TFAP2C

Summary

TFAP2C (transcription factor AP-2 gamma, HGNC:11744) is a protein-coding gene on chromosome 20q13.31, encoding Transcription factor AP-2 gamma (Q92754). Sequence-specific DNA-binding transcription factor that interacts with cellular enhancer elements to regulate transcription of selected genes, and which plays a key role in early embryonic development.

The protein encoded by this gene is a sequence-specific DNA-binding transcription factor involved in the activation of several developmental genes. The encoded protein can act as either a homodimer or heterodimer with other family members and is induced during retinoic acid-mediated differentiation. It plays a role in the development of the eyes, face, body wall, limbs, and neural tube.

Source: NCBI Gene 7022 — RefSeq curated summary.

At a glance

• GWAS associations: 10
• Clinical variants (ClinVar): 47 total
• Phenotypes (HPO): 1
• Transcription factor: yes — 38 downstream targets (CollecTRI)
• MANE Select transcript: NM_003222

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11744
Approved symbol	TFAP2C
Name	transcription factor AP-2 gamma
Location	20q13.31
Locus type	gene with protein product
Status	Approved
Aliases	AP2-GAMMA, ERF1, TFAP2G, hAP-2g
Ensembl gene	ENSG00000087510
Ensembl biotype	protein_coding
OMIM	601602
Entrez	7022

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000201031, ENST00000416606, ENST00000882953

RefSeq mRNA: 1 — MANE Select: NM_003222 NM_003222

CCDS: CCDS13454

Canonical transcript exons

ENST00000201031 — 7 exons

Exon	Start	End
ENSE00000662911	56631805	56631856
ENSE00000662916	56636610	56636754
ENSE00000845721	56633353	56633569
ENSE00001029211	56637728	56639283
ENSE00001029212	56629306	56629592
ENSE00001805908	56634150	56634268
ENSE00003598338	56631205	56631690

Expression profiles

Bgee: expression breadth ubiquitous, 198 present calls, max score 98.25.

FANTOM5 (CAGE): breadth broad, TPM avg 15.3624 / max 319.7162, expressed in 709 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
185448	14.5253	691
185449	0.6680	165
185447	0.1691	92

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endometrium epithelium	UBERON:0004811	98.25	gold quality
ventricular zone	UBERON:0003053	98.05	gold quality
epithelium of mammary gland	UBERON:0003244	97.15	gold quality
mammary duct	UBERON:0001765	96.97	gold quality
upper leg skin	UBERON:0004262	96.83	gold quality
mammalian vulva	UBERON:0000997	95.85	gold quality
skin of hip	UBERON:0001554	95.82	gold quality
gingival epithelium	UBERON:0001949	95.65	gold quality
tongue squamous epithelium	UBERON:0006919	95.63	gold quality
gingiva	UBERON:0001828	95.41	gold quality
hair follicle	UBERON:0002073	95.39	gold quality
upper arm skin	UBERON:0004263	95.26	gold quality
buccal mucosa cell	CL:0002336	94.18	gold quality
nipple	UBERON:0002030	93.63	gold quality
esophagus squamous epithelium	UBERON:0006920	93.06	gold quality
skin of abdomen	UBERON:0001416	92.77	gold quality
zone of skin	UBERON:0000014	92.45	gold quality
squamous epithelium	UBERON:0006914	92.37	gold quality
epithelium of esophagus	UBERON:0001976	92.09	gold quality
ganglionic eminence	UBERON:0004023	91.89	gold quality
skin of leg	UBERON:0001511	91.32	gold quality
placenta	UBERON:0001987	91.25	gold quality
palpebral conjunctiva	UBERON:0001812	91.15	gold quality
pharyngeal mucosa	UBERON:0000355	90.80	gold quality
oral cavity	UBERON:0000167	90.79	gold quality
oviduct epithelium	UBERON:0004804	89.94	gold quality
penis	UBERON:0000989	89.81	gold quality
cervix epithelium	UBERON:0004801	89.73	gold quality
epithelium of nasopharynx	UBERON:0001951	89.70	gold quality
esophagus mucosa	UBERON:0002469	89.06	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-GEOD-75140	yes	356.86
E-MTAB-9388	yes	135.40
E-GEOD-109979	no	172.80
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

38 targets.

