CTNND2

Summary

CTNND2 (catenin delta 2, HGNC:2516) is a protein-coding gene on chromosome 5p15.2, encoding Catenin delta-2 (Q9UQB3). Has a critical role in neuronal development, particularly in the formation and/or maintenance of dendritic spines and synapses.

This gene encodes an adhesive junction associated protein of the armadillo/beta-catenin superfamily and is implicated in brain and eye development and cancer formation. The protein encoded by this gene promotes the disruption of E-cadherin based adherens junction to favor cell spreading upon stimulation by hepatocyte growth factor. This gene is overexpressed in prostate adenocarcinomas and is associated with decreased expression of tumor suppressor E-cadherin in this tissue. This gene resides in a region of the short arm of chromosome 5 that is deleted in Cri du Chat syndrome. Alternative splicing results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 1501 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complex neurodevelopmental disorder (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 19
• Clinical variants (ClinVar): 402 total — 5 pathogenic, 17 likely-pathogenic
• Phenotypes (HPO): 35
• Cancer driver (intOGen): activating (oncogene-like) across 6 cancer types
• Dosage sensitivity (ClinGen): haploinsufficiency little evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001332

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2516
Approved symbol	CTNND2
Name	catenin delta 2
Location	5p15.2
Locus type	gene with protein product
Status	Approved
Aliases	NPRAP, GT24
Ensembl gene	ENSG00000169862
Ensembl biotype	protein_coding
OMIM	604275
Entrez	1501

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 12 protein_coding, 6 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay, 1 retained_intron

ENST00000304623, ENST00000495388, ENST00000502551, ENST00000503622, ENST00000504354, ENST00000504499, ENST00000506324, ENST00000506735, ENST00000507430, ENST00000508761, ENST00000509868, ENST00000511278, ENST00000511377, ENST00000513588, ENST00000513598, ENST00000514132, ENST00000706271, ENST00000706272, ENST00000923862, ENST00000954646, ENST00000954647

RefSeq mRNA: 5 — MANE Select: NM_001332 NM_001288715, NM_001288716, NM_001288717, NM_001332, NM_001364128

CCDS: CCDS3881, CCDS75227, CCDS75228, CCDS93685

Canonical transcript exons

ENST00000304623 — 22 exons

Exon	Start	End
ENSE00001188982	11384665	11385229
ENSE00002062282	10971836	10973713
ENSE00003460678	11364696	11364890
ENSE00003462551	11397031	11397203
ENSE00003487609	11017974	11018058
ENSE00003511960	11412035	11412069
ENSE00003516960	11199448	11199661
ENSE00003522466	11732136	11732272
ENSE00003542547	11082696	11082846
ENSE00003545467	11117450	11117567
ENSE00003554859	10981773	10981846
ENSE00003558361	11346372	11346627
ENSE00003573941	11236691	11236823
ENSE00003599404	11564944	11565056
ENSE00003603119	11159576	11159759
ENSE00003607167	11411536	11411652
ENSE00003616140	11098575	11098748
ENSE00003627982	11022769	11022979
ENSE00003639426	11110858	11111043
ENSE00003652225	10992551	10992677
ENSE00003688233	10988111	10988242
ENSE00003849079	11903817	11904446

Expression profiles

Bgee: expression breadth ubiquitous, 213 present calls, max score 99.10.

FANTOM5 (CAGE): breadth broad, TPM avg 17.6232 / max 727.1579, expressed in 562 samples.

FANTOM5 promoters (32 alternative TSS)

Promoter ID	TPM avg	Samples expressed
60914	3.3072	180
60923	2.4584	93
60928	2.1790	181
60949	2.0776	438
60944	1.5170	236
60950	0.6390	193
60912	0.6386	106
60948	0.5555	199
60929	0.3974	142
60942	0.3676	136

