ZNF668

Summary

ZNF668 (zinc finger protein 668, HGNC:25821) is a protein-coding gene on chromosome 16p11.2, encoding Zinc finger protein 668 (Q96K58). May be involved in transcriptional regulation.

Predicted to enable DNA-binding transcription repressor activity, RNA polymerase II-specific; RNA polymerase II cis-regulatory region sequence-specific DNA binding activity; and zinc ion binding activity. Involved in DNA repair. Predicted to be active in nucleus.

Source: NCBI Gene 79759 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder with poor growth, large ears, and dysmorphic facies (Moderate, GenCC)
• GWAS associations: 4
• Clinical variants (ClinVar): 100 total — 2 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 30
• MANE Select transcript: NM_024706

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25821
Approved symbol	ZNF668
Name	zinc finger protein 668
Location	16p11.2
Locus type	gene with protein product
Status	Approved
Aliases	FLJ13479
Ensembl gene	ENSG00000167394
Ensembl biotype	protein_coding
OMIM	617103
Entrez	79759

Gene structure

Transcript identifiers

Ensembl transcripts: 20 — 19 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000300849, ENST00000394983, ENST00000414399, ENST00000417935, ENST00000426488, ENST00000442862, ENST00000535577, ENST00000538906, ENST00000539836, ENST00000564456, ENST00000852227, ENST00000852228, ENST00000852229, ENST00000921192, ENST00000921193, ENST00000921194, ENST00000921195, ENST00000969631, ENST00000969632, ENST00000969633

RefSeq mRNA: 4 — MANE Select: NM_024706 NM_001172668, NM_001172669, NM_001172670, NM_024706

CCDS: CCDS10701, CCDS54003

Canonical transcript exons

ENST00000300849 — 3 exons

Exon	Start	End
ENSE00001229511	31073659	31074240
ENSE00003624600	31063813	31064481
ENSE00003841214	31060847	31062280

Expression profiles

Bgee: expression breadth ubiquitous, 173 present calls, max score 82.96.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 6.0121 / max 80.8629, expressed in 1740 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
157125	3.7119	1598
157124	1.3353	897
157123	0.8711	459
157122	0.0679	30
157121	0.0159	5
157120	0.0101	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	82.96	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.53	gold quality
stromal cell of endometrium	CL:0002255	79.57	gold quality
granulocyte	CL:0000094	79.55	gold quality
cortical plate	UBERON:0005343	79.42	gold quality
apex of heart	UBERON:0002098	79.23	gold quality
cervix squamous epithelium	UBERON:0006922	77.98	gold quality
lower esophagus mucosa	UBERON:0035834	77.96	gold quality
leukocyte	CL:0000738	77.84	gold quality
monocyte	CL:0000576	77.83	gold quality
mononuclear cell	CL:0000842	77.73	gold quality
mucosa of transverse colon	UBERON:0004991	77.53	gold quality
prefrontal cortex	UBERON:0000451	77.50	gold quality
ganglionic eminence	UBERON:0004023	76.78	gold quality
hindlimb stylopod muscle	UBERON:0004252	76.25	gold quality
gastrocnemius	UBERON:0001388	75.90	gold quality
lower esophagus	UBERON:0013473	75.72	gold quality
lower esophagus muscularis layer	UBERON:0035833	75.72	gold quality
right adrenal gland cortex	UBERON:0035827	75.64	gold quality
left adrenal gland cortex	UBERON:0035825	75.48	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	75.48	gold quality
left adrenal gland	UBERON:0001234	75.46	gold quality
right adrenal gland	UBERON:0001233	75.44	gold quality
right coronary artery	UBERON:0001625	75.20	gold quality
muscle of leg	UBERON:0001383	75.16	gold quality
left coronary artery	UBERON:0001626	75.14	gold quality
right frontal lobe	UBERON:0002810	74.98	gold quality
skin of leg	UBERON:0001511	74.94	gold quality
anterior cingulate cortex	UBERON:0009835	74.78	gold quality
cingulate cortex	UBERON:0003027	74.77	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.42