Target	Regulation
ADA	Activation
CDKN1A	Repression
CEBPA	Unknown
CGA
CITED2
CRABP2	Activation
CSTA	Unknown
CXCL1
ECM1	Activation
EGFR
ERBB2	Unknown
ERBB3	Activation
ESR1	Activation
FOXA1	Unknown
FOXC1	Unknown
FREM2	Unknown
GPER1	Unknown
GPX1	Activation
GREB1	Unknown
HSD3B1
HSD3B2
IVL	Activation
KRT14	Unknown
MMP2	Unknown
MYB	Unknown
MYC	Unknown
PLAUR
RAD21
RERG	Unknown
RET	Unknown

JASPAR motifs

Motif	Name	Family
MA0524.1	TFAP2C	AP-2
MA0524.2	TFAP2C	AP-2
MA0524.3	TFAP2C	AP-2
MA0814.1	TFAP2C	AP-2
MA0814.2	TFAP2C	AP-2
MA0814.3	TFAP2C	AP-2
MA0815.1	TFAP2C	AP-2

JASPAR matrix evidence (PMIDs): PMID:20629094, PMID:16420676, PMID:23332764

Upstream regulators (CollecTRI, top): ESR1, PRDM1, SMAD1, SP1, SP3, TFAP2A, TFAP2C, TP53

miRNA regulators (miRDB)

71 targeting TFAP2C, 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-MIR-8485	100.00	77.57	4731
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-767-5P	99.95	70.85	993
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-1-3P	99.93	72.35	1914
HSA-MIR-206	99.93	72.50	1893
HSA-MIR-329-3P	99.91	66.56	1234
HSA-MIR-362-3P	99.91	66.38	1267
HSA-MIR-613	99.91	71.50	1710
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-5682	99.89	72.56	1005
HSA-MIR-137-3P	99.87	74.74	2401
HSA-MIR-3919	99.87	69.45	2489

Literature-anchored findings (GeneRIF, showing 40)

