DACT1

Summary

DACT1 (dishevelled binding antagonist of beta catenin 1, HGNC:17748) is a protein-coding gene on chromosome 14q23.1, encoding Dapper homolog 1 (Q9NYF0). Involved in regulation of intracellular signaling pathways during development.

The protein encoded by this gene belongs to the dapper family, characterized by the presence of PDZ-binding motif at the C-terminus. It interacts with, and positively regulates dishevelled-mediated signaling pathways during development. Depletion of this mRNA from xenopus embryos resulted in loss of notochord and head structures, and mice lacking this gene died shortly after birth from severe posterior malformations. Alternatively spliced transcript variants have been found for this gene.

Source: NCBI Gene 51339 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Townes-Brocks syndrome 2 (Moderate, GenCC) — +1 more curated relationship
• GWAS associations: 11
• Clinical variants (ClinVar): 228 total — 5 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 80
• MANE Select transcript: NM_001079520

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17748
Approved symbol	DACT1
Name	dishevelled binding antagonist of beta catenin 1
Location	14q23.1
Locus type	gene with protein product
Status	Approved
Aliases	DAPPER1, THYEX3, HDPR1, DAPPER, FRODO
Ensembl gene	ENSG00000165617
Ensembl biotype	protein_coding
OMIM	607861
Entrez	51339

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 6 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000335867, ENST00000395153, ENST00000421793, ENST00000541264, ENST00000555845, ENST00000556859, ENST00000707126

RefSeq mRNA: 2 — MANE Select: NM_001079520 NM_001079520, NM_016651

CCDS: CCDS41961, CCDS9736

Canonical transcript exons

ENST00000395153 — 4 exons

Exon	Start	End
ENSE00001520729	58645369	58648321
ENSE00001520745	58637962	58638547
ENSE00003533916	58640736	58640868
ENSE00003622590	58641592	58641747

Expression profiles

Bgee: expression breadth ubiquitous, 200 present calls, max score 99.03.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 4.6609 / max 192.3408, expressed in 1005 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
139834	4.3271	988
139835	0.1562	73
139833	0.1304	57
139832	0.0472	22

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	99.03	gold quality
right coronary artery	UBERON:0001625	91.94	gold quality
gall bladder	UBERON:0002110	89.35	gold quality
ganglionic eminence	UBERON:0004023	89.10	gold quality
ascending aorta	UBERON:0001496	88.51	gold quality
thoracic aorta	UBERON:0001515	88.33	gold quality
embryo	UBERON:0000922	87.90	gold quality
left coronary artery	UBERON:0001626	86.31	gold quality
tibial nerve	UBERON:0001323	86.22	gold quality
aorta	UBERON:0000947	85.92	gold quality
cerebellar cortex	UBERON:0002129	85.67	gold quality
cerebellar hemisphere	UBERON:0002245	85.62	gold quality
cartilage tissue	UBERON:0002418	85.61	gold quality
blood vessel layer	UBERON:0004797	85.59	gold quality
descending thoracic aorta	UBERON:0002345	85.33	gold quality
cerebellum	UBERON:0002037	85.12	gold quality
cerebellar vermis	UBERON:0004720	84.89	gold quality
left ovary	UBERON:0002119	84.74	gold quality
coronary artery	UBERON:0001621	84.64	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.42	gold quality
popliteal artery	UBERON:0002250	84.21	gold quality
tibial artery	UBERON:0007610	84.19	gold quality
right hemisphere of cerebellum	UBERON:0014890	84.18	gold quality
calcaneal tendon	UBERON:0003701	83.83	gold quality
ovary	UBERON:0000992	83.24	gold quality
right ovary	UBERON:0002118	83.04	gold quality
cauda epididymis	UBERON:0004360	81.80	gold quality
ventricular zone	UBERON:0003053	81.64	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	81.54	gold quality
smooth muscle tissue	UBERON:0001135	80.83	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-HCAD-5	yes	384.77
E-ANND-3	yes	3.40

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NKX2-5

miRNA regulators (miRDB)