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	99.10	gold quality
prefrontal cortex	UBERON:0000451	97.93	gold quality
amygdala	UBERON:0001876	97.84	gold quality
putamen	UBERON:0001874	97.53	gold quality
right frontal lobe	UBERON:0002810	97.50	gold quality
postcentral gyrus	UBERON:0002581	97.44	gold quality
medial globus pallidus	UBERON:0002477	97.42	gold quality
caudate nucleus	UBERON:0001873	97.40	gold quality
corpus striatum	UBERON:0000369	97.28	gold quality
parietal lobe	UBERON:0001872	97.26	gold quality
globus pallidus	UBERON:0001875	97.26	gold quality
temporal lobe	UBERON:0001871	97.10	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	97.07	gold quality
ganglionic eminence	UBERON:0004023	97.00	gold quality
ventricular zone	UBERON:0003053	96.94	gold quality
telencephalon	UBERON:0001893	96.92	gold quality
nucleus accumbens	UBERON:0001882	96.91	gold quality
Ammon’s horn	UBERON:0001954	96.90	gold quality
frontal cortex	UBERON:0001870	96.89	gold quality
frontal lobe	UBERON:0016525	96.87	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	96.84	gold quality
Brodmann (1909) area 9	UBERON:0013540	96.77	gold quality
cerebral cortex	UBERON:0000956	96.73	gold quality
lateral globus pallidus	UBERON:0002476	96.72	gold quality
neocortex	UBERON:0001950	96.71	gold quality
corpus callosum	UBERON:0002336	96.62	gold quality
superior frontal gyrus	UBERON:0002661	96.56	gold quality
cingulate cortex	UBERON:0003027	96.51	gold quality
cranial nerve II	UBERON:0000941	96.49	gold quality
substantia nigra	UBERON:0002038	96.42	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-180759	yes	5457.24
E-HCAD-35	yes	93.82
E-HCAD-25	yes	20.03
E-ANND-3	yes	8.29

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR, CTNNB1, E2F1, HES1, PAX6, SPI1

miRNA regulators (miRDB)

137 targeting CTNND2, 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-3646	100.00	73.56	5283
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-6758-5P	100.00	66.21	1470
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-493-5P	99.96	72.47	2382
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-101-3P	99.94	75.03	2230
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-9983-3P	99.94	71.48	3631

Functional genomics

ClinGen dosage: haploinsufficiency 1 (little evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 35)

