ZNF446

Summary

ZNF446 (zinc finger protein 446, HGNC:21036) is a protein-coding gene on chromosome 19q13.43, encoding Zinc finger protein 446 (Q9NWS9). May be involved in transcriptional regulation.

Enables identical protein binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Located in extracellular space.

Source: NCBI Gene 55663 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 116 total — 1 pathogenic
• MANE Select transcript: NM_017908

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21036
Approved symbol	ZNF446
Name	zinc finger protein 446
Location	19q13.43
Locus type	gene with protein product
Status	Approved
Aliases	ZKSCAN20, FLJ20626, ZSCAN52
Ensembl gene	ENSG00000083838
Ensembl biotype	protein_coding
Entrez	55663

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 7 protein_coding, 2 retained_intron

ENST00000335841, ENST00000391694, ENST00000594369, ENST00000594468, ENST00000596341, ENST00000600013, ENST00000610298, ENST00000864814, ENST00000943129

RefSeq mRNA: 2 — MANE Select: NM_017908 NM_001304453, NM_017908

CCDS: CCDS12982

Canonical transcript exons

ENST00000594369 — 7 exons

Exon	Start	End
ENSE00002472456	58479643	58479727
ENSE00002999714	58476352	58476504
ENSE00003523298	58477637	58477826
ENSE00003535135	58479930	58480019
ENSE00003589557	58477179	58477560
ENSE00003616680	58480176	58481230
ENSE00003617733	58478087	58478181

Expression profiles

Bgee: expression breadth ubiquitous, 183 present calls, max score 87.13.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 1.7918 / max 27.5975, expressed in 1120 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
177849	1.0153	681
177850	0.7766	552

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right uterine tube	UBERON:0001302	87.13	gold quality
endothelial cell	CL:0000115	86.87	silver quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	85.63	gold quality
adenohypophysis	UBERON:0002196	85.51	gold quality
pituitary gland	UBERON:0000007	84.86	gold quality
left ovary	UBERON:0002119	84.02	gold quality
right ovary	UBERON:0002118	83.93	gold quality
right lobe of thyroid gland	UBERON:0001119	83.87	gold quality
right hemisphere of cerebellum	UBERON:0014890	83.57	gold quality
cerebellar hemisphere	UBERON:0002245	83.19	gold quality
cerebellar cortex	UBERON:0002129	83.06	gold quality
apex of heart	UBERON:0002098	83.02	gold quality
body of uterus	UBERON:0009853	83.02	gold quality
cervix squamous epithelium	UBERON:0006922	82.95	gold quality
right testis	UBERON:0004534	82.72	gold quality
left lobe of thyroid gland	UBERON:0001120	82.69	gold quality
left uterine tube	UBERON:0001303	82.69	gold quality
lower esophagus muscularis layer	UBERON:0035833	82.50	gold quality
cortical plate	UBERON:0005343	82.48	gold quality
lower esophagus	UBERON:0013473	82.46	gold quality
ventricular zone	UBERON:0003053	82.35	gold quality
left testis	UBERON:0004533	82.34	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	82.32	gold quality
muscle layer of sigmoid colon	UBERON:0035805	82.23	gold quality
cerebellum	UBERON:0002037	82.12	gold quality
right lobe of liver	UBERON:0001114	82.07	gold quality
mucosa of stomach	UBERON:0001199	82.01	gold quality
popliteal artery	UBERON:0002250	81.90	gold quality
tibial artery	UBERON:0007610	81.89	gold quality
endocervix	UBERON:0000458	81.71	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.85

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

17 targeting ZNF446, 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-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-1249-5P	99.61	66.55	2049
HSA-MIR-6797-5P	99.61	66.55	2084
HSA-MIR-12122	99.56	69.33	1672
HSA-MIR-12117	99.50	67.57	868
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-4763-3P	99.10	67.83	2649
HSA-MIR-4270	99.02	66.26	1987
HSA-MIR-6840-3P	98.68	65.95	1923
HSA-MIR-6754-5P	98.60	65.54	1627
HSA-MIR-4722-5P	98.46	66.34	1611
HSA-MIR-4768-3P	98.16	66.02	2330

Literature-anchored findings (GeneRIF, showing 1)

• Overexpression of ZNF446 in COS-7 cells inhibits the transcriptional activities of SRE and AP-1. (PMID:15936718)