• AP-2 gamma and Dlx 3, together with an additional transcription factor(s) that are conserved between humans and mice, are required for trophoblast-specific expression of 3 beta-HSD VI. (PMID:11773066)
• AP-2gamma is important in regulation of ErbB-3 expression in human mammary epithelial and lung fibroblast cells (PMID:11859873)
• AP2 regulates human reduced folate carrier gene expression (PMID:12228234)
• we have identified a potential trophoblast cell-specific regulatory element located 6 kb upstream of the murine AP-2gamma gene transcription start site, and that Sp1 and Sp3 bind to cis-regulatory elements located in the promoter proximal region (PMID:12801994)
• likely prognostic indicator for patients with breast tumors (PMID:12833450)
• AP-2gamma expression in breast cancer cells is induced by oestrogens through binding of the oestrogen receptor to a response element within the 5’-untranslated region. (PMID:14565844)
• Expression of MMP-2 and MMP-9 in breast cancer seems to be partly related to expression of AP-2 and HER2 (PMID:15569994)
• Abundant expression of AP-2gamma is associated with intratubular germ cell neoplasias (PMID:15700319)
• Expression microarray results in human breast carcinoma cells with forced p53 expression revealed AP-2gamma as a putative transcriptional target of p53. (PMID:16636674)
• expression of either AP-2gamma or AP-2alpha induces p21 and inhibits breast carcinoma cell growth (PMID:16867219)
• TFAP2C is the key regulator of hormone responsiveness in breast carcinoma cells through the control of multiple pathways of estrogen signaling. TFAP2C regulates the expression of ERalpha directly by binding to the ERalpha promoter. (PMID:17875680)
• Wwox and Ap2gamma emerge are tumor biomarkers that may be superior to PR and Her2 in predicting tamoxifen response (PMID:17947476)
• AP2 transcription factors may play decisive pacemaker roles in initiating and coordinating budding and branching processes during formation of the fetal breast anlage (PMID:18042070)
• Down-modulation of AP-2gamma expression in tumor cells by RNA interference led to enhanced tumor growth and reduced chemotherapy-induced cell death, as well as migration and invasion. (PMID:18443366)
• Reduced expression levels of nuclear AP2gamma is associated with the pathogenesis of basal-like differentiation in breast cancer. (PMID:19130459)
• The present data suggest that AP-2 may suppress trophoblast migration and invasion, thus leading to a shallow placentation in preeclampsia. (PMID:19443578)
• Data show that the combination of increasing chromatin accessibility and inducing TFAP2C provides a more robust activation of the ERalpha gene in ERalpha-negative breast cancer cells. (PMID:19458056)
• ErbB2, CDH2, HPSE and IGSF11 are identified as AP-2gamma target genes in breast cancer cells. (PMID:19671168)
• AP-2gamma promotes proliferation in breast tumour cells by direct repression of the CDKN1A gene. (PMID:19798054)
• Overexpression of TFAP2C is associated with hormone responsive breast carcinoma. (PMID:20629094)
• miR-214 is highly expressed in human melanomas and the data suggest a critical role for this miRNA in disease progression and the establishment of distant metastases through suppression of TFAP2C. (PMID:21468029)
• AP-2gamma is a novel collaborative factor in ERalpha-mediated transcription. (PMID:21572391)
• demonstrated that while TFAP2C and Myc can downregulate the CDKN1A promoter independently, KDM5B acts as a corepressor dependent on the other two proteins (PMID:22371483)
• results substantiate a role for Tcfap2c/ TFAP2C in supporting proliferation and repressing differentiation in cellular compartments representing immature/ progenitor cells.[review] (PMID:22560121)
• We demonstrated that TFAP-2gamma is one of the transcription factors involved in the HuPAR-2 expression in human villous trophoblast cells. (PMID:22702469)
• TFAP2C regulates expression of the RET proto-oncogene through five AP-2 regulatory sites in the RET promoter. (PMID:22878616)
• Results demonstrate that TFAP2C regulates the expression of GPX1, which influences the redox state and sensitivity to oxidative stress induced by peroxides. (PMID:22964634)
• ESDN and AP-2g expression is lower in thick melanomas, it is associated with unfavourable histo-pathological parameters (increased vascularity, vascular invasion and mitoses) and correlates with a shorter DFS like for AP-2a. (PMID:23036739)
• TFAP2C amplification and overexpression represents a genetic dependency in ERBB2+ve breast cancer. (PMID:23334330)
• role for TFAP2C in melanoma via its regulation of ECM1 (PMID:24023917)
• Knockdown of TFAP2C or RET inhibited activation of ERK and AKT in MCF-7 cells. Knockdown of TFAP2C, which controls ER (estrogen receptor) and RET, had a greater effect on cell growth than either RET or ER alone. (PMID:24045439)
• TFAP2C has an important role in regulated luminal-specific genes and may be a viable therapeutic target in breast cancer. (PMID:24469049)
• ShRNA knockdown of AP-2gamma in neuroblastoma cells results in significant inhibit of cell proliferation. (PMID:24969902)
• In all three groups[preeclamptic placentas , healthy control and smokers] expression rates of AP-2gamma did not differ between primary, secondary and tertiary villi. (PMID:25315380)
• Higher TFAP2C protein expression correlates with poor overall survival after 10 years of diagnosis in ERalpha-positive breast cancer. (PMID:26160249)
• TFAP2C might increase oncogenic miR-183 expression and consequently downregulate tumor-suppressive AKAP12 and decrease tumor-suppressive miR-33a expression and subsequently induce CDK6 in NSCLC cells. (PMID:27593936)
• This study shows that TFAP2C promoted lung tumor progression by upregulation of TGFBR1 and consequent activation of PAK1 signaling. (PMID:27885255)
• miR-137 is a Slug-induced miRNA that relays the pro-metastatic effects of Slug by targeting TFAP2C in non-small cell lung cancer cells. (PMID:28610956)
• Study discovered a novel enhancer HER2 gene body enhancer (HGE) in the 3’ gene body of HER2. The HGE activates promoters 1 and 2 in trans., and hence the TFAP2C-mediated transcriptional induction of HER2 expression in breast cancer samples. (PMID:29035388)
• Our findings indicate that TFAP2C may serve as a novel prognostic factor in CRC patients, and a therapeutic target for the treatment of CRC, suggesting that silencing TFAP2C in combination with 5-FU may be an effective therapeutic strategy to improve survival in CRC patients. (PMID:29439714)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	tfap2c	ENSDARG00000040606
mus_musculus	Tfap2c	ENSMUSG00000028640
rattus_norvegicus	Tfap2c	ENSRNOG00000005246
drosophila_melanogaster	TfAP-2	FBGN0261953
caenorhabditis_elegans		WBGENE00009202
caenorhabditis_elegans		WBGENE00009203
caenorhabditis_elegans		WBGENE00013383
caenorhabditis_elegans		WBGENE00019424

Paralogs (4): TFAP2B (ENSG00000008196), TFAP2D (ENSG00000008197), TFAP2E (ENSG00000116819), TFAP2A (ENSG00000137203)

Protein

Protein identifiers

Transcription factor AP-2 gamma — Q92754 (reviewed: Q92754)

Alternative names: Activating enhancer-binding protein 2 gamma, Transcription factor ERF-1