• Increased expression of delta-catenin is associated with the down-regulation and redistribiution of ECAD and p120ctn in prostatic cancer. (PMID:16226102)
• The interaction of scaffolding proteins with cadherin-NPRAP complexes anchors diverse signaling and adhesion molecules at cadherins. (PMID:17687028)
• These studies identify E2F1 as a positive transcriptional regulator for delta-catenin. (PMID:18302937)
• Increased nucleotide polymorphic changes in the 5’-untranslated region of delta-catenin (CTNND2) gene in prostate cancer. (PMID:18978817)
• Using shotgun mass spectrometry, we found this protein differentially expressed in the dorsolateral prefrontal cortex from patients with schizophrenia. (PMID:19165527)
• Data report that either Pax6(+5a) or Pax6(-5a) was sufficient to promote, whereas their knockdown reduced the expression of delta-catenin (CTNND2), a neural specific member of the armadillo/beta-catenin superfamily. (PMID:20074565)
• Cells overexpressing delta-catenin have less p120-catenin than control cells at the cell-cell interface, causing the relocalization of p120-catenin from the plasma membrane to the cytosol. CTNND2 binding to E-cadherin adversely affects CTNND1 stability. (PMID:20108168)
• The delta catenin is essential for N-cadherin-mediated formation of proper junctional structures and thereby the establishment of the cell polarity. (PMID:20859058)
• This study identified a strong association of CTNND2 for high myopia in Asian datasets. The CTNND2 gene maps to a known high myopia linkage region on chromosome 5p15. (PMID:21095009)
• The studies support coordinated regulation of delta-catenin expression by both the activating transcription factor E2F1 and repressive transcription factor Hes1 in prostate cancer progression. (PMID:21106062)
• Multiple genes linked to Alzheimer’s disease are regulated by NPRAP. Furthermore, NPRAP nuclear translocation is required for gene regulation. (PMID:21811021)
• These results confirmed the strong association between CTNND2 polymorphism and myopia. (PMID:21911587)
• delta-catenin upregulates the activity of cdc42 and Rac1 GTPases at transcriptional level, and their coexpression predict a poor clinical outcome in nonsmall cell lung cancer patients (PMID:22213037)
• Specific polymorphisms in the CTNND2 gene and 11q24.1 genomic region were found to be significantly associated with pathological myopia in this Chinese population. (PMID:22759899)
• Genome-wide significant association with CTNND2 single nucleotide polymorphisms rs17183619, rs13155993 and rs13170756 for the bivariate outcome of cortical cataract and temporal horn volume, is reported. (PMID:22984439)
• SNPs in CTNND2 showed an increased signal for schizophrenia and major depressive disorder, but not for bipolar disorder. The association between CTNND2 and anxiety was not strong enough in current generation of human genome-wide analyses. (PMID:24256404)
• Results conclude that the introduction of CTNND2 gene variation is an important milestone in prostate cancer metabolic adaptation. (PMID:24727894)
• our results suggest that delta-catenin acts as an oncoprotein when overexpressed in esophageal squamous cell carcinoma (PMID:25090917)
• co-expression of Delta-catenin and RhoA was significantly associated with histological type, differentiation, pTNM stage, lymphatic metastasis and a poor prognosis in non-small cell lung cancer (PMID:25120748)
• the effect of CTNND2 polymorphisms on normal variability and identified a polymorphism (rs2561622) with significant effect on phonological ability and white matter volume in the left frontal lobe, was investigated. (PMID:25473103)
• Study describes two Ion-syndromic intellectual disability cases, positive for the presence of a small copy number variants, intragenic CTNND2 gene deletion. (PMID:25839933)
• Multigenerational autosomal dominant inheritance of 5p chromosomal deletions resulting in Cri-du-Chat Syndrome with SEMA5A, CTNND2, and ICE1 deficiencies has been described. (PMID:26601658)
• Our data suggested that genetic variants in GRM6 are associated with high myopia. The mechanism of GRM6 in the development of high myopia need to be further investigated. (PMID:27034204)
• At the molecular level, CTNND2 is at the crossroad with interactions to such signaling pathways of Wnt and Rho family small GTPases in the Ras superfamily, which are known to drive human disease pathogenesis. (PMID:27380241)
• Gene Ontology analysis revealed that neuronal differentiation-related genes were enriched among targets that were co-regulated by REST and TRIM28, while the level of CTNND2 was increased by the knockdown of REST and TRIM28. Consistently, during neuronal differentiation, the level of CTNND2 increased while those of REST and TRIM28 decreased, suggesting that CTNND2 expression may be co-regulated by both. (PMID:27976729)
• We propose CTNND2 as the causal gene infamilial cortical myoclonic tremor and epilepsy-3 (PMID:29127138)
• Data provide evidence that delta-catenin may serve an important role in the malignancy of lung adenocarcinoma through activation of canonical Wnt signaling and cancer stem cell maintenance. (PMID:29251319)
• The increase in invasive capacity induced by bevacizumab therapy was associated with upregulation of delta-catenin expression in invasive tumor cells. This finding suggests that delta-catenin is related to tumor invasion and migration. (PMID:30872378)
• These results add further insights into the epigenetic regulation of insulin sensitivity and associated complications, pointing the CTNND2 and LPL genes as potential underlying epigenetic biomarkers for future risk of insulin-related diseases. (PMID:31208038)
• EIF3J-AS1 promotes CTNND2 expression via sponging miR-122-5p. Hypoxia-induced EIF3J-AS1 facilitates hepatocellular carcinoma progression via regulating CTNND2. (PMID:31421822)
• microRNA-218-5p plays a protective role in eosinophilic airway inflammation via targeting delta-catenin, a novel catenin in asthma. (PMID:31520422)
• A child with autism, behavioral issues, and dysmorphic features found to have a tandem duplication within CTNND2 by mate-pair sequencing. (PMID:31814264)
• Intratumor delta-catenin heterogeneity driven by genomic rearrangement dictates growth factor dependent prostate cancer progression. (PMID:32313227)
• Severe manifestation of Rauch-Azzarello syndrome associated with biallelic deletion of CTNND2. (PMID:38604781)
• CTNND2 moderates the pace of synaptic maturation and links human evolution to synaptic neoteny. (PMID:39352808)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ctnnd2b	ENSDARG00000003779
danio_rerio	ctnnd2a	ENSDARG00000062415
mus_musculus	Ctnnd2	ENSMUSG00000022240
rattus_norvegicus	Ctnnd2	ENSRNOG00000010649

Paralogs (6): PKP2 (ENSG00000057294), PKP1 (ENSG00000081277), ARVCF (ENSG00000099889), PKP4 (ENSG00000144283), PKP3 (ENSG00000184363), CTNND1 (ENSG00000198561)

Protein

Protein identifiers

Catenin delta-2 — Q9UQB3 (reviewed: Q9UQB3)

Alternative names: Delta-catenin, GT24, Neural plakophilin-related ARM-repeat protein, Neurojungin

All UniProt accessions (11): Q9UQB3, A0A994J5I1, A0A994J5V2, A0A994J833, B4DRK2, D6RBA8, D6RC65, D6RF55, D6RHE9, E7EPC8, E9PHB5

UniProt curated annotations — full annotation on UniProt →

Function. Has a critical role in neuronal development, particularly in the formation and/or maintenance of dendritic spines and synapses. Involved in the regulation of Wnt signaling. It probably acts on beta-catenin turnover, facilitating beta-catenin interaction with GSK3B, phosphorylation, ubiquitination and degradation. Functions as a transcriptional activator when bound to ZBTB33. May be involved in neuronal cell adhesion and tissue morphogenesis and integrity by regulating adhesion molecules.

