gene	ENSG00000105939
Ensembl biotype	protein_coding
OMIM	607312
Entrez	56829

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 6 protein_coding

ENST00000242351, ENST00000460845, ENST00000464606, ENST00000471652, ENST00000680309, ENST00000921229

RefSeq mRNA: 3 — MANE Select: NM_020119 NM_001363491, NM_020119, NM_024625

CCDS: CCDS55171, CCDS5851, CCDS94214

Canonical transcript exons

ENST00000242351 — 13 exons

Exon	Start	End
ENSE00000833436	139053451	139053581
ENSE00000833437	139053965	139054095
ENSE00000833438	139055205	139055295
ENSE00000833440	139064879	139064999
ENSE00000833441	139073856	139074030
ENSE00000833442	139076286	139076409
ENSE00000899247	139043515	139047853
ENSE00001088327	139078552	139078653
ENSE00001220006	139061036	139061138
ENSE00001826847	139109024	139109720
ENSE00002495081	139079470	139080243
ENSE00002514961	139089624	139089759
ENSE00002522352	139083780	139084032

Expression profiles

Bgee: expression breadth ubiquitous, 283 present calls, max score 96.85.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 45.9908 / max 4932.8240, expressed in 1815 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
86485	29.7498	1746
86483	15.3852	1793
86484	0.3276	97
86486	0.2415	71
204789	0.1870	63
86475	0.0424	18
86487	0.0383	8
86488	0.0190	8

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
trabecular bone tissue	UBERON:0002483	96.85	gold quality
endothelial cell	CL:0000115	96.22	gold quality
cervix squamous epithelium	UBERON:0006922	94.42	gold quality
visceral pleura	UBERON:0002401	94.38	gold quality
blood	UBERON:0000178	94.22	gold quality
choroid plexus epithelium	UBERON:0003911	94.02	gold quality
pleura	UBERON:0000977	93.98	gold quality
parietal pleura	UBERON:0002400	93.94	gold quality
jejunal mucosa	UBERON:0000399	93.74	gold quality
tongue squamous epithelium	UBERON:0006919	93.62	gold quality
bone element	UBERON:0001474	93.24	gold quality
pancreatic ductal cell	CL:0002079	93.09	gold quality
superficial temporal artery	UBERON:0001614	92.89	gold quality
bronchial epithelial cell	CL:0002328	92.74	gold quality
bone marrow	UBERON:0002371	92.30	gold quality
colonic mucosa	UBERON:0000317	92.26	gold quality
mucosa of sigmoid colon	UBERON:0004993	92.25	gold quality
epithelium of bronchus	UBERON:0002031	92.08	gold quality
upper leg skin	UBERON:0004262	92.08	gold quality
buccal mucosa cell	CL:0002336	91.99	gold quality
bronchus	UBERON:0002185	91.86	gold quality
mucosa of paranasal sinus	UBERON:0005030	91.71	gold quality
lower lobe of lung	UBERON:0008949	91.61	gold quality
gingiva	UBERON:0001828	91.57	gold quality
ileal mucosa	UBERON:0000331	91.56	gold quality
bone marrow cell	CL:0002092	91.55	gold quality
parotid gland	UBERON:0001831	91.26	gold quality
seminal vesicle	UBERON:0000998	91.25	gold quality
skin of hip	UBERON:0001554	91.15	gold quality
tibia	UBERON:0000979	91.08	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-7052	yes	9376.67
E-CURD-122	yes	25.14
E-CURD-10	no	1560.73
E-MTAB-10137	no	1183.40
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): STAT1

miRNA regulators (miRDB)

170 targeting ZC3HAV1, 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-3613-3P	100.00	76.36	7965
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-10401-5P	99.99	65.79	948
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4775	99.98	75.00	6394

Literature-anchored findings (GeneRIF, showing 40)

