ZNF81

Summary

ZNF81 (zinc finger protein 81, HGNC:13156) is a protein-coding gene on chromosome Xp11.23, encoding Zinc finger protein 81 (P51508). May be involved in transcriptional regulation.

This gene encodes a protein that likely functions as a transcription factor. The protein contains an N-terminal KRAB domain and several C2H2-type zinc finger motifs. Mutations in this gene cause an X-linked form of intellectual disability (MRX45). Microduplication of a region of chromosome X including this gene has also been associated with other forms of intellectual disability.

Source: NCBI Gene 347344 — RefSeq curated summary.

At a glance

• Gene–disease (curated): non-syndromic X-linked intellectual disability (Supportive, GenCC) — +2 more curated relationships
• Clinical variants (ClinVar): 84 total
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_007137

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13156
Approved symbol	ZNF81
Name	zinc finger protein 81
Location	Xp11.23
Locus type	gene with protein product
Status	Approved
Aliases	HFZ20
Ensembl gene	ENSG00000197779
Ensembl biotype	protein_coding
OMIM	314998
Entrez	347344

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 11 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000334937, ENST00000338637, ENST00000376950, ENST00000376954, ENST00000483520, ENST00000853619, ENST00000853620, ENST00000853621, ENST00000853622, ENST00000853623, ENST00000853624, ENST00000966374

RefSeq mRNA: 5 — MANE Select: NM_007137 NM_001378152, NM_001378153, NM_001378154, NM_001378155, NM_007137

CCDS: CCDS43933

Canonical transcript exons

ENST00000338637 — 5 exons

Exon	Start	End
ENSE00001421864	47895845	47895940
ENSE00001472254	47846105	47846321
ENSE00001472256	47836902	47836987
ENSE00001722367	47887999	47888125
ENSE00002208407	47914924	47925627

Expression profiles

Bgee: expression breadth ubiquitous, 249 present calls, max score 79.92.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 4.7778 / max 100.4753, expressed in 1597 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
196230	3.0318	1359
196231	1.5882	986
196229	0.1578	76

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
colonic epithelium	UBERON:0000397	79.92	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	79.78	gold quality
germinal epithelium of ovary	UBERON:0001304	77.91	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	76.92	gold quality
upper leg skin	UBERON:0004262	76.65	gold quality
tibia	UBERON:0000979	76.52	gold quality
islet of Langerhans	UBERON:0000006	75.89	gold quality
apex of heart	UBERON:0002098	75.86	gold quality
visceral pleura	UBERON:0002401	75.86	gold quality
monocyte	CL:0000576	75.38	gold quality
parietal pleura	UBERON:0002400	75.20	gold quality
mononuclear cell	CL:0000842	75.14	gold quality
leukocyte	CL:0000738	75.12	gold quality
corpus callosum	UBERON:0002336	75.09	gold quality
pleura	UBERON:0000977	75.02	gold quality
endothelial cell	CL:0000115	74.95	silver quality
skin of hip	UBERON:0001554	74.77	gold quality
seminal vesicle	UBERON:0000998	74.13	gold quality
mucosa of sigmoid colon	UBERON:0004993	73.88	gold quality
cortical plate	UBERON:0005343	73.61	gold quality
ganglionic eminence	UBERON:0004023	73.47	gold quality
bone marrow	UBERON:0002371	73.41	gold quality
heart left ventricle	UBERON:0002084	73.34	gold quality
stromal cell of endometrium	CL:0002255	73.32	gold quality
adrenal tissue	UBERON:0018303	73.32	gold quality
lower lobe of lung	UBERON:0008949	73.17	gold quality
cardiac ventricle	UBERON:0002082	73.16	gold quality
ventricular zone	UBERON:0003053	73.04	gold quality
cauda epididymis	UBERON:0004360	73.04	gold quality
corpus epididymis	UBERON:0004359	72.86	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	5.44

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): STAT1

miRNA regulators (miRDB)

160 targeting ZNF81, 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-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-432-3P	100.00	67.86	705
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6740-5P	100.00	65.64	932
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-335-3P	99.93	73.36	4958