Subunit / interactions. Binds to E-cadherin at a juxtamembrane site within the cytoplasmic domain. Interacts with PDZD2. Interacts with ZBTB33. Binds to PSEN1. Interacts with ARHGEF28. Interacts (via the extreme C-terminus) with FRMPD2 (via the PDZ 2 domain). Interacts with CDK5. Interacts with CTNNB1. Interacts with GSK3A and GSK3B. Interacts with DNM2. Interacts with CCDC85B.

Subcellular location. Nucleus. Cell junction. Adherens junction. Cell projection. Dendrite. Perikaryon.

Tissue specificity. Expressed in brain; highest expression is observed in fetal brain.

Post-translational modifications. O-glycosylated. Phosphorylated by CDK5. Phosphorylated by GSK3B.

Disease relevance. Defects in CTNND2, including deleterious missense and copy number variants (CNVs) are involved in autism, a complex multifactorial, pervasive developmental disorder characterized by impairments in reciprocal social interaction and communication, restricted and stereotyped patterns of interests and activities, and the presence of developmental abnormalities by 3 years of age. Most individuals with autism also manifest moderate intellectual disability.

Similarity. Belongs to the beta-catenin family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9UQB3-1	1, NPRAPa	yes
Q9UQB3-2	2, NPRAPc

RefSeq proteins (5): NP_001275644, NP_001275645, NP_001275646, NP_001323, NP_001351057 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000225	Armadillo	Repeat
IPR011989	ARM-like	Homologous_superfamily
IPR016024	ARM-type_fold	Homologous_superfamily
IPR028435	Plakophilin/d_Catenin	Family

Pfam: PF00514

UniProt features (63 total): modified residue 14, sequence variant 13, compositionally biased region 10, repeat 9, region of interest 7, sequence conflict 7, chain 1, coiled-coil region 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UQB3-F1	58.88	0.32

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 (14): 209, 264, 267, 276, 282, 296, 327, 360, 415, 461, 514, 516, 1065, 1076

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 351 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_DN, GOBP_DENDRITE_DEVELOPMENT, E2F_Q4, GNF2_RTN1, E2F_Q4_01, BENPORATH_ES_WITH_H3K27ME3, GRUETZMANN_PANCREATIC_CANCER_DN, BERTUCCI_MEDULLARY_VS_DUCTAL_BREAST_CANCER_DN, GOZGIT_ESR1_TARGETS_DN, GOBP_DENDRITIC_SPINE_DEVELOPMENT, GTTAAAG_MIR302B, GOBP_NEUROGENESIS, GOBP_REGULATION_OF_WNT_SIGNALING_PATHWAY, GGGTGGRR_PAX4_03, ATGTTAA_MIR302C

GO Biological Process (7): cell adhesion (GO:0007155), signal transduction (GO:0007165), Wnt signaling pathway (GO:0016055), synapse organization (GO:0050808), regulation of canonical Wnt signaling pathway (GO:0060828), dendritic spine morphogenesis (GO:0060997), cell-cell adhesion (GO:0098609)

GO Molecular Function (3): beta-catenin binding (GO:0008013), cadherin binding (GO:0045296), protein binding (GO:0005515)

GO Cellular Component (11): nucleus (GO:0005634), cytoplasm (GO:0005737), plasma membrane (GO:0005886), adherens junction (GO:0005912), postsynaptic density (GO:0014069), dendrite (GO:0030425), perikaryon (GO:0043204), cell junction (GO:0030054), cell projection (GO:0042995), organelle (GO:0043226), anchoring junction (GO:0070161)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
cellular process	2
cell communication	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
cell surface receptor signaling pathway	1
cell junction organization	1
regulation of Wnt signaling pathway	1
canonical Wnt signaling pathway	1
neuron projection development	1
neuron projection morphogenesis	1
dendrite morphogenesis	1
dendritic spine development	1
dendritic spine organization	1
cell adhesion	1
protein binding	1
cell adhesion molecule binding	1
binding	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
membrane	1
cell periphery	1
cell-cell junction	1
asymmetric synapse	1
postsynaptic specialization	1
neuron projection	1
dendritic tree	1
neuronal cell body	1
cell junction	1

Protein interactions and networks

STRING

2252 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CTNND2	CDH17	Q12864	991
CTNND2	PSEN1	P49768	988
CTNND2	ZBTB33	Q86T24	922
CTNND2	PDZD2	O15018	895
CTNND2	CDH1	P12830	848
CTNND2	RAPSN	Q13702	799
CTNND2	ARHGAP5	Q13017	787
CTNND2	RETREG1	Q9H6L5	785
CTNND2	CYREN	Q9BWK5	760
CTNND2	ERBIN	Q96RT1	758
CTNND2	CTTN	Q14247	750
CTNND2	HCLS1	P14317	740
CTNND2	LRRC7	Q96NW7	726
CTNND2	CTNNB1	P35222	722
CTNND2	FRMPD2	Q68DX3	699