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

16 targeting ZNF668, 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-4673	100.00	66.64	1490
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-3659	99.70	67.97	694
HSA-MIR-1276	99.36	68.18	1642
HSA-MIR-4755-3P	98.77	65.59	1915
HSA-MIR-637	97.91	64.05	1517
HSA-MIR-4294	97.86	65.72	1110
HSA-MIR-3085-5P	97.72	65.43	544
HSA-MIR-5194	96.77	63.91	1021
HSA-MIR-6738-5P	96.33	63.61	815
HSA-MIR-1914-3P	95.07	63.37	762

Literature-anchored findings (GeneRIF, showing 3)

• ZNF668 was identified as a novel breast tumor suppressor protein that regeulates the stability p53 tumor suppression proteins. (PMID:21852383)
• ZNF668 is a key molecule that links chromatin relaxation with DNA damage response in DNA repair control. (PMID:23777805)
• ZNF668 deficiency causes a recognizable disorder of DNA damage repair. (PMID:34313816)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Zfp668	ENSMUSG00000049728
rattus_norvegicus	Zfp668	ENSRNOG00000016683

Paralogs (4): PRDM5 (ENSG00000138738), ZNF358 (ENSG00000198816), ZNF579 (ENSG00000218891), ZNF850 (ENSG00000267041)

Protein

Protein identifiers

Zinc finger protein 668 — Q96K58 (reviewed: Q96K58)

All UniProt accessions (4): C9J092, C9JCJ0, C9JG35, Q96K58

UniProt curated annotations — full annotation on UniProt →

Function. May be involved in transcriptional regulation. May play a role in DNA repair process.

Subcellular location. Nucleus.

Disease relevance. Neurodevelopmental disorder with poor growth, large ears, and dysmorphic facies (NEDGEF) [MIM:620194] An autosomal recessive neurodevelopmental disorder characterized by severe global developmental delay, brain malformation, microcephaly, growth deficiency, and distinct facial dysmorphism. Disease severity is variable and death in infancy may occur. The disease is caused by variants affecting the gene represented in this entry.

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

Isoforms (2)

UniProt ID	Names	Canonical?
Q96K58-1	1	yes
Q96K58-2	2

RefSeq proteins (4): NP_001166139, NP_001166140, NP_001166141, NP_078982* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR013087	Znf_C2H2_type	Domain
IPR036236	Znf_C2H2_sf	Homologous_superfamily

Pfam: PF00096

UniProt features (41 total): zinc finger region 16, sequence variant 9, cross-link 6, modified residue 3, region of interest 2, sequence conflict 2, chain 1, compositionally biased region 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96K58-F1	72.87	0.15

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 (9): 1, 10, 387, 57, 59, 65, 80, 154, 512

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-212436	Generic Transcription Pathway

MSigDB gene sets: 170 (showing top): TGCGCANK_UNKNOWN, AP4_Q6, CAGCTG_AP4_Q5, SOX9_B1, KESHELAVA_MULTIPLE_DRUG_RESISTANCE, chr16p11, GOBP_DNA_DAMAGE_RESPONSE, RYTTCCTG_ETS2_B, YY1_01, SOX5_01, YYCATTCAWW_UNKNOWN, XU_GH1_EXOGENOUS_TARGETS_UP, GCCATNTTG_YY1_Q6, PAX2_02, GOBP_DNA_METABOLIC_PROCESS

GO Biological Process (3): DNA repair (GO:0006281), regulation of transcription by RNA polymerase II (GO:0006357), negative regulation of transcription by RNA polymerase II (GO:0000122)