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Cross-species orthologs

1 orthologs

Organism	Symbol	Gene ID
rattus_norvegicus	Znf81	ENSRNOG00000066471

Paralogs (176): ZNF195 (ENSG00000005801), ZNF112 (ENSG00000062370), ZNF275 (ENSG00000063587), ZNF37A (ENSG00000075407), ZNF510 (ENSG00000081386), ZNF506 (ENSG00000081665), ZNF268 (ENSG00000090612), MZF1 (ENSG00000099326), ZNF629 (ENSG00000102870), ZNF175 (ENSG00000105497), ZNF85 (ENSG00000105750), ZFP30 (ENSG00000120784), ZNF45 (ENSG00000124459), ZNF391 (ENSG00000124613), ZNF436 (ENSG00000125945), ZNF484 (ENSG00000127081), ZNF835 (ENSG00000127903), ZNF780B (ENSG00000128000), ZSCAN10 (ENSG00000130182), ZNF317 (ENSG00000130803), ZNF331 (ENSG00000130844), ZNF227 (ENSG00000131115), ZNF141 (ENSG00000131127), ZNF132 (ENSG00000131849), ZNF189 (ENSG00000136870), ZIM3 (ENSG00000141946), ZFP14 (ENSG00000142065), ZNF514 (ENSG00000144026), ZNF300 (ENSG00000145908), RBAK (ENSG00000146587), ZNF157 (ENSG00000147117), ZNF182 (ENSG00000147118), ZNF41 (ENSG00000147124), ZNF7 (ENSG00000147789), ZNF117 (ENSG00000152926), ZNF221 (ENSG00000159905), ZNF235 (ENSG00000159917), ZNF714 (ENSG00000160352), ZNF577 (ENSG00000161551), ZNF12 (ENSG00000164631)

Protein

Protein identifiers

Zinc finger protein 81 — P51508 (reviewed: P51508)

Alternative names: HFZ20

All UniProt accessions (3): B1AJV1, B1AJV2, P51508

UniProt curated annotations — full annotation on UniProt →

Function. May be involved in transcriptional regulation.

Subcellular location. Nucleus.

Disease relevance. A chromosomal aberration involving ZNF81 is found in a severe intellectual disability patient. Translocation t(X;9)(p11.23;q34.3).

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

RefSeq proteins (5): NP_001365081, NP_001365082, NP_001365083, NP_001365084, NP_009068* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001909	KRAB	Domain
IPR013087	Znf_C2H2_type	Domain
IPR036051	KRAB_dom_sf	Homologous_superfamily
IPR036236	Znf_C2H2_sf	Homologous_superfamily

Pfam: PF00096, PF01352

UniProt features (22 total): zinc finger region 12, sequence variant 7, chain 1, domain 1, cross-link 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P51508-F1	63.12	0.19

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 (1): 266

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 68 (showing top): DODD_NASOPHARYNGEAL_CARCINOMA_UP, KRIGE_RESPONSE_TO_TOSEDOSTAT_24HR_UP, GOMF_SEQUENCE_SPECIFIC_DNA_BINDING, chrXp11, GOMF_TRANSCRIPTION_REGULATOR_ACTIVITY, CIITA_TARGET_GENES, UBN1_TARGET_GENES, ZNF513_TARGET_GENES, ZNF766_TARGET_GENES, ZNF8_TARGET_GENES, ZSCAN2_TARGET_GENES, MIR153_5P, MIR1277_5P, MIR4659A_3P_MIR4659B_3P, MIR1250_3P

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

GO Molecular Function (5): 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), DNA binding (GO:0003677), 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
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
nucleic acid binding	1
cation binding	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

906 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ZNF81	ZNF385B	Q569K4	870
ZNF81	ARAF	P07557	794
ZNF81	TIMP1	P01033	603
ZNF81	POGZ	Q7Z3K3	596
ZNF81	TRIM28	Q13263	544
ZNF81	TBC1D25	Q3MII6	516
ZNF81	PHF8	Q9UPP1	508
ZNF81	CHST7	Q9NS84	459
ZNF81	ZHX2	Q9Y6X8	437
ZNF81	TSHZ3	Q63HK5	426
ZNF81	SPACA5B	Q96QH8	418
ZNF81	NXF5	Q9H1B4	397
ZNF81	WDR13	Q9H1Z4	395
ZNF81	EFCAB14	O75071	326
ZNF81	ARHGEF6	Q15052	324

IntAct

4 interactions, top by confidence:

A	B	Type	Score
KLHL40	CBX4	psi-mi:“MI:0914”(association)	0.530
ZNF81	TRIM28	psi-mi:“MI:0914”(association)	0.350

BioGRID (8): ZNF81 (Affinity Capture-MS), ZNF81 (Affinity Capture-RNA), ZNF81 (Two-hybrid), ZNF81 (Affinity Capture-MS), TRIM39 (Affinity Capture-MS), TRIM28 (Affinity Capture-MS), ZNF81 (Affinity Capture-MS), ZNF81 (Affinity Capture-RNA)

ESM2 similar proteins: A0A1W2PQL4, A0JPL0, A2RRD8, A6NHJ4, A6NP11, B4DX44, O75346, O95780, P0CB33, P21506, P51508, P52738, Q0D2J5, Q0VGE8, Q12901, Q13360, Q14593, Q15973, Q2M218, Q2M3X9, Q2VY69, Q3SXZ3, Q5HY98, Q5RCJ2, Q5VIY5, Q6J6I6, Q7L2R6, Q86XU0, Q86Y25, Q8IW36, Q8IYN0, Q8IYX0, Q8N782, Q8N883, Q8N9Z0, Q8NDP4, Q95K49, Q969W8, Q96H40, Q96N58

Diamond homologs: A0JPL0, A2VDP4, A6QLU5, A6QPT6, A8MQ14, A8MUZ8, A8MWA4, B1APH4, B2RXC5, E9PYI1, E9Q8G5, O75290, O94892, P08042, P0CH99, P0CI00, P17014, P17025, P17030, P17031, P17032, P17098, P21506, P51508, P51523, P51786, P51814, P52736, P52738, Q02525, Q03923, Q03936, Q06730, Q06732, Q0VCB0, Q13401, Q14587, Q16587, Q2M218, Q2M3X9

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	54
Likely benign	8
Benign	10

Top pathogenic / likely-pathogenic (0)

SpliceAI

1752 predictions. Top by Δscore:

Variant	Effect	Δscore
X:47836979:G:T	donor_gain	1.0000
X:47846376:A:T	donor_gain	1.0000
X:47879436:G:GG	donor_gain	1.0000
X:47888086:G:GT	donor_gain	1.0000
X:47888122:GTGG:G	donor_gain	1.0000
X:47977795:CTT:C	acceptor_gain	1.0000
X:47836954:G:GT	donor_gain	0.9900
X:47836979:G:GT	donor_gain	0.9900
X:47836985:G:GT	donor_gain	0.9900
X:47846103:A:AG	acceptor_gain	0.9900
X:47846104:G:GG	acceptor_gain	0.9900
X:47846104:GA:G	acceptor_gain	0.9900
X:47861482:A:AG	donor_gain	0.9900
X:47861482:A:G	donor_gain	0.9900
X:47888085:GGAT:G	donor_gain	0.9900
X:47888121:AGTGG:A	donor_loss	0.9900
X:47888124:GG:G	donor_gain	0.9900
X:47888125:GG:G	donor_gain	0.9900
X:47888125:GGTAA:G	donor_loss	0.9900
X:47888126:G:GG	donor_gain	0.9900
X:47888127:T:A	donor_loss	0.9900
X:47890892:GAGGT:G	donor_gain	0.9900
X:47914919:TTTA:T	acceptor_loss	0.9900
X:47914920:TTAG:T	acceptor_loss	0.9900
X:47914922:A:AG	acceptor_gain	0.9900
X:47914922:A:AT	acceptor_loss	0.9900
X:47914922:AGAT:A	acceptor_gain	0.9900
X:47914922:AGATG:A	acceptor_gain	0.9900
X:47914923:G:A	acceptor_loss	0.9900
X:47914923:G:GG	acceptor_gain	0.9900

