ZNHIT2

Summary

ZNHIT2 (zinc finger HIT-type containing 2, HGNC:1177) is a protein-coding gene on chromosome 11q13.1, encoding Zinc finger HIT domain-containing protein 2 (Q9UHR6). May act as a bridging factor mediating the interaction between the R2TP/Prefoldin-like (R2TP/PFDL) complex and U5 small nuclear ribonucleoprotein (U5 snRNP). It is a common-essential gene (DepMap: required in 100.0% of cancer cell lines).

Predicted to enable zinc ion binding activity.

Source: NCBI Gene 741 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 101 total
• Cancer dependency (DepMap): dependent in 100.0% of screened cell lines (common-essential)
• MANE Select transcript: NM_014205

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1177
Approved symbol	ZNHIT2
Name	zinc finger HIT-type containing 2
Location	11q13.1
Locus type	gene with protein product
Status	Approved
Aliases	FON
Ensembl gene	ENSG00000174276
Ensembl biotype	protein_coding
OMIM	604575
Entrez	741

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000310597, ENST00000528598

RefSeq mRNA: 1 — MANE Select: NM_014205 NM_014205

CCDS: CCDS8094

Canonical transcript exons

ENST00000310597 — 1 exons

Exon	Start	End
ENSE00001192854	65116403	65117701

Expression profiles

Bgee: expression breadth ubiquitous, 169 present calls, max score 93.47.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 11.5059 / max 104.6967, expressed in 1763 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
120529	10.5330	1760
120528	0.9729	363

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right testis	UBERON:0004534	93.47	gold quality
left testis	UBERON:0004533	93.15	gold quality
testis	UBERON:0000473	89.59	gold quality
right uterine tube	UBERON:0001302	88.09	gold quality
right adrenal gland cortex	UBERON:0035827	87.71	gold quality
left adrenal gland	UBERON:0001234	87.35	gold quality
right adrenal gland	UBERON:0001233	87.11	gold quality
left adrenal gland cortex	UBERON:0035825	86.96	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	86.60	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	86.21	gold quality
adrenal cortex	UBERON:0001235	84.85	gold quality
adrenal gland	UBERON:0002369	82.81	gold quality
mucosa of transverse colon	UBERON:0004991	82.73	gold quality
sperm	CL:0000019	82.16	gold quality
adenohypophysis	UBERON:0002196	82.01	gold quality
apex of heart	UBERON:0002098	81.75	gold quality
gastrocnemius	UBERON:0001388	81.44	gold quality
pituitary gland	UBERON:0000007	80.67	gold quality
hindlimb stylopod muscle	UBERON:0004252	80.18	gold quality
right lobe of liver	UBERON:0001114	79.92	gold quality
muscle of leg	UBERON:0001383	79.62	gold quality
male germ cell	CL:0000015	79.46	gold quality
skin of leg	UBERON:0001511	79.39	gold quality
body of stomach	UBERON:0001161	78.93	gold quality
skin of abdomen	UBERON:0001416	78.88	gold quality
body of pancreas	UBERON:0001150	78.81	gold quality
right lobe of thyroid gland	UBERON:0001119	78.69	gold quality
granulocyte	CL:0000094	78.48	gold quality
left uterine tube	UBERON:0001303	78.30	gold quality
left lobe of thyroid gland	UBERON:0001120	78.24	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.11

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CTCF, TP53

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 100.0% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 2)

• The unique three-dimensional structure of the zinc finger HIT domain revealed a novel zinc-binding fold, as a new member of the treble clef domain family (PMID:17656577)
• The interaction between RUVBL1/RUVBL2 and the U5 small nuclear ribonucleoprotein is mostly mediated by the previously uncharacterized factor ZNHIT2. (PMID:28561026)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	znhit2	ENSDARG00000030805
mus_musculus	Znhit2	ENSMUSG00000075227
rattus_norvegicus	Znhit2	ENSRNOG00000021794
drosophila_melanogaster	CG31223	FBGN0051223
caenorhabditis_elegans		WBGENE00009648

Protein

Protein identifiers

Zinc finger HIT domain-containing protein 2 — Q9UHR6 (reviewed: Q9UHR6)

Alternative names: Protein FON

All UniProt accessions (2): Q9UHR6, E9PQB8

UniProt curated annotations — full annotation on UniProt →

Function. May act as a bridging factor mediating the interaction between the R2TP/Prefoldin-like (R2TP/PFDL) complex and U5 small nuclear ribonucleoprotein (U5 snRNP). Required for the interaction of R2TP complex subunit RPAP3 and prefoldin-like subunit URI1 with U5 snRNP proteins EFTUD2 and PRPF8. May play a role in regulating the composition of the U5 snRNP complex.

Subunit / interactions. Interacts (via HIT-type zinc finger) with RUVBL2 in the presence of ATP or ADP; shows a stronger interaction in the presence of ADP.

Tissue specificity. Low expression in most tissues; highly expressed in testis.

RefSeq proteins (1): NP_055020* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007529	Znf_HIT	Domain
IPR039646	ZNHIT2	Family

Pfam: PF04438

UniProt features (22 total): binding site 8, sequence variant 3, strand 3, modified residue 2, helix 2, chain 1, zinc finger region 1, turn 1, region of interest 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
1X4S	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UHR6-F1	79.37	0.45

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 (8): 41; 7; 10; 22; 25; 30; 34; 38

Post-translational modifications (2): 1, 161

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 83 (showing top): chr11q13, SCGGAAGY_ELK1_02, KRIGE_RESPONSE_TO_TOSEDOSTAT_6HR_DN, WHITFIELD_CELL_CYCLE_G2, MARTENS_TRETINOIN_RESPONSE_DN, GCNP_SHH_UP_LATE.V1_DN, P53_DN.V2_DN, RELA_DN.V1_UP, PRC2_EED_DN.V1_UP, RPS14_DN.V1_DN, CBX7_TARGET_GENES, CTR9_TARGET_GENES, E2F2_TARGET_GENES, FOXN3_TARGET_GENES, HOXC6_TARGET_GENES

GO Biological Process (0):

GO Molecular Function (3): zinc ion binding (GO:0008270), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (0):

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transition metal ion binding	1
binding	1
cation binding	1

Protein interactions and networks

STRING

1285 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ZNHIT2	TM7SF2	O76062	902
ZNHIT2	AAR2	Q9Y312	748
ZNHIT2	EFTUD2	Q15029	707
ZNHIT2	ZNHIT3	Q15649	681
ZNHIT2	PRPF8	Q6P2Q9	680
ZNHIT2	ZNHIT6	Q9NWK9	660
ZNHIT2	NCDN	Q9UBB6	650
ZNHIT2	PIH1D1	Q9NWS0	622
ZNHIT2	INO80B	Q9C086	594
ZNHIT2	RPAP3	Q9H6T3	591
ZNHIT2	MEN1	O00255	587
ZNHIT2	NOPCHAP1	Q8N5I9	572
ZNHIT2	RUVBL2	Q9Y230	572
ZNHIT2	ENTHD1	Q8IYW4	531
ZNHIT2	RUVBL1	P82276	524

IntAct

90 interactions, top by confidence:

A	B	Type	Score
RUVBL1	ZNHIT1	psi-mi:“MI:0914”(association)	0.860
SNRNP40	SNRNP200	psi-mi:“MI:0914”(association)	0.810
ZNHIT2	RUVBL1	psi-mi:“MI:0915”(physical association)	0.800
CD2BP2	ZNHIT2	psi-mi:“MI:0915”(physical association)	0.670
GPR156	PLD2	psi-mi:“MI:0914”(association)	0.640
RUVBL2	POLR3A	psi-mi:“MI:0914”(association)	0.640
RUVBL1	POLR3A	psi-mi:“MI:0914”(association)	0.640
EFTUD2	SART1	psi-mi:“MI:0914”(association)	0.610
LONRF1	ZNHIT2	psi-mi:“MI:0915”(physical association)	0.560
JAKMIP1	ZNHIT2	psi-mi:“MI:0915”(physical association)	0.560
	ZNHIT2	psi-mi:“MI:0915”(physical association)	0.560
AAR2	SNRNP200	psi-mi:“MI:0914”(association)	0.530
TFDP3	E2F3	psi-mi:“MI:0914”(association)	0.530
CBLC	GAK	psi-mi:“MI:0914”(association)	0.530
KIAA1143	AQR	psi-mi:“MI:0914”(association)	0.530
ECD	SNRNP200	psi-mi:“MI:0914”(association)	0.530
EFTUD2	AQR	psi-mi:“MI:0914”(association)	0.530
EAPP	SNRNP200	psi-mi:“MI:0914”(association)	0.530

BioGRID (166): ZNHIT2 (Affinity Capture-MS), ZNHIT2 (Affinity Capture-MS), ZNHIT2 (Affinity Capture-MS), ZNHIT2 (Affinity Capture-MS), ZNHIT2 (Affinity Capture-MS), ZNHIT2 (Affinity Capture-MS), ZNHIT2 (Affinity Capture-MS), ZNHIT2 (Affinity Capture-MS), CKAP5 (Co-fractionation), ZNHIT2 (Co-fractionation), ZNHIT2 (Co-fractionation), ZNHIT2 (Affinity Capture-MS), ZNHIT2 (Affinity Capture-MS), ZNHIT2 (Affinity Capture-MS), ZNHIT2 (Affinity Capture-MS)

ESM2 similar proteins: A0A2K3E7S8, A8B1U4, A8I4E9, A8ICS9, A8ID74, A8IF44, A8IGK2, A8IH47, A8INQ0, A8ITV9, A8IUG5, A8J0N6, A8J1V4, A8JAF2, A8JAN3, A8JBB2, A8JID5, A8Q1F0, B0WTU5, B5BUZ8, D4P3R7, F5A894, P0C7L7, P0DL09, P46870, P53787, Q2QPW2, Q2XQY7, Q4PDA7, Q53JI9, Q5Z6N9, Q688R3, Q69T21, Q6R2V6, Q6RCE1, Q750K9, Q751Z6, Q752S4, Q756C3, Q759H4

Diamond homologs: Q2TBW5, Q9QY66, Q9UHR6

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 84 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
mRNA Splicing - Major Pathway	8	9.3×	7e-04

GO biological processes:

GO term	Partners	Fold	FDR
mRNA splicing, via spliceosome	8	9.9×	6e-04
protein stabilization	7	6.3×	1e-02

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	96
Likely benign	3
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

105 predictions. Top by Δscore:

Variant	Effect	Δscore
11:65116960:C:CT	acceptor_gain	0.6200
11:65116923:A:T	acceptor_gain	0.6100
11:65116963:CGTGA:C	acceptor_gain	0.6100
11:65116922:CAG:C	acceptor_gain	0.5900
11:65116784:G:GT	donor_gain	0.5700
11:65116919:G:T	acceptor_gain	0.5500
11:65116924:G:C	acceptor_gain	0.5400
11:65116910:G:T	acceptor_gain	0.5300
11:65116924:G:GC	acceptor_gain	0.5300
11:65116891:G:A	donor_gain	0.5200
11:65117208:C:CT	donor_gain	0.5100
11:65117209:T:TT	donor_gain	0.5100
11:65116840:C:A	donor_gain	0.5000
11:65116909:C:CT	acceptor_gain	0.5000
11:65116796:AGCC:A	donor_gain	0.4900
11:65116932:C:CT	acceptor_gain	0.4900
11:65116930:C:CT	acceptor_gain	0.4700
11:65116987:C:CT	acceptor_gain	0.4700
11:65116874:C:CT	acceptor_gain	0.4600
11:65117418:T:TA	donor_gain	0.4300
11:65116872:T:TA	donor_gain	0.4200
11:65116918:C:CT	acceptor_gain	0.4200
11:65116967:A:C	acceptor_gain	0.4200
11:65116926:G:GC	acceptor_gain	0.4100
11:65116908:C:G	acceptor_gain	0.3900
11:65116933:A:T	acceptor_gain	0.3900
11:65116839:T:TA	donor_gain	0.3800
11:65117407:C:A	donor_gain	0.3800
11:65116907:TCC:T	acceptor_gain	0.3700
11:65117406:T:TA	donor_gain	0.3700

AlphaMissense

2529 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:65117519:G:C	F45L	0.987
11:65117519:G:T	F45L	0.987
11:65117521:A:G	F45L	0.987
11:65116618:A:G	W346R	0.984
11:65116618:A:T	W346R	0.984
11:65116628:G:C	F342L	0.983
11:65116628:G:T	F342L	0.983
11:65116630:A:G	F342L	0.983
11:65116883:G:C	F257L	0.979
11:65116883:G:T	F257L	0.979
11:65116885:A:G	F257L	0.979
11:65117264:C:A	W130C	0.973
11:65117264:C:G	W130C	0.973
11:65116616:C:A	W346C	0.971
11:65116616:C:G	W346C	0.971
11:65117266:A:G	W130R	0.971
11:65117266:A:T	W130R	0.971
11:65117580:C:G	C25S	0.971
11:65117581:A:T	C25S	0.971
11:65117590:A:G	C22R	0.971
11:65117003:A:C	N217K	0.970
11:65117003:A:T	N217K	0.970
11:65116640:T:A	K338N	0.968
11:65116640:T:G	K338N	0.968
11:65116776:A:G	I293T	0.968
11:65117324:G:C	F110L	0.968
11:65117324:G:T	F110L	0.968
11:65117326:A:G	F110L	0.968
11:65117357:C:A	W99C	0.967
11:65117357:C:G	W99C	0.967

dbSNP variants (sampled 300 via entrez): RS1001542660 (11:65117560 G>A,C), RS1002431275 (11:65117519 G>C,T), RS1002573048 (11:65118280 G>C), RS1002948993 (11:65118624 C>A,T), RS1003451174 (11:65118210 C>G,T), RS1003507305 (11:65119462 T>C,G), RS1004379825 (11:65118998 C>T), RS1004404017 (11:65117714 G>A,T), RS1004410970 (11:65118686 CTG>C), RS1004741210 (11:65116775 G>C), RS1004875494 (11:65116433 G>A), RS1005877509 (11:65117552 G>A,T), RS1005907478 (11:65116352 A>C), RS1007103302 (11:65119002 A>G), RS1007301345 (11:65117892 T>G)

Disease associations

OMIM: gene MIM:604575 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

26 total (human), top 26 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression	2
Air Pollutants	affects expression, increases abundance, increases expression	2
Smoke	decreases expression, increases abundance, increases expression	2
FR900359	affects phosphorylation	1
bisphenol A	decreases expression, increases methylation	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
abrine	increases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	affects cotreatment, decreases expression	1
(4-amino-1,4-dihydro-3-(2-pyridyl)-5-thioxo-1,2,4-triazole)copper(II)	decreases expression	1
MT19c compound	decreases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	1
Amiodarone	increases expression	1
Benzo(a)pyrene	increases expression	1
Cadmium	increases expression	1
Cisplatin	decreases expression	1
Methotrexate	decreases expression	1
Ozone	affects expression, increases abundance	1
Tetrachlorodibenzodioxin	decreases expression, affects cotreatment	1
Thiram	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Urethane	decreases expression	1
Valproic Acid	affects expression	1
Antirheumatic Agents	increases expression	1
Cadmium Chloride	decreases expression	1
Copper Sulfate	decreases expression	1

Clinical trials (associated diseases)

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