IntAct

150 interactions, top by confidence:

A	B	Type	Score
SCRIB	CTNND2	psi-mi:“MI:0915”(physical association)	0.720
DLG1	CTNND2	psi-mi:“MI:0915”(physical association)	0.720
SCRIB	CTNND2	psi-mi:“MI:0407”(direct interaction)	0.720
DLG1	CTNND2	psi-mi:“MI:0407”(direct interaction)	0.720
CTNND2	SCRIB	psi-mi:“MI:0407”(direct interaction)	0.720
CTNND2	DLG1	psi-mi:“MI:0407”(direct interaction)	0.720
TAX1BP3	ARVCF	psi-mi:“MI:0914”(association)	0.690
DLG4	CTNND2	psi-mi:“MI:0407”(direct interaction)	0.620
CTNND2	DLG4	psi-mi:“MI:0407”(direct interaction)	0.620
LRRC7	CTNND2	psi-mi:“MI:0915”(physical association)	0.610
ERBIN	CTNND2	psi-mi:“MI:0915”(physical association)	0.610
CTNND2	ERBIN	psi-mi:“MI:0407”(direct interaction)	0.610
CTNND2	LRRC7	psi-mi:“MI:0407”(direct interaction)	0.610
HTRA1	CTNND2	psi-mi:“MI:0915”(physical association)	0.590
CTNND2	TAX1BP3	psi-mi:“MI:0407”(direct interaction)	0.590
CTNND2	HTRA1	psi-mi:“MI:0407”(direct interaction)	0.590
SYNGAP1	SEC16A	psi-mi:“MI:0914”(association)	0.530
CDH8	ARVCF	psi-mi:“MI:0914”(association)	0.530
CTNND2	PDZD2	psi-mi:“MI:0407”(direct interaction)	0.440
CTNND2	HTRA3	psi-mi:“MI:0407”(direct interaction)	0.440
CTNND2	MAGI2	psi-mi:“MI:0407”(direct interaction)	0.440
CTNND2	PTPN3	psi-mi:“MI:0407”(direct interaction)	0.440
CTNND2	SYNJ2BP	psi-mi:“MI:0407”(direct interaction)	0.440
CTNND2	SNX27	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (35): CTNND2 (Biochemical Activity), CTNND2 (Affinity Capture-MS), CTNND2 (Affinity Capture-Western), CTNND2 (Reconstituted Complex), CTNND2 (Affinity Capture-MS), CTNND2 (Two-hybrid), CTNND2 (Affinity Capture-Western), CTNND2 (Reconstituted Complex), CTNND2 (Two-hybrid), CTNND2 (Proximity Label-MS), KAT2B (Affinity Capture-Western), CTNND2 (Two-hybrid), NUDT12 (Affinity Capture-MS), CTNND2 (Two-hybrid), TRIM47 (Affinity Capture-MS)

ESM2 similar proteins: A0A0G2K2P5, B1WAP7, O14640, O14641, O35927, O60716, O75069, O75122, O97758, P39447, P50636, P51140, P51141, P51142, P54792, Q05AS8, Q06455, Q07157, Q0V989, Q2VJ60, Q4VGL6, Q5F3B1, Q5IS48, Q5R585, Q60838, Q61062, Q61909, Q62136, Q62728, Q6DKE2, Q6NRE7, Q6NUC6, Q6NYW6, Q7KW14, Q7PQ25, Q80X66, Q8BRT1, Q8CID0, Q8VHI6, Q920B0

Diamond homologs: B0BF33, F1M7L9, O35116, O35927, P97350, Q08DQ0, Q13835, Q28161, Q68FH0, Q99569, Q99959, Q9CQ73, Q9QY23, Q9UQB3, Q9Y446, B4F7F3, O00192, O60716, P30999, P98203, Q8AXM9, Q9U308, Q9C9A6, Q86V71, Q8NHA8, Q96N38, A2AAJ9, H2KZ60, O01761, O80742, Q8N9C0

SIGNOR signaling

12 interactions.