111 targeting DACT1, 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-656-3P	100.00	72.15	2788
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-10523-5P	99.91	69.22	2038
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-182-5P	99.87	74.03	2589
HSA-MIR-3941	99.86	70.54	2735

Literature-anchored findings (GeneRIF, showing 33)

• Downregulation of HDPR1 is common in hepatic cellular carcinomas, frequently involves hypermethylation of the promoter region. (PMID:15580286)
• DACT1 antagonizes Wnt signaling by promoting DVL2 degradation. (PMID:16446366)
• Dpr1 negatively modulates the basal activity of Wnt1/beta-catenin signaling in the nucleus by keeping LEF1 in the repressive state. (PMID:18936100)
• Dact1 regulates adipogenesis through coordinated effects on gene expression that selectively alter intracellular and paracrine/autocrine components of the Wnt/beta-catenin signaling pathway. (PMID:19073771)
• Knockdown of HDPR1 gene enhanced the invasive ability of lung cancer cells, which was dependent on p120ctn and independent of beta-catenin (PMID:20232357)
• As(2)O(3) induces demethylation of hdpr1 gene from abnormal hypermethylation status and activates its reexpression, thus suppressing the proliferation of Jurkat cells. (PMID:21176356)
• 14-3-3beta interacts with human Dapper1, attenuating the ability of hDpr1 to promote Dishevelled (Dvl) degradation, thus enhancing Wnt signaling (PMID:21262972)
• Cytoplasmic HDPR1 protein expression was associated with tumor malignant progression via beta-catenin accumulation. (PMID:21525190)
• DACT1 stabilizes beta-catenin via DACT1-induced effects on GSK-3beta and directly interacts with beta-catenin proteins. (PMID:22470507)
• five missense heterozygote mutations of the DACT1 gene are specifically identified in 167 stillborn or miscarried Han Chinese fetuses with neural tube defects. (PMID:22610794)
• These findings provided insight into the role of DACT1 as a novel functional tumor suppressor in gastric cancer through inhibiting NF-kappaB signaling pathway. (PMID:23073659)
• Data indicate that Sestd1 cooperates with Dact1 in Vangl2 regulation and in the planar cell polarity (PCP) pathway during mammalian embryonic development. (PMID:23696638)
• Dpr1 directly interacts with Beclin1 and Atg14L and enhances the Beclin1-Vps34 interaction and Vps34 activity. (PMID:24980960)
• our results suggested that DACT1 was upregulated during human placenta development. (PMID:25424899)
• There was no statistical difference between groups concerning DACT1 and DACT2 either in promoter hypermethylation or transcript levels. Age was associated with DACT2 promoter hypermethylation, especially over 56 years old. (PMID:25524937)
• Overexpression of Dapper-1 allows the translocation of MIZ-1 from the nucleus to the cytoplasm. (PMID:25558878)
• Dpr1 promotes the ubiquitination of Dvl2 by pVHL and mediates the protein aggregate-elicited autophagy initiation (PMID:25825496)
• Dact1 has a critical role in the ability support keratinocyte proliferation, by attenuating Wnt/beta catenin signaling. (PMID:26099026)
• Dact1 is up-regulated by TGF-beta1, inducing apoptosis in mesangial cells. (PMID:27714812)
• DACT1alpha plays a pivotal role as a potential tumor suppressor in migration and invasion of gastric cancer. DACT1alpha methylation may serve as a biomarker for the prognosis of gastric cancer. (PMID:27833078)
• Findings suggest that the DACT1 c.1256G>A nonsense variant is causative of a specific genetic syndrome with features overlapping Townes-Brocks syndrome. (PMID:28054444)
• The simultaneous methylation of DACT1 and DACT2 may play important roles in progression of ESCC and may serve as prognostic methylation biomarkers for ESCC patients. (PMID:28077137)
• Dapper1 attenuates hepatic gluconeogenesis and lipogenesis in Ttype 2 diabetes. (PMID:28237722)
• We identified DACT1 as a negative regulator in type I EOC, protecting against malignant expansion by inhibiting canonical Wnt signalling and cis-platinum resistance by regulating autophagy. (PMID:28839145)
• An inhibitory role for DACT1 in leukemogenesis. (PMID:29037126)
• This study demonstrates that cyclin G2 suppresses Wnt/beta-catenin signaling and inhibits gastric cancer cell growth and migration through Dapper1. (PMID:30547803)
• Cyclin G2 regulates canonical Wnt signalling via interaction with Dapper1 to attenuate tubulointerstitial fibrosis in diabetic nephropathy. (PMID:31978940)
• DACT1 variants and colorectal cancer. (PMID:33843483)
• Histone Deacetylation Regulated by KDM1A to Suppress DACT1 in Proliferation and Migration of Cervical Cancer. (PMID:34350095)
• M(6)A demethylase FTO-mediated downregulation of DACT1 mRNA stability promotes Wnt signaling to facilitate osteosarcoma progression. (PMID:35121825)
• Disheveled binding antagonist of beta-catenin 1 interacted with beta-catenin and connexin 43 in human-induced pluripotent stem cells-derived cardiomyocytes. (PMID:35510412)
• Heterozygous variants in the DVL2 interaction region of DACT1 cause CAKUT and features of Townes-Brocks syndrome 2. (PMID:36066768)
• Different expression of DACT1, DACT2, and CYCLIN D1 genes in human colorectal cancer tissues and its association with clinicopathological characteristics. (PMID:37610179)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	dact1	ENSDARG00000101635
mus_musculus	Dact1	ENSMUSG00000044548
rattus_norvegicus	Dact1	ENSRNOG00000008445

Paralogs (2): DACT2 (ENSG00000164488), DACT3 (ENSG00000197380)

Protein

Protein identifiers

Dapper homolog 1 — Q9NYF0 (reviewed: Q9NYF0)

Alternative names: Dapper antagonist of catenin 1, Hepatocellular carcinoma novel gene 3 protein

All UniProt accessions (3): B7Z673, C9JGV7, Q9NYF0

UniProt curated annotations — full annotation on UniProt →

Function. Involved in regulation of intracellular signaling pathways during development. Specifically thought to play a role in canonical and/or non-canonical Wnt signaling pathways through interaction with DSH (Dishevelled) family proteins. The activation/inhibition of Wnt signaling may depend on the phosphorylation status. Proposed to regulate the degradation of CTNNB1/beta-catenin, thereby modulating the transcriptional activation of target genes of the Wnt signaling pathway. Its function in stabilizing CTNNB1 may involve inhibition of GSK3B activity. Promotes the membrane localization of CTNNB1. The cytoplasmic form can induce DVL2 degradation via a lysosome-dependent mechanism; the function is inhibited by PKA-induced binding to 14-3-3 proteins, such as YWHAB. Seems to be involved in morphogenesis at the primitive streak by regulating VANGL2 and DVL2; the function seems to be independent of canonical Wnt signaling and rather involves the non-canonical Wnt/planar cell polarity (PCP) pathway. The nuclear form may prevent the formation of LEF1:CTNNB1 complex and recruit HDAC1 to LEF1 at target gene promoters to repress transcription thus antagonizing Wnt signaling. May be involved in positive regulation of fat cell differentiation. During neuronal differentiation may be involved in excitatory synapse organization, and dendrite formation and establishment of spines.

Subunit / interactions. Can form homodimers and heterodimers with DACT2 or DACT3. Interacts with CSNK1D, PKA catalytic subunit, PKC-type kinase, CSNK2A1, CSNK2B, DVL1, DVL3, VANGL1, VANGL2, CTNND1 and HDAC1. Interacts with DVL2. Interacts with YWHAB; the interaction is enhanced by PKA phosphorylating DACT1 at Ser-237 and Ser-827. Interacts with CTNNB1 and HDAC1. Interacts with GSK3B; the interaction is indicative for an association of DACT1 with the beta-catenin destruction complex. Interacts with GSK3A.

Subcellular location. Cytoplasm. Nucleus. Synapse.

Disease relevance. Neural tube defects (NTD) [MIM:182940] Congenital malformations of the central nervous system and adjacent structures related to defective neural tube closure during the first trimester of pregnancy. Failure of neural tube closure can occur at any level of the embryonic axis. Common NTD forms include anencephaly, myelomeningocele and spina bifida, which result from the failure of fusion in the cranial and spinal region of the neural tube. NTDs have a multifactorial etiology encompassing both genetic and environmental components. Disease susceptibility is associated with variants affecting the gene represented in this entry. Townes-Brocks syndrome 2 (TBS2) [MIM:617466] A form of Townes-Brocks syndrome, a rare autosomal dominant disease characterized by the triad of imperforate anus, dysplastic ears, and thumb malformations. Minor features of the condition include hearing loss, foot malformations, renal impairment with or without renal malformations, genitourinary malformations, and congenital heart disease. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The C-terminal PDZ-binding motif mediates interaction with the PDZ domains of DSH (Dishevelled) family proteins.

Similarity. Belongs to the dapper family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9NYF0-1	1, Alpha, Long	yes
Q9NYF0-2	2, Beta, Short

RefSeq proteins (2): NP_001072988, NP_057735 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR024843	Dapper	Family

Pfam: PF15268

UniProt features (38 total): sequence variant 13, region of interest 6, compositionally biased region 6, mutagenesis site 5, short sequence motif 3, modified residue 2, chain 1, splice variant 1, coiled-coil region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NYF0-F1	50.95	0.03

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 (2): 237, 827

Mutagenesis-validated functional residues (5):

Position	Phenotype
132	abolishes nuclear export; when associated with a-136.
136	abolishes nuclear export; when associated with a-132.
237	impairs interaction with ywhab. abolishes interaction with ywhab; when associated with a-827.
622–623	partial nuclear accumulation upon lmb treatment.
827	abolishes interaction with ywhab; when associated with a-237.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-4641258	Degradation of DVL

MSigDB gene sets: 456 (showing top): GOBP_NEGATIVE_REGULATION_OF_PROTEIN_CONTAINING_COMPLEX_ASSEMBLY, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, RORA1_01, GCANCTGNY_MYOD_Q6, GOBP_NON_CANONICAL_WNT_SIGNALING_PATHWAY, GOBP_REGULATION_OF_NON_CANONICAL_WNT_SIGNALING_PATHWAY, GOBP_CELL_CYCLE_PHASE_TRANSITION, GOBP_POSITIVE_REGULATION_OF_PROTEIN_CATABOLIC_PROCESS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, CREBP1_Q2, GOBP_NEURAL_TUBE_DEVELOPMENT, TGACCTY_ERR1_Q2, GOBP_REGULATION_OF_WNT_SIGNALING_PATHWAY, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS

GO Biological Process (16): negative regulation of transcription by RNA polymerase II (GO:0000122), Wnt signaling pathway (GO:0016055), neural tube development (GO:0021915), positive regulation of Wnt signaling pathway (GO:0030177), negative regulation of Wnt signaling pathway (GO:0030178), regulation of protein stability (GO:0031647), positive regulation of protein catabolic process (GO:0045732), negative regulation of JNK cascade (GO:0046329), embryonic hindgut morphogenesis (GO:0048619), regulation of canonical Wnt signaling pathway (GO:0060828), negative regulation of canonical Wnt signaling pathway (GO:0090090), positive regulation of canonical Wnt signaling pathway (GO:0090263), negative regulation of beta-catenin-TCF complex assembly (GO:1904864), regulation of Wnt signaling pathway, planar cell polarity pathway (GO:2000095), negative regulation of G1/S transition of mitotic cell cycle (GO:2000134), nervous system development (GO:0007399)

GO Molecular Function (8): protein kinase C binding (GO:0005080), beta-catenin binding (GO:0008013), histone deacetylase binding (GO:0042826), protein kinase A binding (GO:0051018), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), delta-catenin binding (GO:0070097), transcription regulator inhibitor activity (GO:0140416), protein binding (GO:0005515)