• ZAP, TIPARP and FLJ22693 proteins with TPH, WW and PARP-like domains constitute the TIPARP family. (PMID:12851707)
• Our findings demonstrate that ZAP can synergize with another IFN-induced factor(s) for maximal alphaviruses antiviral activity and that ZAP’s intrinsic antiviral activity on virion production and cell survival can have cell-type-specific outcomes. (PMID:17928353)
• This study finds that human ZAP encodes a potent antiviral activity against alphaviruses. (PMID:18225958)
• ZAP is a direct target gene of IRF3 action in cellular antiviral respon (PMID:20048147)
• These findings suggest that ZAP recruits the cellular RNA degradation machinery for the degradation of viral RNA. (PMID:20451500)
• shorter isoform (ZAPS)stimulates interferon responses mediated by the RNA helicase RIG-I (PMID:21102435)
• Results indicate that ZAP inhibits HIV-1 by recruiting both the 5’ and 3’ mRNA degradation machinery to specifically promote the degradation of multiply spliced HIV-1 mRNAs. (PMID:21876179)
• The Thr851Ile SNP of ZC3HAV1 is significantly associated with susceptibility to multiple sclerosis (PMID:22319148)
• ZAP inhibits M2 expression and regulates the maintenance of MHV-68 latency (PMID:22951821)
• S-farnesylation is crucial for targeting the long-isoform of ZAP to endolysosomes and enhancing the antiviral activity of this immune effector. (PMID:23776219)
• Data suggest that two isoforms of ZAP (ZAP-long and -short) inhibit replication of hepatitis B virus and replication of viral DNA in hepatocytes through posttranscriptional down-regulation of viral RNA. (PMID:23853601)
• Contrary to previous assumptions, these results indicate an essential function of the PARP-like domain in hZAP-L’s antiviral activity. (PMID:24457973)
• PARP13 regulates cellular mRNA post-transcriptionally and functions as a pro-apoptotic factor by destabilizing TRAILR4 transcript. (PMID:25382312)
• results show that PARP13 lacks the structural requirements for ADP-ribosyltransferase activity (PMID:25635049)
• PARP13 regulates RNA in stress and disease. [review] (PMID:25851173)
• The association of the ZAP ribonucleoprotein particle with many interferon-stimulated gene products indicates it may be a key player in the interferon response. (PMID:26001115)
• Suppressing Matrin 3 powers a heightened and broader ZAP restriction of HIV-1 gene expression. (PMID:26129669)
• Herpes simplex virus 1 UL41 was shown for the first time to evade the antiviral function of human ZAP via its RNase activity. (PMID:26625984)
• In response to DNA damage, activated and auto-poly-ADP-ribosylated PARP1 dissociates from HSF1-PARP13, and redistributes to DNA lesions and DNA damage-inducible gene loci. (PMID:29158484)
• The results indicate that an equilibrium between ZAP and enterovirus 3C protease controls viral infection. (PMID:29182509)
• ZAP may act as an intrinsic antiviral factor through specific RNA binding to fight against Japanese encephalitis virus infection (PMID:30016363)
• results indicate that low ZAP expression is common in hepatocellular carcinoma (HCC), is correlated with the progression of HCC and with a poorer prognosis for HCC patients, and plays an important role in HCC carcinogenesis (PMID:30196292)
• This is the first study that defines the antiviral capacities of individual ZAP isoforms in the absence of endogenous ZAP expression and, hence, cross talk with other isoforms. Data demonstrate that ZAP is expressed as four different forms: ZAPS, ZAPM, ZAPL, and ZAPXL. (PMID:31118263)
• The dependence on expression of ZAP antiviral protein (ZAP), 2’-5’-oligoadenylate synthetase (OAS3) and 2-5A-dependent ribonuclease (RNAseL) for CpG/UpA-mediated attenuation and the variable and often low level expression of these pathway proteins in certain cell types. (PMID:31276592)
• KHNYN as a novel cofactor for ZAP to target CpG-containing retroviral RNA for degradation. (PMID:31284899)
• ZAP 4 zinc fingers create a basic patch on the ZAP RNA-binding domain surface.ZAP crystal structure explains how ZAP is able to specifically recognize foreign, CG-rich viral RNA. (PMID:31719195)
• this study shows that RNA-binding protein isoforms ZAP-S and ZAP-L have distinct antiviral and immune resolution functions (PMID:31740798)
• CpG Dinucleotides Inhibit HIV-1 Replication through Zinc Finger Antiviral Protein (ZAP)-Dependent and -Independent Mechanisms. (PMID:31748389)
• there was a dose-dependent reduction in virus production with ZAP expression (PMID:31842935)
• CpG Frequency in the 5’ Third of the env Gene Determines Sensitivity of Primary HIV-1 Strains to the Zinc-Finger Antiviral Protein. (PMID:31937644)
• Zinc-finger antiviral protein (ZAP) is a restriction factor for replication of modified vaccinia virus Ankara (MVA) in human cells. (PMID:32866210)
• Human cytomegalovirus evades ZAP detection by suppressing CpG dinucleotides in the major immediate early 1 gene. (PMID:32886716)
• SARS-CoV-2 Is Restricted by Zinc Finger Antiviral Protein despite Preadaptation to the Low-CpG Environment in Humans. (PMID:33067384)
• Coronavirus genomes carry the signatures of their habitats. (PMID:33351847)
• Association of Zinc Finger Antiviral Protein Binding to Viral Genomic RNA with Attenuation of Replication of Echovirus 7. (PMID:33408233)
• Chemical genetics and proteome-wide site mapping reveal cysteine MARylation by PARP-7 on immune-relevant protein targets. (PMID:33475084)
• The Interaction of Human and Epstein-Barr Virus miRNAs with Multiple Sclerosis Risk Loci. (PMID:33805769)
• The Zinc Finger Antiviral Protein ZAP Restricts Human Cytomegalovirus and Selectively Binds and Destabilizes Viral UL4/UL5 Transcripts. (PMID:33947766)
• ZC3HAV1 promotes the proliferation and metastasis via regulating KRAS in pancreatic cancer. (PMID:34319912)
• Expression of Zinc-Finger Antiviral Protein in hCMEC/D3 Human Cerebral Microvascular Endothelial Cells: Effect of a Toll-Like Receptor 3 Agonist. (PMID:34937041)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Zc3hav1	ENSMUSG00000029826
rattus_norvegicus	Zc3hav1	ENSRNOG00000013948