All UniProt accessions (2): Q92754, A2A2R7

UniProt curated annotations — full annotation on UniProt →

Function. Sequence-specific DNA-binding transcription factor that interacts with cellular enhancer elements to regulate transcription of selected genes, and which plays a key role in early embryonic development. AP-2 factors bind to the consensus sequence 5’-GCCNNNGGC-3’ and activate genes involved in a large spectrum of important biological functions. TFAP2C plays a key role in early embryonic development by regulating both inner cell mass (ICM) and trophectoderm differentiation. At the 8-cell stage, during morula development, controls expression of cell-polarity genes. Upon trophoblast commitment, binds to late trophectoderm genes in blastocysts together with CDX2, and later to extra-embryonic ectoderm genes together with SOX2. Binds to both closed and open chromatin with other transcription factors. Involved in the MTA1-mediated epigenetic regulation of ESR1 expression in breast cancer.

Subunit / interactions. Binds DNA as a dimer. Can form homodimers or heterodimers with other AP-2 family members. Interacts with WWOX. Interacts with UBE2I. Interacts with KCTD1; this interaction represses transcription activation. Interacts with CITED2 (via C-terminus); the interaction stimulates TFAP2B-transcriptional activity. Interacts with CITED4. Interacts with MTA1.

Subcellular location. Nucleus.

Post-translational modifications. Sumoylated on Lys-10; which inhibits transcriptional activity.

Domain organisation. The PPxY motif mediates interaction with WWOX.

Induction. During retinoic acid-mediated differentiation.

Similarity. Belongs to the AP-2 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q92754-1	1	yes
Q92754-2	2

RefSeq proteins (1): NP_003213* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004979	TF_AP2	Family
IPR008123	TF_AP2_gamma	Family
IPR013854	TF_AP2_C	Domain

Pfam: PF03299

UniProt features (14 total): region of interest 4, mutagenesis site 2, compositionally biased region 2, modified residue 2, chain 1, cross-link 1, splice variant 1, short sequence motif 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q92754-F1	66.37	0.36

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 (3): 10, 252, 434

Mutagenesis-validated functional residues (2):

Position	Phenotype
59	loss of interaction with wwox; when associated with a-64.
64	loss of interaction with wwox; when associated with a-59.

Function

Pathways and Gene Ontology

Reactome pathways

20 pathways

ID	Pathway
R-HSA-3232118	SUMOylation of transcription factors
R-HSA-8866904	Negative regulation of activity of TFAP2 (AP-2) family transcription factors
R-HSA-8866906	TFAP2 (AP-2) family regulates transcription of other transcription factors
R-HSA-8866907	Activation of the TFAP2 (AP-2) family of transcription factors
R-HSA-8866910	TFAP2 (AP-2) family regulates transcription of growth factors and their receptors
R-HSA-8866911	TFAP2 (AP-2) family regulates transcription of cell cycle factors
R-HSA-9827857	Specification of primordial germ cells
R-HSA-9834899	Specification of the neural plate border
R-HSA-9938206	Developmental Lineage of Mammary Stem Cells
R-HSA-1266738	Developmental Biology
R-HSA-1474165	Reproduction
R-HSA-212436	Generic Transcription Pathway
R-HSA-2990846	SUMOylation
R-HSA-3108232	SUMO E3 ligases SUMOylate target proteins
R-HSA-392499	Metabolism of proteins
R-HSA-597592	Post-translational protein modification
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)
R-HSA-8864260	Transcriptional regulation by the AP-2 (TFAP2) family of transcription factors
R-HSA-9758941	Gastrulation

MSigDB gene sets: 269 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_UP, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, ELVIDGE_HYPOXIA_DN, MODULE_92, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_MAMMARY_GLAND_MORPHOGENESIS, GOBP_SOMATIC_STEM_CELL_POPULATION_MAINTENANCE, WWTAAGGC_UNKNOWN, GOBP_GLAND_MORPHOGENESIS, GOBP_REGULATION_OF_EPIDERMIS_DEVELOPMENT, GOBP_EPITHELIAL_CELL_DEVELOPMENT, JAEGER_METASTASIS_DN, GOBP_BRANCH_ELONGATION_OF_AN_EPITHELIUM, GCANCTGNY_MYOD_Q6

GO Biological Process (26): inner cell mass cell differentiation (GO:0001826), trophectodermal cell differentiation (GO:0001829), hair follicle development (GO:0001942), keratinocyte development (GO:0003334), regulation of transcription by RNA polymerase II (GO:0006357), transcription by RNA polymerase II (GO:0006366), cell-cell signaling (GO:0007267), male gonad development (GO:0008584), forebrain neuron fate commitment (GO:0021877), cerebral cortex development (GO:0021987), germ-line stem cell population maintenance (GO:0030718), somatic stem cell population maintenance (GO:0035019), regulation of cell population proliferation (GO:0042127), regulation of epidermis development (GO:0045682), negative regulation of gene expression, epigenetic (GO:0045814), positive regulation of transcription by RNA polymerase II (GO:0045944), sebaceous gland development (GO:0048733), stem cell differentiation (GO:0048863), dichotomous subdivision of terminal units involved in mammary gland duct morphogenesis (GO:0060598), epithelial cell proliferation involved in mammary gland duct elongation (GO:0060750), morula formation (GO:0140001), negative regulation of transcription by RNA polymerase II (GO:0000122), regulation of DNA-templated transcription (GO:0006355), stem cell population maintenance (GO:0019827), epithelial cell differentiation (GO:0030855), skin development (GO:0043588)

GO Molecular Function (9): RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription repressor activity, RNA polymerase II-specific (GO:0001227), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), sequence-specific double-stranded DNA binding (GO:1990837), protein binding (GO:0005515)

GO Cellular Component (5): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), mitochondrion (GO:0005739), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-12 pathways:

Category	Pathways
Transcriptional regulation by the AP-2 (TFAP2) family of transcription factors	5
SUMO E3 ligases SUMOylate target proteins	1
Reproduction	1
Gastrulation	1
Developmental Lineages of the Mammary Gland	1
RNA Polymerase II Transcription	1
Post-translational protein modification	1
SUMOylation	1
Metabolism of proteins	1
Gene expression (Transcription)	1
Generic Transcription Pathway	1
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA polymerase II transcription regulatory region sequence-specific DNA binding	4
cell differentiation	3
cellular anatomical structure	3
blastocyst formation	2
anatomical structure development	2
regulation of DNA-templated transcription	2
transcription by RNA polymerase II	2
stem cell population maintenance	2
regulation of transcription by RNA polymerase II	2
branch elongation involved in mammary gland duct branching	2
transcription cis-regulatory region binding	2
DNA-binding transcription factor activity, RNA polymerase II-specific	2
intracellular membrane-bounded organelle	2
cytoplasm	2
hair cycle process	1
skin epidermis development	1
epithelial cell development	1
keratinocyte differentiation	1
DNA-templated transcription	1
cell communication	1
signaling	1
gonad development	1
development of primary male sexual characteristics	1
forebrain neuron differentiation	1
neuron fate commitment	1
pallium development	1
cell population proliferation	1
regulation of cellular process	1
epidermis development	1
regulation of developmental process	1
negative regulation of gene expression	1
epigenetic regulation of gene expression	1
positive regulation of DNA-templated transcription	1
skin development	1
gland development	1
dichotomous subdivision of an epithelial terminal unit	1
mammary gland epithelial cell proliferation	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1

Protein interactions and networks

STRING

1662 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TFAP2C	WWOX	Q9NZC7	869
TFAP2C	MYC	P01106	861
TFAP2C	KCTD1	Q719H9	810
TFAP2C	GATA3	P23771	808
TFAP2C	KDM5B	Q9UGL1	771
TFAP2C	PRDM14	Q9GZV8	761
TFAP2C	FOXA1	P55317	706
TFAP2C	CITED2	Q99967	675
TFAP2C	NANOS3	P60323	665
TFAP2C	PRDM1	O75626	633
TFAP2C	SOX17	Q9H6I2	603
TFAP2C	ELF5	Q9UKW6	593
TFAP2C	POU5F1	P31359	588
TFAP2C	NANOG	Q9H9S0	587
TFAP2C	STX16	O14662	586

IntAct

108 interactions, top by confidence:

A	B	Type	Score
RARA	NCOR1	psi-mi:“MI:0914”(association)	0.800
TFAP2C	UBE2I	psi-mi:“MI:0915”(physical association)	0.650
TFAP2C		psi-mi:“MI:0915”(physical association)	0.580
	TFAP2C	psi-mi:“MI:0915”(physical association)	0.580
	TFAP2C	psi-mi:“MI:0914”(association)	0.580
TFAP2C	RARA	psi-mi:“MI:0914”(association)	0.530
CITED2	TFAP2C	psi-mi:“MI:0915”(physical association)	0.510
TFAP2C	CITED2	psi-mi:“MI:0915”(physical association)	0.510
RARA	FOS	psi-mi:“MI:0914”(association)	0.460
	TFAP2C	psi-mi:“MI:0915”(physical association)	0.370
TFAP2C	CCNG1	psi-mi:“MI:0915”(physical association)	0.370
GPR22	TFAP2C	psi-mi:“MI:0915”(physical association)	0.370
TFAP2C	IKBKB	psi-mi:“MI:0915”(physical association)	0.370
TFAP2C	NR1I2	psi-mi:“MI:0915”(physical association)	0.370
TFAP2C	ZFAND4	psi-mi:“MI:0915”(physical association)	0.370
TFAP2C	EYA2	psi-mi:“MI:0915”(physical association)	0.370
DPP7	TFAP2C	psi-mi:“MI:0915”(physical association)	0.370
CCDC80	TFAP2C	psi-mi:“MI:0915”(physical association)	0.370
CFH	TFAP2C	psi-mi:“MI:0915”(physical association)	0.370
TFAP2C	COL15A1	psi-mi:“MI:0915”(physical association)	0.370
TFAP2C	IFI27L2	psi-mi:“MI:0915”(physical association)	0.370
TFAP2C	COL1A2	psi-mi:“MI:0915”(physical association)	0.370
COL1A1	TFAP2C	psi-mi:“MI:0915”(physical association)	0.370
TFAP2C	FCGBP	psi-mi:“MI:0915”(physical association)	0.370
TFAP2C	TNXA	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (50): ERBB4 (Affinity Capture-Western), TFAP2C (Reconstituted Complex), TFAP2C (Affinity Capture-Western), TFAP2C (Two-hybrid), TFAP2C (Reconstituted Complex), TFAP2C (Co-localization), TFAP2C (Co-localization), TFAP2C (Co-localization), TFAP2C (Affinity Capture-MS), WWOX (Affinity Capture-Western), TFAP2C (Affinity Capture-Western), TFAP2C (Reconstituted Complex), TFAP2C (Reconstituted Complex), TFAP2C (Reconstituted Complex), TFAP2C (Affinity Capture-MS)

ESM2 similar proteins: A1A4R9, A9CB91, O54835, O70436, P05549, P06435, P08651, P09286, P09414, P0C734, P11823, P11824, P13623, P17923, P19893, P21999, P30119, P34056, P42003, P58197, P70257, Q02780, Q09585, Q0ZME3, Q12857, Q14938, Q14EA6, Q15796, Q1HVD3, Q1W668, Q2T9K2, Q3KPS4, Q5R7C0, Q5RJ20, Q61312, Q61313, Q62432, Q6SW29, Q6SWP7, Q76HI7

Diamond homologs: A1A4R9, P05549, P34056, P58197, Q09585, Q2T9K2, Q5RJ20, Q61312, Q61313, Q6P0E7, Q6VUC0, Q6VUP9, Q76HI7, Q7Z6R9, Q91ZK0, Q92481, Q92754, Q9N0N3, G2HK15

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
TFAP2C	“up-regulates quantity by expression”	ECM1	“transcriptional regulation”
TFAP2C	“up-regulates quantity by expression”	CRABP2	“transcriptional regulation”
TFAP2C	“up-regulates quantity by expression”	SULT1E1	“transcriptional regulation”
SOX17/POU5F1	“up-regulates quantity by expression”	TFAP2C	“transcriptional regulation”
TFAP2C	up-regulates	Pluripotency

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 89 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
Syndecan interactions	5	30.6×	4e-05
MET activates PTK2 signaling	5	27.6×	6e-05
Molecules associated with elastic fibres	6	26.8×	2e-05
Assembly of collagen fibrils and other multimeric structures	8	23.2×	7e-07
Developmental Lineage of Pancreatic Ductal Cells	6	19.9×	4e-05
Collagen chain trimerization	5	18.8×	3e-04
ECM proteoglycans	7	15.2×	4e-05
Non-integrin membrane-ECM interactions	6	13.4×	3e-04

GO biological processes:

GO term	Partners	Fold	FDR
cellular response to epidermal growth factor stimulus	5	18.5×	2e-03
collagen fibril organization	7	18.3×	5e-05
positive regulation of fibroblast proliferation	5	17.2×	2e-03
cell-matrix adhesion	6	11.4×	2e-03
cellular response to tumor necrosis factor	6	11.4×	2e-03
integrin-mediated signaling pathway	6	11.2×	2e-03
heart development	7	6.4×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	34
Likely benign	1
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

1144 predictions. Top by Δscore:

Variant	Effect	Δscore
20:56631686:TGCAG:T	donor_loss	1.0000
20:56631689:AGG:A	donor_loss	1.0000
20:56631691:GT:G	donor_loss	1.0000
20:56631692:T:G	donor_loss	1.0000
20:56631803:A:AG	acceptor_gain	1.0000
20:56631804:G:GG	acceptor_gain	1.0000
20:56631804:GAAT:G	acceptor_gain	1.0000
20:56631855:AGG:A	donor_loss	1.0000
20:56631856:GGTA:G	donor_loss	1.0000
20:56631857:G:A	donor_loss	1.0000
20:56631858:T:G	donor_loss	1.0000
20:56634146:TTA:T	acceptor_loss	1.0000
20:56634147:TA:T	acceptor_loss	1.0000
20:56634148:A:AG	acceptor_gain	1.0000
20:56634148:A:AT	acceptor_loss	1.0000
20:56634149:G:GT	acceptor_gain	1.0000
20:56634149:GA:G	acceptor_gain	1.0000
20:56634149:GAGC:G	acceptor_gain	1.0000
20:56634149:GAGCC:G	acceptor_gain	1.0000
20:56634265:GAAG:G	donor_gain	1.0000
20:56634268:GGT:G	donor_loss	1.0000
20:56634269:G:GG	donor_gain	1.0000
20:56634269:GTCA:G	donor_loss	1.0000
20:56634270:T:G	donor_loss	1.0000
20:56636750:GCCCA:G	donor_gain	1.0000
20:56636751:CCCA:C	donor_gain	1.0000
20:56636752:CCA:C	donor_gain	1.0000
20:56636753:CA:C	donor_gain	1.0000
20:56636753:CAGT:C	donor_loss	1.0000
20:56636754:AGT:A	donor_loss	1.0000

AlphaMissense

2922 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:56633436:T:C	F224L	1.000
20:56633437:T:C	F224S	1.000
20:56633437:T:G	F224C	1.000
20:56633438:C:A	F224L	1.000
20:56633438:C:G	F224L	1.000
20:56633446:T:A	V227D	1.000
20:56633451:G:A	G229R	1.000
20:56633451:G:C	G229R	1.000
20:56633452:G:A	G229E	1.000
20:56633455:G:C	R230T	1.000
20:56633456:A:C	R230S	1.000
20:56633456:A:T	R230S	1.000
20:56633458:T:G	L231W	1.000
20:56633464:T:A	L233H	1.000
20:56633464:T:C	L233P	1.000
20:56633467:T:A	L234H	1.000
20:56633484:T:C	Y240H	1.000
20:56633502:G:A	E246K	1.000
20:56633512:G:C	R249T	1.000
20:56633512:G:T	R249M	1.000
20:56633513:G:C	R249S	1.000
20:56633513:G:T	R249S	1.000
20:56633518:T:C	L251P	1.000
20:56633527:C:A	P254H	1.000
20:56633536:T:C	L257S	1.000
20:56633538:A:G	N258D	1.000
20:56633539:A:T	N258I	1.000
20:56633540:T:A	N258K	1.000
20:56633540:T:G	N258K	1.000
20:56633542:C:A	A259D	1.000

dbSNP variants (sampled 300 via entrez): RS1000447310 (20:56634306 A>T), RS1000478393 (20:56634573 A>G), RS1000642112 (20:56635077 T>C), RS1000783855 (20:56635693 G>A,C,T), RS1000792482 (20:56628887 C>A,T), RS1001211831 (20:56630015 C>A,T), RS1001273001 (20:56629236 C>G,T), RS1002409416 (20:56636458 G>A), RS1002675038 (20:56632073 GT>G,GTT), RS1002698938 (20:56638335 A>C,G), RS1002763755 (20:56636900 T>C,G), RS1002860617 (20:56637155 T>C), RS1002866177 (20:56631544 G>A,C,T), RS1003229794 (20:56638795 G>A), RS1003508842 (20:56627505 CG>C)

Disease associations

OMIM: gene MIM:601602 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): microcephaly (MONDO:0001149)

Orphanet (0):

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPO	Term
HP:0000252	Microcephaly

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST002351_9	Chronic obstructive pulmonary disease (moderate to severe)	4.000000e-07
GCST003075_72	Cognitive decline rate in late mild cognitive impairment	2.000000e-07
GCST004070_4	Cerebrospinal P-tau181p levels	8.000000e-08
GCST006988_138	Blond vs. brown/black hair color	6.000000e-17
GCST007239_27	Ovarian cancer	8.000000e-06
GCST008062_20	Blood urea nitrogen levels	9.000000e-11
GCST010002_69	Refractive error	3.000000e-09
GCST010539_6	Sum of stenosis	5.000000e-06
GCST010540_4	Mean degree of stenosis	2.000000e-07
GCST010541_8	Maximum stenosis	3.000000e-07