GO Cellular Component (6): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), synapse (GO:0045202), beta-catenin destruction complex (GO:0030877)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
TCF dependent signaling in response to WNT	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of Wnt signaling pathway	3
canonical Wnt signaling pathway	3
protein binding	3
cellular anatomical structure	3
Wnt signaling pathway	2
regulation of canonical Wnt signaling pathway	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
cell surface receptor signaling pathway	1
nervous system development	1
tube development	1
chordate embryonic development	1
epithelium development	1
positive regulation of signal transduction	1
negative regulation of signal transduction	1
regulation of biological quality	1
positive regulation of catabolic process	1
protein catabolic process	1
regulation of protein catabolic process	1
positive regulation of protein metabolic process	1
JNK cascade	1
negative regulation of MAPK cascade	1
regulation of JNK cascade	1
hindgut morphogenesis	1
embryonic morphogenesis	1
negative regulation of Wnt signaling pathway	1
positive regulation of Wnt signaling pathway	1
negative regulation of protein-containing complex assembly	1
beta-catenin-TCF complex assembly	1
regulation of beta-catenin-TCF complex assembly	1
Wnt signaling pathway, planar cell polarity pathway	1
regulation of non-canonical Wnt signaling pathway	1
G1/S transition of mitotic cell cycle	1
negative regulation of mitotic cell cycle phase transition	1
negative regulation of cell cycle G1/S phase transition	1
regulation of G1/S transition of mitotic cell cycle	1
system development	1
protein kinase binding	1
enzyme binding	1

Protein interactions and networks

STRING

920 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DACT1	DVL1	O14640	953
DACT1	VANGL2	Q9ULK5	866
DACT1	DVL2	O14641	801
DACT1	DVL3	Q92997	733
DACT1	VANGL1	Q8TAA9	713
DACT1	DBF4	Q9UBU7	694
DACT1	PTK7	Q13308	694
DACT1	CTNND1	O60716	676
DACT1	CTNNB1	P35222	663
DACT1	SFRP1	Q8N474	630
DACT1	TICRR	Q7Z2Z1	586
DACT1	ZBTB33	Q86T24	579
DACT1	GAPDH	P00354	571
DACT1	FZD7	O75084	567
DACT1	WNT5A	P41221	555

IntAct

153 interactions, top by confidence:

A	B	Type	Score
DACT1	DVL2	psi-mi:“MI:0915”(physical association)	0.650
DVL2	DACT1	psi-mi:“MI:0403”(colocalization)	0.650
DVL2	DACT1	psi-mi:“MI:0915”(physical association)	0.650
DACT1	DVL2	psi-mi:“MI:0403”(colocalization)	0.650
YWHAB	DACT1	psi-mi:“MI:0915”(physical association)	0.580
DACT1	GSK3B	psi-mi:“MI:0915”(physical association)	0.540
DACT1	CTNNB1	psi-mi:“MI:0915”(physical association)	0.540
DACT1	CTNNB1	psi-mi:“MI:0914”(association)	0.540
CTNNB1	DACT1	psi-mi:“MI:0403”(colocalization)	0.540
GSK3B	DACT1	psi-mi:“MI:0403”(colocalization)	0.540
CBX6	IGF2BP3	psi-mi:“MI:0914”(association)	0.530
DACT1	DLG1	psi-mi:“MI:0407”(direct interaction)	0.440
DACT1	MAST2	psi-mi:“MI:0407”(direct interaction)	0.440
DACT1	MAGI2	psi-mi:“MI:0407”(direct interaction)	0.440
DLG2	DACT1	psi-mi:“MI:0407”(direct interaction)	0.440
DACT1	DLG4	psi-mi:“MI:0407”(direct interaction)	0.440
DACT1	PDZD7	psi-mi:“MI:0407”(direct interaction)	0.440
DACT1	MAGI3	psi-mi:“MI:0407”(direct interaction)	0.440
DACT1	DLG3	psi-mi:“MI:0407”(direct interaction)	0.440
DACT1	MAGI1	psi-mi:“MI:0407”(direct interaction)	0.440
ARHGEF11	DACT1	psi-mi:“MI:0407”(direct interaction)	0.440
DACT1	LNX2	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (34): DACT1 (Affinity Capture-MS), ZBTB17 (Affinity Capture-Western), DACT1 (Affinity Capture-Western), DACT1 (Affinity Capture-Western), VHL (Affinity Capture-Western), DACT1 (Affinity Capture-Western), YWHAB (Two-hybrid), YWHAB (Affinity Capture-Western), DACT1 (Affinity Capture-Western), PRKACA (Affinity Capture-Western), DVL2 (Affinity Capture-Western), DACT1 (Two-hybrid), DACT1 (Affinity Capture-MS), DACT1 (Two-hybrid), MICAL1 (Affinity Capture-MS)

ESM2 similar proteins: A0A8I5ZM56, A2AG50, A2AI08, A2AJI0, A5D7K1, D4A4L4, E1C2Q8, F1LR10, O00515, O14529, O75128, O88573, O88735, P51825, P57016, Q14244, Q32LQ1, Q3KQU3, Q3U2K0, Q5JTD0, Q5NBX1, Q5PR69, Q5R7F9, Q5XHX2, Q5ZIA2, Q5ZJJ1, Q68DK7, Q6IPM2, Q6NV74, Q6NZF1, Q6PDH0, Q6PDM1, Q6PG95, Q6ZU35, Q86UU1, Q8CCJ4, Q8K124, Q8N7J2, Q8TD55, Q96PV7

Diamond homologs: Q0PHV7, Q66KC9, Q6QZN6, Q8JJ48, Q8QG92, Q8R4A3, Q96B18, Q9NYF0, Q5SW24, Q673G8, Q7TN08

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
DACT1	down-regulates	DVL2	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 102 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
Activation of BAD and translocation to mitochondria	7	78.4×	2e-10
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	7	69.2×	3e-10
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	7	69.2×	3e-10
Activation of BH3-only proteins	7	51.1×	3e-09
Ras activation upon Ca2+ influx through NMDA receptor	5	42.0×	3e-06
Unblocking of NMDA receptors, glutamate binding and activation	5	40.0×	3e-06
Negative regulation of NMDA receptor-mediated neuronal transmission	5	40.0×	3e-06
RHO GTPases activate PKNs	8	37.3×	2e-09

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	11	66.6×	3e-15
protein localization to synapse	6	47.9×	4e-07
receptor clustering	7	45.5×	6e-08
regulation of postsynaptic membrane neurotransmitter receptor levels	7	36.1×	2e-07
protein targeting	7	26.7×	9e-07
establishment of cell polarity	5	19.9×	3e-04
intracellular protein localization	11	12.0×	4e-07
protein-containing complex assembly	10	11.9×	1e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	3
Uncertain significance	159
Likely benign	33
Benign	17

Top pathogenic / likely-pathogenic (8)

Variant ID	HGVS	Classification
2443964	NM_001079520.2(DACT1):c.1592G>A (p.Arg531Lys)	Pathogenic
2443965	NM_001079520.2(DACT1):c.1660C>T (p.Leu554Phe)	Pathogenic
2443966	NM_001079520.2(DACT1):c.2357T>G (p.Leu786Arg)	Pathogenic
2443967	NM_001079520.2(DACT1):c.1779G>T (p.Lys593Asn)	Pathogenic
424859	NM_001079520.2(DACT1):c.1145G>A (p.Trp382Ter)	Pathogenic
1184920	NM_001079520.2(DACT1):c.1362_1363del (p.Ser454fs)	Likely pathogenic
3899992	NM_001079520.2(DACT1):c.763C>T (p.Leu255=)	Likely pathogenic
545119	NM_001079520.2(DACT1):c.868_869del (p.Trp290fs)	Likely pathogenic

SpliceAI

389 predictions. Top by Δscore:

Variant	Effect	Δscore
14:58638533:C:G	donor_gain	1.0000
14:58638549:T:A	donor_loss	1.0000
14:58640730:A:AG	acceptor_gain	1.0000
14:58640731:A:G	acceptor_gain	1.0000
14:58640733:CAGA:C	acceptor_loss	1.0000
14:58640734:A:AG	acceptor_gain	1.0000
14:58640734:AGAA:A	acceptor_loss	1.0000
14:58640735:G:GT	acceptor_gain	1.0000
14:58640735:GA:G	acceptor_gain	1.0000
14:58640735:GAA:G	acceptor_gain	1.0000
14:58640735:GAAC:G	acceptor_gain	1.0000
14:58640735:GAACT:G	acceptor_gain	1.0000
14:58640866:CAGGT:C	donor_loss	1.0000
14:58640867:AGG:A	donor_loss	1.0000
14:58640869:G:GG	donor_gain	1.0000
14:58640869:GTGA:G	donor_loss	1.0000
14:58641590:AG:A	acceptor_gain	1.0000
14:58641591:GG:G	acceptor_gain	1.0000
14:58638544:ATTG:A	donor_gain	0.9900
14:58638545:TTG:T	donor_gain	0.9900
14:58638548:G:GG	donor_gain	0.9900
14:58640719:T:TA	acceptor_gain	0.9900
14:58640864:CTCAG:C	donor_gain	0.9900
14:58640865:TCAG:T	donor_gain	0.9900
14:58640866:CAG:C	donor_gain	0.9900
14:58640867:AG:A	donor_gain	0.9900
14:58640868:GG:G	donor_gain	0.9900
14:58640870:T:A	donor_loss	0.9900
14:58641586:TTGTA:T	acceptor_loss	0.9900
14:58641587:TGTA:T	acceptor_loss	0.9900

AlphaMissense

5185 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:58640755:A:T	D122V	1.000
14:58640776:T:C	L129S	1.000
14:58640785:T:A	L132H	1.000
14:58640785:T:C	L132P	1.000
14:58640797:T:A	I136K	1.000
14:58640806:T:C	L139P	1.000
14:58640862:A:C	S158R	1.000
14:58640864:C:A	S158R	1.000
14:58640864:C:G	S158R	1.000
14:58640868:G:A	G160R	1.000
14:58640868:G:C	G160R	1.000
14:58641592:G:A	G160E	1.000
14:58641594:T:C	F161L	1.000
14:58641596:T:A	F161L	1.000
14:58641596:T:G	F161L	1.000
14:58645434:A:C	S271R	1.000
14:58645436:T:A	S271R	1.000
14:58645436:T:G	S271R	1.000
14:58645453:C:A	A277D	1.000
14:58647058:T:G	I812S	1.000
14:58647062:G:C	K813N	1.000
14:58647062:G:T	K813N	1.000
14:58647064:C:A	A814D	1.000
14:58647076:T:A	L818H	1.000
14:58647076:T:C	L818P	1.000
14:58647080:G:C	K819N	1.000
14:58647080:G:T	K819N	1.000
14:58647088:T:A	I822N	1.000
14:58647088:T:C	I822T	1.000
14:58647088:T:G	I822S	1.000

dbSNP variants (sampled 300 via entrez): RS1000081611 (14:58637506 A>G), RS1000561370 (14:58641858 T>A), RS1000582980 (14:58647979 C>T), RS1000685661 (14:58638653 C>T), RS1000688266 (14:58635249 G>A), RS1000863224 (14:58645173 T>C), RS1000917393 (14:58638211 G>A,T), RS1000933280 (14:58641484 A>G), RS1001052005 (14:58647676 G>A,C,T), RS1001242606 (14:58637572 G>C), RS1001589069 (14:58637843 C>T), RS1001685059 (14:58637184 T>C), RS1001957164 (14:58643174 G>T), RS1001986258 (14:58632390 T>C), RS1002193647 (14:58638880 A>G)

Disease associations

OMIM: gene MIM:607861 | disease phenotypes: MIM:617466, MIM:107480

GenCC curated gene-disease

Disease	Classification	Inheritance
Townes-Brocks syndrome 2	Moderate	Autosomal dominant
Townes-Brocks syndrome	Supportive	Autosomal dominant

Mondo (3): Townes-Brocks syndrome 2 (MONDO:0054582), Rieger anomaly (MONDO:0019628), Townes-Brocks syndrome (MONDO:0007142)

Orphanet (2): Rieger anomaly (Orphanet:91483), Townes-Brocks syndrome (Orphanet:857)

HPO phenotypes

80 total (30 of 80 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000028	Cryptorchidism
HP:0000047	Hypospadias
HP:0000048	Bifid scrotum
HP:0000076	Vesicoureteral reflux
HP:0000083	Renal insufficiency
HP:0000086	Ectopic kidney
HP:0000089	Renal hypoplasia
HP:0000130	Abnormality of the uterus
HP:0000136	Bifid uterus
HP:0000142	Abnormal vagina morphology
HP:0000143	Rectovaginal fistula
HP:0000154	Wide mouth
HP:0000324	Facial asymmetry
HP:0000365	Hearing impairment
HP:0000377	Abnormal pinna morphology
HP:0000378	Cupped ear
HP:0000384	Preauricular skin tag
HP:0000396	Overfolded helix
HP:0000486	Strabismus
HP:0000504	Abnormality of vision
HP:0000518	Cataract
HP:0000567	Chorioretinal coloboma
HP:0000568	Microphthalmia
HP:0000581	Blepharophimosis
HP:0000612	Iris coloboma
HP:0000772	Abnormal rib morphology
HP:0000776	Congenital diaphragmatic hernia
HP:0000821	Hypothyroidism
HP:0000823	Delayed puberty

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST006874_2	Hippocampal subfield CA1 volume (corrected for total hippocampal volume)	2.000000e-10
GCST006877_1	Dentate gyrus granule cell layer volume (corrected for total hippocampal volume)	2.000000e-09
GCST006881_4	Hippocampal tail volume (corrected for total hippocampal volume)	2.000000e-17
GCST007856_15	Colorectal cancer or advanced adenoma	5.000000e-11
GCST008707_4	Occipital lobe volume	3.000000e-09
GCST008710_2	Parietal lobe volume	2.000000e-06
GCST009391_1175	Metabolite levels	2.000000e-07
GCST010703_93	Brain morphology (MOSTest)	6.000000e-54
GCST010796_1429	Electrocardiogram morphology (amplitude at temporal datapoints)	5.000000e-08
GCST90010427_16	Left–right brain asymmetry	5.000000e-12
GCST90093325_14	Language functional connectivity	2.000000e-11

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0009394	hippocampal CA1 volume
EFO:0010461	argininosuccinate measurement
EFO:0004346	neuroimaging measurement
EFO:0004327	electrocardiography
EFO:0007797	language measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C536974	Townes-Brocks syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, decreases expression	7
sodium arsenite	increases expression, decreases expression, affects cotreatment, increases abundance	4
trichostatin A	affects cotreatment, increases expression	3
Benzo(a)pyrene	increases expression, increases methylation	3
Estradiol	affects cotreatment, decreases expression, increases expression	3
entinostat	increases expression, affects cotreatment	2
belinostat	increases expression, affects cotreatment	2
Arsenic Trioxide	decreases methylation, increases expression, decreases expression	2
Vorinostat	affects cotreatment, increases expression	2
Panobinostat	increases expression, affects cotreatment	2
Dexamethasone	decreases expression, affects cotreatment	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Progesterone	affects cotreatment, decreases expression	2
Aflatoxin B1	affects expression, increases expression	2
aristolochic acid I	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects expression	1
butyraldehyde	increases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
potassium chromate(VI)	decreases expression	1
nickel sulfate	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	1
clothianidin	decreases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
jinfukang	affects cotreatment, decreases expression	1
incobotulinumtoxinA	decreases expression	1
2,6-dichloro-(1,4)benzoquinone	increases expression	1

Clinical trials (associated diseases)

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