GO Molecular Function (6): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription repressor activity, RNA polymerase II-specific (GO:0001227), zinc ion binding (GO:0008270), DNA binding (GO:0003677), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (1): 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
transcription by RNA polymerase II	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
DNA metabolic process	1
DNA damage response	1
regulation of DNA-templated transcription	1
regulation of transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
cis-regulatory region sequence-specific DNA binding	1
negative regulation of transcription by RNA polymerase II	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription repressor activity	1
transition metal ion binding	1
nucleic acid binding	1
binding	1
cation binding	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1062 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ZNF668	GTF2F1	P35269	670
ZNF668	GRIP2	Q9C0E4	659
ZNF668	AKAP6	Q13023	622
ZNF668	RUSC2	Q8N2Y8	586
ZNF668	ZNF280A	P59817	565
ZNF668	SEC23IP	Q9Y6Y8	529
ZNF668	BMPR2	Q13873	516
ZNF668	KAT8	Q9H7Z6	508
ZNF668	KAT5	Q92993	505
ZNF668	NCBP3	Q53F19	501
ZNF668	RFT1	Q96AA3	480
ZNF668	HDAC2	Q92769	480
ZNF668	PRSS36	Q5K4E3	477
ZNF668	SYPL1	Q16563	474
ZNF668	SFT2D3	Q587I9	471

IntAct

130 interactions, top by confidence:

A	B	Type	Score
H2AX	PPM1G	psi-mi:“MI:0914”(association)	0.730
RPL14	RRP8	psi-mi:“MI:0914”(association)	0.640
H1-1	RRP8	psi-mi:“MI:0914”(association)	0.640
NOL12	RRP8	psi-mi:“MI:0914”(association)	0.640
LIN28A	IGF2BP3	psi-mi:“MI:0914”(association)	0.640
HMGB2	ZNF668	psi-mi:“MI:0915”(physical association)	0.550
H1-6	ZNF724	psi-mi:“MI:0914”(association)	0.530
ZNF512	ZNF724	psi-mi:“MI:0914”(association)	0.530
RRP8	NVL	psi-mi:“MI:0914”(association)	0.530
H1-4	IGF2BP3	psi-mi:“MI:0914”(association)	0.530
PRR11	NVL	psi-mi:“MI:0914”(association)	0.530
RPL30	RRP8	psi-mi:“MI:0914”(association)	0.530
RPL7	ZBTB24	psi-mi:“MI:0914”(association)	0.530
N	NOP56	psi-mi:“MI:0914”(association)	0.530
N	RBM47	psi-mi:“MI:0914”(association)	0.530
RPS3	ZNF316	psi-mi:“MI:0914”(association)	0.530
MAGEB2	POLRMT	psi-mi:“MI:0914”(association)	0.530
ABT1	ZNF316	psi-mi:“MI:0914”(association)	0.530
RPL7A	NVL	psi-mi:“MI:0914”(association)	0.530
H1-1	SURF6	psi-mi:“MI:0914”(association)	0.530
Pip4k2c	LAMA5	psi-mi:“MI:0914”(association)	0.350
Csk	PLCG2	psi-mi:“MI:0914”(association)	0.350

BioGRID (290): ZNF668 (Affinity Capture-MS), ZNF668 (Affinity Capture-MS), ZNF668 (Affinity Capture-MS), ZNF668 (Affinity Capture-MS), ZNF668 (Affinity Capture-MS), ZNF668 (Affinity Capture-MS), ZNF668 (Affinity Capture-MS), ZNF668 (Affinity Capture-MS), ZNF668 (Affinity Capture-MS), ZNF668 (Affinity Capture-MS), ZNF668 (Affinity Capture-MS), ZNF668 (Affinity Capture-MS), ZNF668 (Affinity Capture-MS), ZNF668 (Affinity Capture-MS), ZNF668 (Affinity Capture-MS)

ESM2 similar proteins: A2APF3, B1WBS3, D3ZUU2, E9Q3T6, E9Q8T2, G5E8B9, O15060, O43167, O70237, O93567, O95625, O95863, P10074, P10754, Q02085, Q05516, Q13105, Q1H9T6, Q1L8W0, Q2TA17, Q3B725, Q3B7N9, Q3URR7, Q4VBD9, Q5R633, Q5T619, Q5VTD9, Q60821, Q6DDV0, Q6GL52, Q6NS86, Q6YND2, Q7TS63, Q80X44, Q811F1, Q811H0, Q8BI69, Q8BXX2, Q8BY46, Q8K2R5

Diamond homologs: Q2TA17, Q4R3I5, Q8K2R5, Q96K58, Q96JB3

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 129 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
Peptide chain elongation	18	30.1×	2e-20
Viral mRNA Translation	18	30.1×	2e-20
PELO:HBS1L and ABCE1 dissociate a ribosome on a non-stop mRNA	18	29.7×	2e-20
Selenocysteine synthesis	18	28.5×	2e-20
Eukaryotic Translation Termination	18	28.5×	2e-20
Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC)	18	27.9×	3e-20
ZNF598 and the Ribosome-associated Quality Trigger (RQT) complex dissociate a ribosome stalled on a no-go mRNA	18	27.9×	3e-20
Formation of a pool of free 40S subunits	18	26.5×	6e-20

GO biological processes:

GO term	Partners	Fold	FDR
negative regulation of DNA recombination	5	49.7×	3e-06
chromosome condensation	5	37.3×	1e-05
cytoplasmic translation	19	31.1×	7e-21
ribosomal large subunit biogenesis	7	27.5×	6e-07
ribosomal small subunit biogenesis	10	20.1×	8e-09
rRNA processing	15	18.8×	4e-13
translation	18	16.4×	1e-14
regulation of alternative mRNA splicing, via spliceosome	7	15.1×	3e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	1
Uncertain significance	85
Likely benign	6
Benign	4

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
1184621	NM_024706.5(ZNF668):c.955C>T (p.Gln319Ter)	Pathogenic
1184622	NM_024706.5(ZNF668):c.1111C>T (p.Arg371Ter)	Pathogenic
3384008	NM_024706.5(ZNF668):c.1197del (p.Lys399fs)	Likely pathogenic

SpliceAI

438 predictions. Top by Δscore:

Variant	Effect	Δscore
16:31063807:CCTCA:C	donor_loss	1.0000
16:31063808:CTCAC:C	donor_loss	1.0000
16:31063809:TCA:T	donor_loss	1.0000
16:31063810:CACCG:C	donor_loss	1.0000
16:31063811:A:AC	donor_gain	1.0000
16:31063811:A:C	donor_loss	1.0000
16:31063812:C:CC	donor_gain	1.0000
16:31063812:C:CG	donor_loss	1.0000
16:31063812:CCG:C	donor_gain	1.0000
16:31063812:CCGCT:C	donor_gain	1.0000
16:31063831:T:TA	donor_gain	1.0000
16:31062277:GGACC:G	acceptor_loss	0.9900
16:31062279:ACC:A	acceptor_loss	0.9900
16:31062281:C:CC	acceptor_gain	0.9900
16:31062282:T:C	acceptor_loss	0.9900
16:31063867:CAG:C	donor_gain	0.9900
16:31064993:T:A	donor_gain	0.9900
16:31064479:TCT:T	acceptor_gain	0.9800
16:31064480:CT:C	acceptor_gain	0.9800
16:31064480:CTC:C	acceptor_gain	0.9800
16:31064481:TCT:T	acceptor_gain	0.9800
16:31064482:C:CC	acceptor_gain	0.9800
16:31062276:GGGAC:G	acceptor_gain	0.9700
16:31062277:GGAC:G	acceptor_gain	0.9700
16:31062278:GAC:G	acceptor_gain	0.9700
16:31064478:TTCT:T	acceptor_gain	0.9700
16:31064805:T:TA	donor_gain	0.9700
16:31062289:G:C	acceptor_gain	0.9600
16:31062289:G:GC	acceptor_gain	0.9600
16:31063802:G:C	donor_gain	0.9600

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000169971 (16:31074952 G>A), RS1000246556 (16:31066004 A>C,G), RS1000402423 (16:31072655 G>C), RS1000701390 (16:31065816 C>T), RS1000904962 (16:31065643 G>A), RS1001180413 (16:31075559 A>G,T), RS1001324583 (16:31075068 C>T), RS1001608399 (16:31064550 C>T), RS1001763317 (16:31071430 G>A), RS1001893163 (16:31066171 C>A), RS1002076385 (16:31070865 T>C), RS1002149601 (16:31072736 C>T), RS1002233753 (16:31071105 C>T), RS1002320301 (16:31064840 G>A), RS1002742270 (16:31067830 G>A,T)