Paralogs (8): PARP12 (ENSG00000059378), PARP11 (ENSG00000111224), PARP9 (ENSG00000138496), ZC3HAV1L (ENSG00000146858), TIPARP (ENSG00000163659), PARP14 (ENSG00000173193), PARP15 (ENSG00000173200), PARP10 (ENSG00000178685)

Protein

Protein identifiers

Zinc finger CCCH-type antiviral protein 1 — Q7Z2W4 (reviewed: Q7Z2W4)

Alternative names: ADP-ribosyltransferase diphtheria toxin-like 13, Inactive Poly [ADP-ribose] polymerase 13, Zinc finger CCCH domain-containing protein 2, Zinc finger antiviral protein

All UniProt accessions (4): Q7Z2W4, A0A7P0T8C6, C9J6P4, H7C5K1

UniProt curated annotations — full annotation on UniProt →

Function. Antiviral protein which inhibits the replication of viruses by recruiting the cellular RNA degradation machineries to degrade the viral mRNAs. Binds to a ZAP-responsive element (ZRE) present in the target viral mRNA, recruits cellular poly(A)-specific ribonuclease PARN to remove the poly(A) tail, and the 3’-5’ exoribonuclease complex exosome to degrade the RNA body from the 3’-end. It also recruits the decapping complex DCP1-DCP2 through RNA helicase p72 (DDX17) to remove the cap structure of the viral mRNA to initiate its degradation from the 5’-end. Its target viruses belong to families which include retroviridae, including human immunodeficiency virus type 1, filoviridae: ebola virus (EBOV) and marburg virus (MARV), togaviridae: sindbis virus (SINV) and Ross river virus (RRV). Specifically targets the multiply spliced but not unspliced or singly spliced HIV-1 mRNAs for degradation. Exhibits stronger antiviral activity than isoform 2 against MuLV expression and Semliki forest virus infection. Increased antiviral activity may be due to more efficient targeting to endocytic membranes through S-farnesylation. Similarly to isoform 2, prevents HIV-1 infection. Positive regulator of RIGI signaling during the innate antiviral immune response. Associates with RIGI to promote its oligomerization and ATPase activity stimulation, leading to robust activation of IRF3 and NF-kappa-B transcription factors and eventually to the expression of type I IFNs and IFN stimulated genes (ISGs). Similarly to isoform 1, prevents HIV-1 infection.

Subunit / interactions. Homodimer or homooligomer. Homooligomerization is essential for its antiviral activity. Interacts with EXOSC5. Interacts (via N-terminal domain) with DDX17 in an RNA-independent manner. Interacts with EXOSC3, EXOSC7, DCP2 and DCP1A. Interacts with PARN in an RNA-independent manner. Interacts with XRN1 in an RNA-dependent manner. Interacts (via N-terminal domain) with DHX30 (via N-terminus) in an RNA-independent manner. Interacts (via zinc-fingers) with RIGI; this interaction positively modulates the oligomerization and activation of RIGI.

Subcellular location. Nucleus. Lysosome. Late endosome Nucleus. Cytoplasm. Membrane.

Post-translational modifications. Farnesylation at Cys-899 is necessary for localization to late endosomes/lysosomes. It enhances membrane targeting and antiviral activity. Phosphorylation at Ser-275 is essential for sequential phosphorylation of Ser-271, Ser-267, Ser-263 and Ser-257 by GSK3-beta. Phosphorylation by GSK3-beta enhances its antiviral activity.

Domain organisation. The N-terminal domain is sufficient to bind to viral RNAs and promote their degradation. The second and fourth zinc fingers are involved in binding to specific viral RNAs. Contains a divergent PARP homology ADP-ribosyltransferase domain which lacks the structural requirements for NAD[+] binding. It is therefore inactive.

Induction. Up-regulated by interferon-alpha and by 3’-PPP-RNA, contrary to isoform 1, which is not affected by these treatments.

Similarity. Belongs to the ARTD/PARP family.

Isoforms (5)

UniProt ID	Names	Canonical?
Q7Z2W4-1	1, ZAPL	yes
Q7Z2W4-2	2, ZAPS
Q7Z2W4-3	3
Q7Z2W4-4	4
Q7Z2W4-5	5

RefSeq proteins (3): NP_001350420, NP_064504, NP_078901 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000571	Znf_CCCH	Domain
IPR004170	WWE_dom	Domain
IPR012317	Poly(ADP-ribose)pol_cat_dom	Domain
IPR036388	WH-like_DNA-bd_sf	Homologous_superfamily
IPR037197	WWE_dom_sf	Homologous_superfamily
IPR040954	Znf-CCCH_8	Domain
IPR041360	ZAP_HTH	Domain
IPR051712	ARTD-AVP	Family
IPR057602	Zfn-CCCH_PARP12	Domain

Pfam: PF00644, PF02825, PF18606, PF18633, PF23466, PF25261

UniProt features (112 total): strand 29, helix 24, modified residue 22, region of interest 6, turn 5, compositionally biased region 4, zinc finger region 4, splice variant 4, sequence variant 4, short sequence motif 2, domain 2, mutagenesis site 2, initiator methionine 1, chain 1, lipid moiety-binding region 1, sequence conflict 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
2X5Y	X-RAY DIFFRACTION	1.05
7TGQ	X-RAY DIFFRACTION	2
4X52	X-RAY DIFFRACTION	2.08
6UEJ	X-RAY DIFFRACTION	2.21
9BGL	X-RAY DIFFRACTION	2.29
7KZH	X-RAY DIFFRACTION	2.49
6UEI	X-RAY DIFFRACTION	2.51

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q7Z2W4-F1	70.53	0.43

Functional residue map

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

Post-translational modifications (23): 572, 2, 257, 263, 267, 271, 273, 275, 284, 302, 327, 335, 355, 378, 387, 393, 407, 469, 492, 494 …

Mutagenesis-validated functional residues (2):

Position	Phenotype
810	no effect on the structural inability to bind nad(+); when associated with y-830.
830	no effect on the structural inability to bind nad(+); when associated with n-810.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-6802952	Signaling by BRAF and RAF1 fusions

MSigDB gene sets: 294 (showing top): GSE45365_NK_CELL_VS_BCELL_UP, BROWNE_HCMV_INFECTION_4HR_UP, GOBP_POSITIVE_REGULATION_OF_TYPE_I_INTERFERON_PRODUCTION, GOBP_REGULATION_OF_MRNA_CATABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_VIRAL_PROCESS, GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, MITSIADES_RESPONSE_TO_APLIDIN_DN, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION, GOBP_POSITIVE_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, BACOLOD_RESISTANCE_TO_ALKYLATING_AGENTS_DN, RICKMAN_TUMOR_DIFFERENTIATED_WELL_VS_POORLY_DN, GOBP_POSITIVE_REGULATION_OF_INTERFERON_BETA_PRODUCTION

GO Biological Process (11): response to virus (GO:0009615), positive regulation of type I interferon production (GO:0032481), positive regulation of interferon-alpha production (GO:0032727), positive regulation of interferon-beta production (GO:0032728), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), negative regulation of viral genome replication (GO:0045071), innate immune response (GO:0045087), defense response to virus (GO:0051607), positive regulation of mRNA catabolic process (GO:0061014), positive regulation of RIG-I signaling pathway (GO:1900246), immune system process (GO:0002376)

GO Molecular Function (6): RNA binding (GO:0003723), zinc ion binding (GO:0008270), cadherin binding (GO:0045296), NAD+ poly-ADP-ribosyltransferase activity (GO:0003950), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (5): nucleus (GO:0005634), cytoplasm (GO:0005737), lysosome (GO:0005764), late endosome (GO:0005770), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Oncogenic MAPK signaling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
positive regulation of type I interferon production	2
positive regulation of intracellular signal transduction	2
cellular anatomical structure	2
response to other organism	1
positive regulation of cytokine production	1
regulation of type I interferon production	1
type I interferon production	1
interferon-alpha production	1
regulation of interferon-alpha production	1
interferon-beta production	1
regulation of interferon-beta production	1
canonical NF-kappaB signal transduction	1
regulation of canonical NF-kappaB signal transduction	1
viral genome replication	1
regulation of viral genome replication	1
negative regulation of viral process	1
immune response	1
defense response to symbiont	1
defense response	1
response to virus	1
mRNA catabolic process	1
positive regulation of catabolic process	1
regulation of mRNA catabolic process	1
positive regulation of mRNA metabolic process	1
RIG-I signaling pathway	1
regulation of RIG-I signaling pathway	1
positive regulation of pattern recognition receptor signaling pathway	1
biological_process	1
nucleic acid binding	1
transition metal ion binding	1
cell adhesion molecule binding	1
pentosyltransferase activity	1
binding	1
cation binding	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
lytic vacuole	1
endosome	1
cytoplasm	1

Protein interactions and networks

STRING

2104 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ZC3HAV1	RIGI	O95786	932
ZC3HAV1	PARP1	P09874	894
ZC3HAV1	EXOSC5	Q9NQT4	817
ZC3HAV1	EXOSC7	Q15024	815
ZC3HAV1	KHNYN	O15037	717
ZC3HAV1	PARP2	Q9UGN5	662
ZC3HAV1	PARP3	Q9Y6F1	660
ZC3HAV1	PARN	O95453	648
ZC3HAV1	DDX17	Q92841	632
ZC3HAV1	PARP16	Q8N5Y8	628
ZC3HAV1	EIF4A1	P04765	618
ZC3HAV1	PARP6	Q2NL67	616
ZC3HAV1	PARP4	Q9UKK3	612
ZC3HAV1	PARG	Q86W56	609
ZC3HAV1	HSF1	Q00613	608

IntAct

308 interactions, top by confidence:

A	B	Type	Score
H2AX	PPM1G	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
ESR1	TRIM24	psi-mi:“MI:0914”(association)	0.640
YWHAH	BLTP3B	psi-mi:“MI:2364”(proximity)	0.570
ZC3HAV1	MDFI	psi-mi:“MI:0915”(physical association)	0.560
KRTAP10-6	ZC3HAV1	psi-mi:“MI:0915”(physical association)	0.560
ZC3HAV1	EXOSC5	psi-mi:“MI:0915”(physical association)	0.540
ILK	HAX1	psi-mi:“MI:0914”(association)	0.530
ZC3HAV1	KHNYN	psi-mi:“MI:0914”(association)	0.530
RPN1	APBB1	psi-mi:“MI:0914”(association)	0.530
MRPL2	GTPBP10	psi-mi:“MI:0914”(association)	0.530
H1-6	ZNF724	psi-mi:“MI:0914”(association)	0.530
ZNF512	ZNF724	psi-mi:“MI:0914”(association)	0.530
MAGEB2	POLRMT	psi-mi:“MI:0914”(association)	0.530
RPL37A	MPHOSPH10	psi-mi:“MI:0914”(association)	0.530
RSBN1	SETD1A	psi-mi:“MI:0914”(association)	0.530
RIGI	ZC3HAV1	psi-mi:“MI:0915”(physical association)	0.520
CFTR	CNOT1	psi-mi:“MI:0914”(association)	0.480
ESR2	FBLL1	psi-mi:“MI:0914”(association)	0.460
ZC3HAV1	EXOSC3	psi-mi:“MI:0915”(physical association)	0.400
DCP2	ZC3HAV1	psi-mi:“MI:0915”(physical association)	0.400
ZC3HAV1	XRN1	psi-mi:“MI:0915”(physical association)	0.400
DCP1A	ZC3HAV1	psi-mi:“MI:0915”(physical association)	0.400
ZC3HAV1	PARN	psi-mi:“MI:0915”(physical association)	0.400
ZC3HAV1	Exosc7	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (880): ZC3HAV1 (Affinity Capture-MS), ZC3HAV1 (Affinity Capture-MS), ZC3HAV1 (Affinity Capture-MS), ZC3HAV1 (Affinity Capture-MS), ZC3HAV1 (Affinity Capture-MS), ZC3HAV1 (Affinity Capture-MS), ZC3HAV1 (Affinity Capture-MS), ZC3HAV1 (Affinity Capture-MS), ZC3HAV1 (Affinity Capture-MS), ZC3HAV1 (Affinity Capture-MS), ZC3HAV1 (Affinity Capture-MS), ZC3HAV1 (Affinity Capture-MS), ZC3HAV1 (Reconstituted Complex), ZC3HAV1 (Affinity Capture-MS), ZC3HAV1 (Proximity Label-MS)

ESM2 similar proteins: A0A1B0GUJ8, A1A5R7, A2CJ06, A7E3N2, B1H224, B8QB46, D3Z8Y2, D3ZSP7, O55036, P0CG32, P54274, P70371, Q14BQ3, Q29RJ0, Q2HJ46, Q2T9U5, Q3TTP0, Q4R8X0, Q4R9F7, Q4VA55, Q5DTT8, Q5RBH9, Q5TKR9, Q5U310, Q5ZIX8, Q6DJS0, Q6ZQF7, Q71M44, Q7Z2W4, Q7Z7J5, Q80VH0, Q80VM8, Q8BMD7, Q8BZ21, Q8CCG4, Q8CDN1, Q8JZW8, Q8ND61, Q8TE76, Q8VD24

Diamond homologs: A1Z1Q3, A4W960, A7MG20, A8AI35, B4T2X8, B5F961, B5RBF3, B5XXK9, B7LT90, C9Y0V8, D2TT52, D3RKJ0, D5CE05, E1PL40, E1SDF1, O28751, O59182, O75367, O93327, P0A8D6, P0A8D7, P0A8D8, P0C6F6, P0C6T4, P0C6T6, P0C6T8, P0C6T9, P0C6U0, P0C6U1, P0C6U7, P0C6W3, P0C6W5, P0C6W7, P0C6W8, P0C6W9, P0C6X0, P0C6X6, P67341, P67342, P9WK28

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
ZC3HAV1	“up-regulates activity”	PARN	binding
GSK3B	“up-regulates activity”	ZC3HAV1	phosphorylation
TRIM25	“up-regulates activity”	ZC3HAV1	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 223 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Butyrate Response Factor 1 (BRF1) binds and destabilizes mRNA	6	25.9×	2e-06
Tristetraprolin (TTP, ZFP36) binds and destabilizes mRNA	6	25.9×	2e-06
KSRP (KHSRP) binds and destabilizes mRNA	5	21.6×	7e-05
PD-L1(CD274) glycosylation and translocation to plasma membrane	5	17.7×	2e-04
Peptide chain elongation	19	16.4×	3e-16
Viral mRNA Translation	19	16.4×	3e-16
PELO:HBS1L and ABCE1 dissociate a ribosome on a non-stop mRNA	19	16.2×	3e-16
SRP-dependent cotranslational protein targeting to membrane	23	15.7×	5e-19

GO biological processes:

GO term	Partners	Fold	FDR
cytoplasmic translation	21	19.9×	8e-19
ribosomal small subunit biogenesis	11	12.8×	2e-07
translation	22	11.6×	1e-14
rRNA processing	14	10.2×	3e-08
regulation of alternative mRNA splicing, via spliceosome	8	10.0×	2e-04
negative regulation of translation	9	9.0×	1e-04
RNA processing	7	7.9×	3e-03
RNA splicing	12	5.4×	3e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	106
Likely benign	20
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

1825 predictions. Top by Δscore:

Variant	Effect	Δscore
7:139055293:TGG:T	acceptor_gain	1.0000
7:139055296:C:CC	acceptor_gain	1.0000
7:139061034:A:AC	donor_gain	1.0000
7:139061035:C:CC	donor_gain	1.0000
7:139061035:CT:C	donor_gain	1.0000
7:139064891:G:C	donor_gain	1.0000
7:139065004:T:TC	acceptor_gain	1.0000
7:139073850:GCTCA:G	donor_loss	1.0000
7:139073851:CTCAC:C	donor_loss	1.0000
7:139073852:TCA:T	donor_loss	1.0000
7:139073853:CACCT:C	donor_loss	1.0000
7:139073854:A:C	donor_loss	1.0000
7:139073855:C:CT	donor_loss	1.0000
7:139073855:CCT:C	donor_gain	1.0000
7:139076280:A:AC	donor_gain	1.0000
7:139076280:ACTT:A	donor_loss	1.0000
7:139076281:C:CC	donor_gain	1.0000
7:139076282:TTAC:T	donor_loss	1.0000
7:139076284:A:AC	donor_gain	1.0000
7:139076284:ACAG:A	donor_loss	1.0000
7:139076285:C:CT	donor_gain	1.0000
7:139076285:CA:C	donor_gain	1.0000
7:139076285:CAG:C	donor_gain	1.0000
7:139076285:CAGG:C	donor_gain	1.0000
7:139076285:CAGGT:C	donor_gain	1.0000
7:139076308:AG:A	donor_gain	1.0000
7:139076406:CTAC:C	acceptor_gain	1.0000
7:139076407:TAC:T	acceptor_gain	1.0000
7:139076410:C:CC	acceptor_gain	1.0000
7:139076410:CT:C	acceptor_loss	1.0000

AlphaMissense

5948 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:139083933:A:G	C182R	0.999
7:139083955:A:C	C174W	0.999
7:139083956:C:A	C174F	0.999
7:139083956:C:G	C174S	0.999
7:139083956:C:T	C174Y	0.999
7:139083957:A:G	C174R	0.999
7:139083957:A:T	C174S	0.999
7:139084029:A:G	C150R	0.999
7:139109115:A:G	C73R	0.999
7:139076371:A:G	W538R	0.998
7:139076371:A:T	W538R	0.998
7:139083916:G:C	C187W	0.998
7:139083917:C:G	C187S	0.998
7:139083918:A:G	C187R	0.998
7:139083918:A:T	C187S	0.998
7:139083932:C:G	C182S	0.998
7:139083933:A:T	C182S	0.998
7:139083946:G:C	F177L	0.998
7:139083946:G:T	F177L	0.998
7:139083947:A:G	F177S	0.998
7:139083948:A:G	F177L	0.998
7:139089752:A:G	C106R	0.998
7:139109068:G:C	C88W	0.998
7:139109069:C:G	C88S	0.998
7:139109070:A:G	C88R	0.998
7:139109070:A:T	C88S	0.998
7:139109113:G:C	C73W	0.998
7:139109114:C:G	C73S	0.998
7:139109114:C:T	C73Y	0.998
7:139109115:A:T	C73S	0.998

dbSNP variants (sampled 300 via entrez): RS1000011294 (7:139084707 G>C), RS1000026527 (7:139068442 T>A,C), RS1000156805 (7:139050496 T>C,G), RS1000179461 (7:139073797 G>A), RS1000260294 (7:139056025 A>G), RS1000414546 (7:139103062 C>T), RS1000419955 (7:139062970 A>C), RS1000461082 (7:139043228 A>G), RS1000523272 (7:139062593 T>C), RS1000558037 (7:139050205 G>C), RS1000577738 (7:139091340 T>C), RS1000710063 (7:139096957 A>G), RS1000710530 (7:139092056 T>A), RS1000713328 (7:139056367 G>A), RS1000767067 (7:139051667 T>C)

Disease associations

OMIM: gene MIM:607312 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST009597_227	Multiple sclerosis	3.000000e-09
GCST90002381_364	Eosinophil count	5.000000e-12
GCST90002382_164	Eosinophil percentage of white cells	8.000000e-17
GCST90002388_407	Lymphocyte count	2.000000e-16
GCST90002400_58	Plateletcrit	6.000000e-19
GCST90002402_37	Platelet count	7.000000e-11
GCST90002407_495	White blood cell count	4.000000e-09

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0004842	eosinophil count
EFO:0007991	eosinophil percentage of leukocytes
EFO:0004587	lymphocyte count
EFO:0007985	platelet crit
EFO:0004309	platelet count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295879 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 4 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.32	Kd	48.29	nM	CHEMBL5653589
7.32	ED50	48.29	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 9 total; 1 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
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149808: Binding affinity to human ZC3HAV1 incubated for 45 mins by Kinobead based pull down assay	kd	0.0483	uM

CTD chemical–gene interactions

76 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	7
trichostatin A	affects cotreatment, increases expression, affects expression	4
sodium arsenite	decreases expression, increases abundance, increases expression	3
Tobacco Smoke Pollution	affects expression, increases expression	3
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression, increases expression	2
Benzene	increases expression	2
Benzo(a)pyrene	affects methylation, decreases expression	2
Lipopolysaccharides	affects expression, increases expression, affects reaction, affects response to substance	2
Nickel	increases expression	2
Toluene	increases expression	2
Cyclosporine	decreases expression	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
ethylbenzene	increases expression	1
methylmercuric chloride	decreases expression	1
bisphenol A	decreases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
ochratoxin A	increases expression	1
2-xylene	increases expression	1
nickel sulfate	decreases expression	1
coumarin	increases phosphorylation	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
2-palmitoylglycerol	increases expression	1
nutlin 3	affects cotreatment, increases secretion	1
abrine	decreases expression	1
elesclomol	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4272755	Binding	Stabilization of human ARTD13 expressed in Escherichia coli assessed as change in melting temperature at 100 uM by SYPRO Orange-dye based differential scanning fluorimetric method	4-(Phenoxy) and 4-(benzyloxy)benzamides as potent and selective inhibitors of mono-ADP-ribosyltransferase PARP10/ARTD10. — Eur J Med Chem

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B1IH	Abcam A-549 ZC3HAV1 KO 2	Cancer cell line	Male
CVCL_B2R0	Abcam A-549 ZC3HAV1 KO 1	Cancer cell line	Male

Clinical trials (associated diseases)

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