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0007710	cognitive decline measurement
EFO:0004763	p-tau measurement
EFO:0003924	hair color
EFO:0006501	carotid plaque build

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, affects expression, affects cotreatment	6
Estradiol	decreases expression, increases activity, increases expression, affects expression, affects cotreatment	5
methylmercuric chloride	decreases expression, increases expression, affects cotreatment	4
trichostatin A	affects binding, affects cotreatment, increases reaction, increases expression	4
Decitabine	affects expression, affects cotreatment, increases expression, affects binding, increases reaction	3
bisphenol A	affects expression, decreases expression	2
arsenite	affects binding, decreases reaction, increases methylation	2
entinostat	affects cotreatment, increases expression	2
belinostat	increases expression, affects cotreatment	2
Resveratrol	affects cotreatment, decreases expression, increases activity, increases localization	2
Temozolomide	increases expression, affects response to substance	2
Vorinostat	affects cotreatment, increases expression	2
Panobinostat	affects cotreatment, increases expression	2
Benzo(a)pyrene	affects methylation	2
Tobacco Smoke Pollution	increases expression, increases methylation	2
Asbestos, Crocidolite	decreases expression, increases expression	2
TAK-243	increases sumoylation	1
2-methyl-4-isothiazolin-3-one	increases expression	1
terbufos	increases methylation	1
sodium arsenite	decreases expression	1
benzo(e)pyrene	increases methylation	1
potassium chromate(VI)	increases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, decreases expression	1
aflatoxin B2	increases methylation	1
nickel sulfate	increases expression	1
indeno(1,2,3-cd)pyrene	decreases expression	1
mercuric bromide	affects cotreatment, increases expression	1
picene	decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
cylindrospermopsin	increases expression	1

Cellosaurus cell lines

3 cell lines: 3 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A7H0	SEES3-1V human TFAP2C, clone1	Embryonic stem cell	Male
CVCL_A7H1	SEES3-1V human TFAP2C, clone2	Embryonic stem cell	Male
CVCL_A7H2	SEES3-1V human TFAP2C, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05518188	PHASE1/PHASE2	RECRUITING	Melpida: Recombinant Adeno-associated Virus (serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)
NCT00001639	Not specified	COMPLETED	Evaluation of Patients With Unresolved Chromosome Abnormalities
NCT01151462	Not specified	WITHDRAWN	Postnatal HCMV Infection in Very Preterm Infants. Implications, Morbidity, Growth and Neurodevelopmental Outcomes.
NCT01565005	Not specified	COMPLETED	Microcephaly Genetic Deficiency in Neural Progenitors
NCT02510170	Not specified	COMPLETED	Fetal and Maternal Head Circumference During Pregnancy in Israeli Population
NCT02741882	Not specified	COMPLETED	Zika and Microcephaly: Case-control Study
NCT02943304	Not specified	COMPLETED	Neurodevelopment Outcome of Newborns Exposed to Zika Virus (ZIKV) in Utero
NCT03255369	Not specified	UNKNOWN	Vertical Exposure to Zika Virus and Its Consequences for Child Neurodevelopment (ZIKVIRUSIFF)
NCT03325946	Not specified	RECRUITING	The FBRI VTC Neuromotor Research Clinic
NCT03330600	Not specified	COMPLETED	Efficacy of Aquatic Physiotherapy in Children With Microcephaly by Zika Virus Congenital Syndrome
NCT03548779	Not specified	COMPLETED	North Carolina Genomic Evaluation by Next-generation Exome Sequencing, 2
NCT03651687	Not specified	COMPLETED	Guangzhou Surveillance and Clinical Study in Microcephaly (GSCSM)
NCT03922594	Not specified	TERMINATED	Surveillance of Zika-related Microcephaly in Sub-Saharan Africa and Asia
NCT04816175	Not specified	COMPLETED	Intensive Therapy for Children With Microcephaly, Hyperkinetic Movements, or Global Developmental Delay
NCT05322980	Not specified	COMPLETED	Summary of Infants Weighing 500 Grams or Less
NCT06019182	Not specified	RECRUITING	MEHMO Natural History and Biomarkers
NCT06566066	Not specified	RECRUITING	Register for Patients With Thyroid Hormone Resistance.