AlphaMissense

4446 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:47915913:T:C	F423L	0.999
X:47915915:T:A	F423L	0.999
X:47915915:T:G	F423L	0.999
X:47915997:T:C	F451L	0.999
X:47915999:C:A	F451L	0.999
X:47915999:C:G	F451L	0.999
X:47916081:T:C	F479L	0.999
X:47916083:C:A	F479L	0.999
X:47916083:C:G	F479L	0.999
X:47916165:T:C	F507L	0.999
X:47916167:C:A	F507L	0.999
X:47916167:C:G	F507L	0.999
X:47916184:T:C	L513P	0.999
X:47916333:T:C	F563L	0.999
X:47916335:C:A	F563L	0.999
X:47916335:C:G	F563L	0.999
X:47916417:T:C	F591L	0.999
X:47916419:C:A	F591L	0.999
X:47916419:C:G	F591L	0.999
X:47916451:G:C	R602P	0.999
X:47916501:T:C	F619L	0.999
X:47916503:C:A	F619L	0.999
X:47916503:C:G	F619L	0.999
X:47916585:T:C	F647L	0.999
X:47916587:C:A	F647L	0.999
X:47916587:C:G	F647L	0.999
X:47916100:T:C	L485P	0.998
X:47916249:T:C	F535L	0.998
X:47916251:C:A	F535L	0.998
X:47916251:C:G	F535L	0.998

dbSNP variants (sampled 300 via entrez): RS1000026715 (X:47872232 A>G), RS1000227935 (X:47915658 G>A,T), RS1000498231 (X:47864195 A>G), RS1000778912 (X:47853462 G>A), RS1000810008 (X:47853737 A>T), RS1001036698 (X:47863680 A>G), RS1001080506 (X:47873931 G>A), RS1001145838 (X:47835383 T>A), RS1001208489 (X:47906742 C>T), RS1001234149 (X:47918102 A>G), RS1001446356 (X:47835974 A>C), RS1001779462 (X:47855206 T>C), RS1001891733 (X:47907184 C>T), RS1001899869 (X:47866203 C>T), RS1001900604 (X:47886073 A>G)

Disease associations

OMIM: gene MIM:314998 | disease phenotypes: MIM:309530, MIM:300498

GenCC curated gene-disease

Disease	Classification	Inheritance
non-syndromic X-linked intellectual disability	Supportive	X-linked
intellectual disability, X-linked 45	Limited	Unknown
X-linked intellectual disability	Disputed Evidence	X-linked

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
X-linked intellectual disability	Disputed	XL

Mondo (3): non-syndromic X-linked intellectual disability (MONDO:0019181), intellectual disability, X-linked 45 (MONDO:0010344), X-linked intellectual disability (MONDO:0100284)

Orphanet (1): X-linked non-syndromic intellectual disability (Orphanet:777)

HPO phenotypes

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

GWAS associations

0 associations (top):

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
C564503	Mental Retardation, X-Linked 45 (supp.)
C564490	Mental Retardation, X-Linked Nonsyndromic (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

17 total (human), top 17 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
TAK-243	increases sumoylation	1
triphenyl phosphate	affects expression	1
bisphenol A	increases expression, decreases expression	1
beta-lapachone	increases expression, decreases expression	1
mono-(2-ethylhexyl)phthalate	decreases expression	1
4-aminophenylarsenoxide	affects binding, decreases reaction	1
di-n-butylphosphoric acid	affects expression	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	increases expression	1
Arsenic Trioxide	affects binding, decreases reaction	1
Arbutin	decreases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Cadmium	increases abundance, increases expression	1
Ethyl Methanesulfonate	increases expression	1
Methyl Methanesulfonate	increases expression	1
Plant Extracts	affects cotreatment, increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT06500260	Not specified	RECRUITING	CNKSR2 Natural History Study