A	Effect	B	Mechanism
CTNND2	“up-regulates activity”	ERBIN	binding
CTNND2	“up-regulates quantity by stabilization”	CDH3	binding
CTNND2	“up-regulates quantity by stabilization”	CDH2	binding
CTNND2	“up-regulates quantity by stabilization”	CDH5	binding
CTNND2	“up-regulates quantity by stabilization”	CDH1	binding
SRC	“up-regulates activity”	CTNND2	phosphorylation
CDK5	“up-regulates activity”	CTNND2	phosphorylation
GSK3B	“down-regulates quantity”	CTNND2	phosphorylation
E2F1	“up-regulates quantity by expression”	CTNND2	“transcriptional regulation”
HES1	“down-regulates quantity by repression”	CTNND2	“transcriptional regulation”
PAX6	“up-regulates quantity by expression”	CTNND2	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 99 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
Ras activation upon Ca2+ influx through NMDA receptor	5	40.8×	8e-06
Unblocking of NMDA receptors, glutamate binding and activation	5	38.8×	8e-06
Negative regulation of NMDA receptor-mediated neuronal transmission	5	38.8×	8e-06
Assembly and cell surface presentation of NMDA receptors	10	36.2×	2e-11
Dopamine Neurotransmitter Release Cycle	5	35.5×	1e-05
Long-term potentiation	5	34.0×	1e-05
Neurexins and neuroligins	11	30.9×	1e-11
Protein-protein interactions at synapses	7	26.6×	7e-07

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	10	60.5×	3e-13
receptor clustering	8	52.0×	7e-10
protein localization to synapse	6	47.9×	3e-07
regulation of postsynaptic membrane neurotransmitter receptor levels	7	36.1×	2e-07
cell-cell adhesion	12	12.7×	5e-08
protein-containing complex assembly	8	9.5×	2e-04
axonogenesis	5	8.4×	1e-02
chemical synaptic transmission	9	7.2×	3e-04

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 6 cancer types — ESCA, LUAD, LUSC, MEL, OVT, PAAD.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	17
Uncertain significance	187
Likely benign	75
Benign	87

Top pathogenic / likely-pathogenic (22)

Variant ID	HGVS	Classification
1299319	NM_001332.4:c.(1761+1_1762-1)_(3084+1_3085-1)del	Pathogenic
3344428	NM_001332.4(CTNND2):c.1510C>T (p.Arg504Ter)	Pathogenic
4839380	NM_001332.4(CTNND2):c.1183_1184del (p.Ser395fs)	Pathogenic
4839829	NM_001332.4(CTNND2):c.3058C>T (p.Arg1020Ter)	Pathogenic
685165	GRCh37/hg19 5p15.2(chr5:11220861-11288711)x1	Pathogenic
1340769	GRCh37/hg19 5p15.2(chr5:11142662-11208440)x1	Likely pathogenic
2228502	NM_001332.4(CTNND2):c.121del (p.Asp41fs)	Likely pathogenic
2630604	NM_001332.4(CTNND2):c.1687T>G (p.Phe563Val)	Likely pathogenic
3062810	GRCh37/hg19 5p15.2(chr5:11691081-11883119)x1	Likely pathogenic
3242296	GRCh37/hg19 5p15.2(chr5:11190118-11200548)x1	Likely pathogenic
372985	NM_001332.4(CTNND2):c.470A>G (p.Gln157Arg)	Likely pathogenic
3765512	NM_001332.4(CTNND2):c.2002_2006del (p.Asp668fs)	Likely pathogenic
3906918	GRCh37/hg19 5p15.2(chr5:11117700-11207796)x1	Likely pathogenic
423559	NM_001332.4(CTNND2):c.896C>A (p.Ser299Ter)	Likely pathogenic
504460	NM_001332.4(CTNND2):c.1087A>T (p.Lys363Ter)	Likely pathogenic
520703	NM_001332.4(CTNND2):c.1629-2A>G	Likely pathogenic
545309	NC_000005.10:g.(?11567352)(11629138_?)del	Likely pathogenic
620420	NM_001332.4(CTNND2):c.3092G>A (p.Trp1031Ter)	Likely pathogenic
814663	GRCh37/hg19 5p15.2(chr5:11134771-11170014)x1	Likely pathogenic
817363	NM_001332.4(CTNND2):c.1645_1646insGG (p.Asp549fs)	Likely pathogenic
817476	NM_001332.4(CTNND2):c.748del (p.Ala250fs)	Likely pathogenic
979514	GRCh37/hg19 5p15.2(chr5:11383308-11414552)x1	Likely pathogenic

SpliceAI

5781 predictions. Top by Δscore:

Variant	Effect	Δscore
5:10973712:AC:A	acceptor_gain	1.0000
5:10973713:CC:C	acceptor_gain	1.0000
5:10973714:C:CC	acceptor_gain	1.0000
5:10981842:TTGAG:T	acceptor_gain	1.0000
5:10981843:TGAG:T	acceptor_gain	1.0000
5:10981844:GAG:G	acceptor_gain	1.0000
5:10981845:AGC:A	acceptor_loss	1.0000
5:10981846:GCTA:G	acceptor_loss	1.0000
5:10981847:C:CC	acceptor_gain	1.0000
5:10981847:C:T	acceptor_loss	1.0000
5:10986640:AGAGT:A	donor_gain	1.0000
5:10992545:TCTTA:T	donor_loss	1.0000
5:10992546:CTTAC:C	donor_loss	1.0000
5:10992547:TTACC:T	donor_loss	1.0000
5:10992548:TA:T	donor_loss	1.0000
5:10992549:A:AT	donor_loss	1.0000
5:10992550:C:G	donor_loss	1.0000
5:11022767:A:AC	donor_gain	1.0000
5:11022768:C:CC	donor_gain	1.0000
5:11022771:ATCT:A	donor_gain	1.0000
5:11022772:T:C	donor_gain	1.0000
5:11022975:TTTGC:T	acceptor_gain	1.0000
5:11022976:TTGC:T	acceptor_gain	1.0000
5:11022977:TGC:T	acceptor_gain	1.0000
5:11022977:TGCC:T	acceptor_loss	1.0000
5:11022978:GC:G	acceptor_gain	1.0000
5:11022978:GCCTG:G	acceptor_loss	1.0000
5:11022979:CC:C	acceptor_gain	1.0000
5:11022980:C:CC	acceptor_gain	1.0000
5:11022980:CT:C	acceptor_loss	1.0000

AlphaMissense

7907 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:10973459:C:A	W1224C	1.000
5:10973459:C:G	W1224C	1.000
5:10973461:A:G	W1224R	1.000
5:10973461:A:T	W1224R	1.000
5:10992654:A:C	F1036L	1.000
5:10992654:A:T	F1036L	1.000
5:10992655:A:C	F1036C	1.000
5:10992655:A:G	F1036S	1.000
5:10992656:A:G	F1036L	1.000
5:11017982:A:C	Y1026D	1.000
5:11017990:C:A	R1023M	1.000
5:11017993:A:G	L1022P	1.000
5:11018009:A:G	W1017R	1.000
5:11018009:A:T	W1017R	1.000
5:11018020:A:G	L1013P	1.000
5:11018023:A:T	V1012D	1.000
5:11018033:C:G	A1009P	1.000
5:11022799:A:C	L990W	1.000
5:11022799:A:G	L990S	1.000
5:11022812:C:G	G986R	1.000
5:11022826:A:G	L981S	1.000
5:11022837:G:C	N977K	1.000
5:11022837:G:T	N977K	1.000
5:11022868:A:C	L967R	1.000
5:11022868:A:G	L967P	1.000
5:11022878:A:G	C964R	1.000
5:11022946:A:G	L941P	1.000
5:11022955:A:T	V938D	1.000
5:11022958:A:C	L937R	1.000
5:11022958:A:G	L937P	1.000

dbSNP variants (sampled 300 via entrez): RS1000002417 (5:11448335 A>G), RS1000003620 (5:11192960 A>G,T), RS1000006094 (5:11099534 T>C), RS1000010438 (5:11524199 C>T), RS1000012634 (5:11408514 T>A), RS1000013645 (5:11881014 A>G), RS1000014658 (5:11233931 C>T), RS1000017110 (5:11369988 C>T), RS1000017861 (5:11785068 G>T), RS1000021703 (5:11441572 C>T), RS1000024076 (5:11530150 T>C), RS1000028195 (5:11239884 C>G,T), RS1000029473 (5:11205580 T>C), RS1000041804 (5:11117248 T>C), RS1000045669 (5:10976413 G>C)

Disease associations

OMIM: gene MIM:604275 | disease phenotypes: MIM:181500

GenCC curated gene-disease

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Strong	Autosomal dominant
neurodevelopmental disorder	Strong	Autosomal dominant
benign adult familial myoclonic epilepsy	Supportive	Autosomal dominant

Mondo (4): neurodevelopmental disorder (MONDO:0700092), complex neurodevelopmental disorder (MONDO:0100038), schizophrenia (MONDO:0005090), benign adult familial myoclonic epilepsy (MONDO:0019448)

Orphanet (2): Non-specific syndromic intellectual disability (Orphanet:528084), NON RARE IN EUROPE: Schizophrenia (Orphanet:3140)

HPO phenotypes

35 total (30 of 35 shown, HPO-id order):