Cross-species orthologs

11 orthologs

Organism	Symbol	Gene ID
danio_rerio	plagx	ENSDARG00000036855
danio_rerio	ovol1a	ENSDARG00000076472
danio_rerio	plagl2	ENSDARG00000076657
danio_rerio	ovol1b	ENSDARG00000078256
mus_musculus	Zfp446	ENSMUSG00000033961
rattus_norvegicus	Zfp446	ENSRNOG00000060429
drosophila_melanogaster	hb	FBGN0001180
drosophila_melanogaster	CG12391	FBGN0033581
caenorhabditis_elegans		WBGENE00001824
caenorhabditis_elegans		WBGENE00003033
caenorhabditis_elegans		WBGENE00012385

Paralogs (29): REST (ENSG00000084093), ZNF174 (ENSG00000103343), OVOL3 (ENSG00000105261), PLAGL1 (ENSG00000118495), ZSCAN18 (ENSG00000121413), ZNF576 (ENSG00000124444), OVOL2 (ENSG00000125850), PLAGL2 (ENSG00000126003), ZSCAN5A (ENSG00000131848), ZSCAN29 (ENSG00000140265), ZSCAN32 (ENSG00000140987), ZSCAN1 (ENSG00000152467), ZNF18 (ENSG00000154957), ZKSCAN2 (ENSG00000155592), ZNF496 (ENSG00000162714), ZNF202 (ENSG00000166261), ZNF641 (ENSG00000167528), ZNF444 (ENSG00000167685), SCAND1 (ENSG00000171222), ZNF274 (ENSG00000171606), ZNF131 (ENSG00000172262), OVOL1 (ENSG00000172818), ZNF518A (ENSG00000177853), ZNF518B (ENSG00000178163), PLAG1 (ENSG00000181690), ZSCAN5B (ENSG00000197213), ZNF770 (ENSG00000198146), PEG3 (ENSG00000198300), ZSCAN5C (ENSG00000204532)

Protein

Protein identifiers

Zinc finger protein 446 — Q9NWS9 (reviewed: Q9NWS9)

Alternative names: Zinc finger protein with KRAB and SCAN domains 20

All UniProt accessions (4): Q9NWS9, A0A0A0MR84, M0R034, M0R202

UniProt curated annotations — full annotation on UniProt →

Function. May be involved in transcriptional regulation.

Subcellular location. Nucleus.

Similarity. Belongs to the krueppel C2H2-type zinc-finger protein family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9NWS9-1	1	yes
Q9NWS9-2	2

RefSeq proteins (2): NP_001291382, NP_060378* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001909	KRAB	Domain
IPR003309	SCAN_dom	Domain
IPR013087	Znf_C2H2_type	Domain
IPR036051	KRAB_dom_sf	Homologous_superfamily
IPR036236	Znf_C2H2_sf	Homologous_superfamily
IPR038269	SCAN_sf	Homologous_superfamily
IPR050916	SCAN-C2H2_zinc_finger	Family

Pfam: PF00096, PF01352, PF02023

UniProt features (21 total): region of interest 4, modified residue 3, sequence variant 3, zinc finger region 3, domain 2, compositionally biased region 2, cross-link 2, chain 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NWS9-F1	58.81	0.04

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 (5): 137, 218, 308, 130, 330

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-212436	Generic Transcription Pathway

MSigDB gene sets: 84 (showing top): FERREIRA_EWINGS_SARCOMA_UNSTABLE_VS_STABLE_DN, GOCC_NUCLEAR_SPECK, GOCC_NUCLEAR_BODY, GOCC_RIBONUCLEOPROTEIN_GRANULE, STAT1_01, GOMF_SEQUENCE_SPECIFIC_DNA_BINDING, VERHAAK_GLIOBLASTOMA_CLASSICAL, SMID_BREAST_CANCER_RELAPSE_IN_BRAIN_DN, GOCC_SUPRAMOLECULAR_COMPLEX, PRC2_EED_DN.V1_DN, PRC2_EZH2_UP.V1_DN, PTEN_DN.V2_DN, IL2_UP.V1_DN, IL21_UP.V1_DN, GOMF_TRANSCRIPTION_REGULATOR_ACTIVITY

GO Biological Process (2): regulation of transcription by RNA polymerase II (GO:0006357), regulation of DNA-templated transcription (GO:0006355)

GO Molecular Function (7): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), zinc ion binding (GO:0008270), identical protein binding (GO:0042802), DNA binding (GO:0003677), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (3): chromatin (GO:0000785), obsolete extracellular space (GO:0005615), nucleus (GO:0005634)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
RNA Polymerase II Transcription	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
regulation of DNA-templated transcription	1
transcription by RNA polymerase II	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
regulation of transcription by RNA polymerase II	1
transition metal ion binding	1
protein binding	1
nucleic acid binding	1
binding	1
cation binding	1
chromosome	1
cellular anatomical structure	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

908 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ZNF446	BBOX1	O75936	456
ZNF446	DDX27	Q96GQ7	449
ZNF446	GLT8D1	Q68CQ7	443
ZNF446	GNL3	Q9BVP2	426
ZNF446	ZNF638	Q14966	423
ZNF446	RNF123	Q5XPI4	415
ZNF446	MROH6	A6NGR9	415
ZNF446	FNDC9	Q8TBE3	380
ZNF446	PDCD2L	Q9BRP1	368
ZNF446	ZBED5	Q49AG3	366
ZNF446	ARHGEF35	A5YM69	357
ZNF446	ZNF770	Q6IQ21	354
ZNF446	NCAPG	Q9BPX3	341
ZNF446	HAGHL	Q6PII5	335
ZNF446	SLITRK5	O94991	323

IntAct

93 interactions, top by confidence:

A	B	Type	Score
ZNF446	ZNF24	psi-mi:“MI:0915”(physical association)	0.850
ZNF446	ZNF397	psi-mi:“MI:0915”(physical association)	0.850
ZNF24	ZNF446	psi-mi:“MI:0915”(physical association)	0.850
ZSCAN21	ZNF24	psi-mi:“MI:0914”(association)	0.830
PGBD1	ZNF446	psi-mi:“MI:0915”(physical association)	0.800
ZNF446	PGBD1	psi-mi:“MI:0915”(physical association)	0.800
ZNF446	ZSCAN9	psi-mi:“MI:0915”(physical association)	0.750
ZSCAN9	ZNF446	psi-mi:“MI:0915”(physical association)	0.750
ZNF396	ZNF24	psi-mi:“MI:0914”(association)	0.700
SCRIB	NOS1AP	psi-mi:“MI:0914”(association)	0.690
ALDH3A1	RCCD1	psi-mi:“MI:0914”(association)	0.640
ZNF576	ZBED1	psi-mi:“MI:0914”(association)	0.640
ZNF397	ZNF24	psi-mi:“MI:0914”(association)	0.640
ZNF397	ZNF213	psi-mi:“MI:0914”(association)	0.640
ZNF232	ZNF446	psi-mi:“MI:0915”(physical association)	0.630
XAGE1A	THAP12	psi-mi:“MI:0914”(association)	0.530
ZSCAN32	ZNF197	psi-mi:“MI:0914”(association)	0.530
ZNF397	ZNF197	psi-mi:“MI:0914”(association)	0.530
ZNF483	ZNF197	psi-mi:“MI:0914”(association)	0.530
ZKSCAN4	ZNF213	psi-mi:“MI:0914”(association)	0.530
PGBD1	ZNF213	psi-mi:“MI:0914”(association)	0.530

BioGRID (150): ZNF446 (Two-hybrid), ZNF446 (Two-hybrid), ZNF446 (Two-hybrid), ZNF446 (Two-hybrid), ZNF446 (Two-hybrid), ZNF446 (Two-hybrid), ZNF446 (Two-hybrid), ZNF446 (Two-hybrid), ZNF446 (Two-hybrid), ZKSCAN7 (Two-hybrid), ZSCAN16 (Two-hybrid), ZNF397 (Two-hybrid), LZTS2 (Two-hybrid), PGBD1 (Two-hybrid), ZNF496 (Two-hybrid)

ESM2 similar proteins: A1YEW3, A1YG31, A2T715, A2T7M0, A6NGD5, A6NJL1, A6QPT6, A8MXV6, A8MZF0, H3BKT1, O08664, P03327, P06936, P0C6A0, P0DPQ3, P54257, P57086, P86478, P86479, P86480, P86481, P86496, Q13487, Q32PG5, Q505G4, Q5R6M8, Q5R7P6, Q68FX5, Q6J1H4, Q6NZN1, Q6ZMS7, Q76NI1, Q7L3V2, Q7YR42, Q7Z6I6, Q8K2W9, Q8NHY3, Q8WUZ0, Q914N2, Q91XA5

Diamond homologs: A1YEP8, A1YEQ3, A1YEV9, A1YFW2, A1YFW6, A1YG26, A1YG48, A1YG60, A1YGJ4, A1YGK6, A2T6E3, A2T6V8, A2T6W2, A2T712, A2T736, A2T7D2, A2T7D7, A2T7F2, A2T7F4, A2T7L7, A2T812, A6QNZ0, A6QPT6, B2KFW1, O14709, O14771, O14978, O15535, O43309, O60304, O95125, P10073, P17022, P17028, P17029, P17040, P28698, P49910, P51815, P59923

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	100
Likely benign	5
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
599531	NM_017908.4(ZNF446):c.1028G>A (p.Trp343Ter)	Pathogenic

SpliceAI

1610 predictions. Top by Δscore:

Variant	Effect	Δscore
19:58477557:CTGGG:C	donor_loss	1.0000
19:58477558:TGGGT:T	donor_loss	1.0000
19:58477559:GGGTG:G	donor_loss	1.0000
19:58477561:GTG:G	donor_loss	1.0000
19:58477796:G:GT	donor_gain	1.0000
19:58477819:GGAA:G	donor_gain	1.0000
19:58477820:G:GT	donor_gain	1.0000
19:58477823:GTGG:G	donor_gain	1.0000
19:58478085:A:AG	acceptor_gain	1.0000
19:58478086:G:GG	acceptor_gain	1.0000
19:58478086:GC:G	acceptor_gain	1.0000
19:58478178:TCAG:T	donor_loss	1.0000
19:58478179:CAGG:C	donor_loss	1.0000
19:58478181:GGTGA:G	donor_loss	1.0000
19:58478182:G:A	donor_loss	1.0000
19:58477174:TGTA:T	acceptor_loss	0.9900
19:58477176:TAGGC:T	acceptor_loss	0.9900
19:58477177:A:AG	acceptor_gain	0.9900
19:58477177:AGGC:A	acceptor_loss	0.9900
19:58477178:G:GA	acceptor_gain	0.9900
19:58477178:GGCCC:G	acceptor_gain	0.9900
19:58477468:GCC:G	donor_gain	0.9900
19:58477504:G:GT	donor_gain	0.9900
19:58477526:G:GT	donor_gain	0.9900
19:58477556:GCTGG:G	donor_gain	0.9900
19:58477559:GG:G	donor_gain	0.9900
19:58477560:GG:G	donor_gain	0.9900
19:58477561:G:GG	donor_gain	0.9900
19:58477562:T:A	donor_loss	0.9900
19:58477563:G:GG	donor_loss	0.9900

AlphaMissense

2879 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:58480394:T:C	F341L	0.999
19:58480396:C:A	F341L	0.999
19:58480396:C:G	F341L	0.999
19:58480583:T:C	F404L	0.999
19:58480585:C:A	F404L	0.999
19:58480585:C:G	F404L	0.999
19:58480667:T:C	F432L	0.999
19:58480669:C:A	F432L	0.999
19:58480669:C:G	F432L	0.999
19:58480610:C:G	H413D	0.998
19:58480668:T:C	F432S	0.998
19:58480694:C:G	H441D	0.998
19:58480395:T:C	F341S	0.997
19:58480584:T:C	F404S	0.997
19:58480602:T:C	L410P	0.997
19:58480646:T:C	C425R	0.997
19:58480667:T:A	F432I	0.997
19:58480686:T:C	L438P	0.997
19:58480421:C:G	H350D	0.996
19:58480610:C:A	H413N	0.996
19:58480694:C:A	H441N	0.996
19:58480612:C:A	H413Q	0.995
19:58480612:C:G	H413Q	0.995
19:58480656:G:A	C428Y	0.995
19:58480668:T:G	F432C	0.995
19:58480696:C:A	H441Q	0.995
19:58480696:C:G	H441Q	0.995
19:58480423:C:A	H350Q	0.994
19:58480423:C:G	H350Q	0.994
19:58480655:T:C	C428R	0.994

dbSNP variants (sampled 300 via entrez): RS1000230786 (19:58484643 G>A), RS1000430399 (19:58475937 G>A,C), RS1000538068 (19:58489220 C>A), RS1000583549 (19:58484984 G>A), RS1000760193 (19:58476534 G>A), RS1000987270 (19:58481042 C>G,T), RS1001194496 (19:58480624 C>T), RS1001247041 (19:58482654 C>G,T), RS1001299582 (19:58482854 C>G), RS1001592452 (19:58487876 A>G), RS1001814217 (19:58487670 G>A), RS1001851002 (19:58478702 C>T), RS1001897208 (19:58475613 T>C), RS1001950987 (19:58475784 G>A,C), RS1002030844 (19:58484215 T>A,C)

Disease associations

OMIM: gene `` | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST001762_582	Obesity-related traits	1.000000e-07
GCST004058_1	Uric acid clearance	8.000000e-08

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004730	hormone measurement
EFO:0004761	uric acid 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
GSK-J4	decreases expression	1
FR900359	affects phosphorylation	1
TAK-243	increases sumoylation	1
triphenyl phosphate	affects expression	1
ferrous chloride	decreases expression	1
coumarin	increases phosphorylation	1
CGP 52608	affects binding, increases reaction	1
2-palmitoylglycerol	increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Sunitinib	decreases expression	1
Caffeine	increases phosphorylation	1
Estradiol	decreases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Smoke	decreases expression	1

Clinical trials (associated diseases)

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