Disease associations

OMIM: gene MIM:617103 | disease phenotypes: MIM:620194

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder with poor growth, large ears, and dysmorphic facies	Moderate	Autosomal recessive

Mondo (2): neurodevelopmental disorder with poor growth, large ears, and dysmorphic facies (MONDO:0859350), myoepithelial tumor (MONDO:0002380)

Orphanet (0):

HPO phenotypes

30 total (30 of 30 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000218	High palate
HP:0000252	Microcephaly
HP:0000347	Micrognathia
HP:0000384	Preauricular skin tag
HP:0000400	Macrotia
HP:0000448	Prominent nose
HP:0000490	Deeply set eye
HP:0000567	Chorioretinal coloboma
HP:0000768	Pectus carinatum
HP:0000819	Diabetes mellitus
HP:0000938	Osteopenia
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001508	Failure to thrive
HP:0001518	Small for gestational age
HP:0001684	Secundum atrial septal defect
HP:0001822	Hallux valgus
HP:0001847	Long hallux
HP:0002061	Lower limb spasticity
HP:0002783	Recurrent lower respiratory tract infections
HP:0003593	Infantile onset
HP:0011304	Broad thumb
HP:0011968	Feeding difficulties
HP:0012444	Brain atrophy
HP:0030084	Clinodactyly
HP:0200134	Epileptic encephalopathy
HP:0430028	Hyperplasia of the maxilla

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST003791_9	Response to metformin (IC50)	9.000000e-06
GCST007293_141	Body fat distribution (arm fat ratio)	4.000000e-15
GCST007293_82	Body fat distribution (arm fat ratio)	3.000000e-15
GCST007293_99	Body fat distribution (arm fat ratio)	1.000000e-14

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0006952	cytotoxicity measurement
EFO:0004341	body fat distribution

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D009208	Myoepithelioma	C04.557.435.585

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

22 total (human), top 22 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Tobacco Smoke Pollution	increases expression	2
aristolochic acid I	increases expression	1
GSK-J4	decreases expression	1
TAK-243	increases sumoylation	1
alpha-pinene	increases oxidation, increases abundance, affects cotreatment, decreases expression	1
beta-lapachone	decreases expression	1
methacrylaldehyde	increases abundance, affects cotreatment, decreases expression, increases oxidation	1
abrine	increases expression	1
Irinotecan	decreases expression	1
Acrolein	affects cotreatment, decreases expression, increases oxidation, increases abundance	1
Air Pollutants	increases abundance, increases oxidation, affects cotreatment, decreases expression	1
Vehicle Emissions	decreases expression, increases abundance	1
Benzo(a)pyrene	affects methylation	1
Doxorubicin	decreases expression	1
Ozone	decreases expression, increases oxidation, increases abundance, affects cotreatment	1
Ribonucleotides	affects binding	1
Smoke	decreases expression	1
Tunicamycin	decreases expression	1
Urethane	increases expression	1
Copper Sulfate	increases expression	1
Particulate Matter	decreases expression, increases abundance	1
Volatile Organic Compounds	increases oxidation, affects cotreatment, decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03600649	PHASE1	UNKNOWN	Clinical Trial of SP-2577 (Seclidemstat) in Patients With Relapsed or Refractory Ewing or Ewing-related Sarcomas
NCT05266196	PHASE1/PHASE2	UNKNOWN	A Rollover Protocol to Allow for Continued Access to the LSD1 Inhibitor Seclidemstat (SP-2577)
NCT06239272	PHASE1/PHASE2	RECRUITING	NRSTS2021, A Risk Adapted Study Evaluating Maintenance Pazopanib, Limited Margin, Dose-Escalated Radiation Therapy and Selinexor in Non-Rhabdomyosarcoma Soft Tissue Sarcoma (NRSTS)
NCT06625190	PHASE1/PHASE2	RECRUITING	Alpha/Beta T and B Cell Depletion With Zoledronic Acid for Solid Tumors
NCT06244420	Not specified	COMPLETED	Malignant Myoepithelioma of Bone and Soft Tissues: Diagnostic Imaging and Histology in Relation to Prognosis