HPO	Term
HP:0000023	Inguinal hernia
HP:0000218	High palate
HP:0000252	Microcephaly
HP:0000286	Epicanthus
HP:0000308	Microretrognathia
HP:0000311	Round face
HP:0000316	Hypertelorism
HP:0000358	Posteriorly rotated ears
HP:0000384	Preauricular skin tag
HP:0000431	Wide nasal bridge
HP:0000470	Short neck
HP:0000494	Downslanted palpebral fissures
HP:0001249	Intellectual disability
HP:0001252	Hypotonia
HP:0001336	Myoclonus
HP:0001382	Joint hypermobility
HP:0001511	Intrauterine growth retardation
HP:0001608	Abnormality of the voice
HP:0001620	Abnormally high-pitched voice
HP:0002197	Generalized-onset seizure
HP:0002315	Headache
HP:0002353	EEG abnormality
HP:0002378	Hand tremor
HP:0002650	Scoliosis
HP:0002757	Recurrent fractures
HP:0004322	Short stature
HP:0004348	Abnormality of bone mineral density
HP:0006101	Finger syndactyly
HP:0007359	Focal-onset seizure
HP:0010864	Severe intellectual disability

GWAS associations

19 associations (top):

Study	Trait	p-value
GCST000878_1	Myopia (pathological)	8.000000e-06
GCST002337_54	Amyotrophic lateral sclerosis (sporadic)	3.000000e-08
GCST002591_14	Lewy body disease	9.000000e-06
GCST002690_7	Very long-chain saturated fatty acid levels (fatty acid 20:0)	8.000000e-06
GCST003465_2	Cannabis dependence symptom count	3.000000e-07
GCST004727_3	Facial emotion recognition	4.000000e-06
GCST005184_6	Common carotid intima-media thickness in HIV infection	2.000000e-07
GCST006976_49	Macular thickness	1.000000e-13
GCST007059_2	Response to antidepressants (symptom improvement)	2.000000e-06
GCST007096_82	Pulse pressure	1.000000e-07
GCST007099_70	Systolic blood pressure	3.000000e-08
GCST007159_17	Corneal astigmatism	3.000000e-06
GCST008891_6	Cognitive performance (processing speed)	6.000000e-06
GCST009310_23	Sensorimotor dexterity	9.000000e-06
GCST010002_22	Refractive error	3.000000e-08
GCST010316_2	Serum docosahexaenoic fatty acid concentration in metabolic syndrome	6.000000e-06
GCST010396_45	Gut microbiota (bacterial taxa, hurdle binary method)	7.000000e-06
GCST012277_2	Clostridioides difficle infection	3.000000e-07
GCST012490_209	Femur bone mineral density x serum urate levels interaction	2.000000e-09

EFO canonical traits (14, from GWAS)

EFO ID	Trait name
EFO:0004207	pathological myopia
EFO:0006799	Lewy body dementia measurement
EFO:0006796	very long-chain saturated fatty acid measurement
EFO:0008457	cannabis dependence measurement
EFO:0008329	facial emotion recognition measurement
EFO:0005763	pulse pressure measurement
EFO:0006335	systolic blood pressure
EFO:1002040	Corneal astigmatism
EFO:0004363	information processing speed
EFO:0008354	cognitive function measurement
EFO:0007761	docosahexaenoic acid measurement
EFO:0007874	gut microbiome measurement
EFO:0009130	clostridium difficile infection
EFO:0004531	urate measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, affects cotreatment, decreases expression	7
Estradiol	affects expression, affects cotreatment, increases expression, decreases expression	5
trichostatin A	affects cotreatment, decreases expression	3
mercuric bromide	decreases expression, affects cotreatment	2
entinostat	decreases expression, affects cotreatment	2
bisphenol S	decreases methylation, increases expression	2
Panobinostat	affects cotreatment, decreases expression	2
Benzo(a)pyrene	increases methylation, affects expression	2
Nickel	decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Tetrachlorodibenzodioxin	affects cotreatment, increases expression, decreases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
fluorene-9-bisphenol	decreases expression	1
methylmercuric chloride	decreases expression	1
propionaldehyde	decreases expression	1
bisphenol A	increases methylation	1
terbufos	increases methylation	1
sodium arsenite	affects methylation	1
zinc chromate	decreases expression, increases abundance	1
aflatoxin B2	increases methylation	1
glycidamide	decreases expression	1
chromium hexavalent ion	decreases expression, increases abundance	1
perfluorooctane sulfonic acid	increases expression	1
CGP 52608	affects binding, increases reaction	1
monomethylarsonous acid	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Vorinostat	affects cotreatment, decreases expression	1

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D9CN	Ubigene HEK293 CTNND2 KO	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT06310681	Not specified	COMPLETED	Pilot Testing of a Co-adapted Group Programme for Parents/Carers of Children With Complex Neurodisability
NCT07303049	Not specified	NOT_YET_RECRUITING	Cognitive Benefit of Intensive Rehabilitation Using Rhythmic Music Training in Children With Complex Neurodevelopmental Disorder
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism