CTNNA2

Summary

CTNNA2 (catenin alpha 2, HGNC:2510) is a protein-coding gene on chromosome 2p12, encoding Catenin alpha-2 (P26232). May function as a linker between cadherin adhesion receptors and the cytoskeleton to regulate cell-cell adhesion and differentiation in the nervous system.

Enables actin filament binding activity. Involved in negative regulation of Arp2/3 complex-mediated actin nucleation; regulation of neuron migration; and regulation of neuron projection development. Located in cytoplasm. Implicated in complex cortical dysplasia with other brain malformations.

Source: NCBI Gene 1496 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cortical dysplasia, complex, with other brain malformations 9 (Strong, GenCC)
• GWAS associations: 34
• Clinical variants (ClinVar): 253 total — 8 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 33
• Cancer driver (intOGen): activating (oncogene-like) across 7 cancer types
• MANE Select transcript: NM_001282597

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2510
Approved symbol	CTNNA2
Name	catenin alpha 2
Location	2p12
Locus type	gene with protein product
Status	Approved
Aliases	CAP-R, CT114
Ensembl gene	ENSG00000066032
Ensembl biotype	protein_coding
OMIM	114025
Entrez	1496

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 12 protein_coding, 5 protein_coding_CDS_not_defined, 2 retained_intron

ENST00000343114, ENST00000361291, ENST00000402739, ENST00000409266, ENST00000409550, ENST00000409971, ENST00000451966, ENST00000465616, ENST00000466387, ENST00000467488, ENST00000467892, ENST00000493024, ENST00000496251, ENST00000496558, ENST00000497804, ENST00000508970, ENST00000540488, ENST00000541047, ENST00000629316

RefSeq mRNA: 8 — MANE Select: NM_001282597 NM_001164883, NM_001282597, NM_001282598, NM_001282599, NM_001282600, NM_001320810, NM_001399737, NM_004389

CCDS: CCDS42703, CCDS54371, CCDS62944, CCDS62945, CCDS74531

Canonical transcript exons

ENST00000402739 — 19 exons

Exon	Start	End
ENSE00000995367	80581706	80581819
ENSE00000995369	80589304	80589485
ENSE00000995374	80608184	80608318
ENSE00001295292	79874076	79874342
ENSE00001301519	79858013	79858179
ENSE00001307724	80574163	80574314
ENSE00001316312	79909594	79909797
ENSE00001318913	80545907	80546063
ENSE00001323360	79869816	79869935
ENSE00001328920	80555693	80555893
ENSE00001561114	80619085	80619228
ENSE00001812610	80647585	80648780
ENSE00003517068	80544982	80545074
ENSE00003560652	80604074	80604179
ENSE00003607792	79651552	79651658
ENSE00003679437	79744387	79744582
ENSE00003717392	80393211	80393291
ENSE00003745756	80419449	80419601
ENSE00003915565	79513051	79513207

Expression profiles

Bgee: expression breadth ubiquitous, 200 present calls, max score 98.62.

FANTOM5 (CAGE): breadth broad, TPM avg 10.3661 / max 615.4159, expressed in 319 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
21144	7.5133	301
21143	1.3934	239
21162	0.4370	47
21163	0.2682	45
21151	0.2480	63
21141	0.2365	31
21164	0.0883	34
21161	0.0865	33
21160	0.0476	25
21159	0.0472	24

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
frontal pole	UBERON:0002795	98.62	gold quality
Brodmann (1909) area 46	UBERON:0006483	97.25	gold quality
superior frontal gyrus	UBERON:0002661	97.16	gold quality
postcentral gyrus	UBERON:0002581	97.07	gold quality
lateral nuclear group of thalamus	UBERON:0002736	97.06	gold quality
Brodmann (1909) area 10	UBERON:0013541	97.05	gold quality
corpus epididymis	UBERON:0004359	97.03	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	96.95	gold quality
orbitofrontal cortex	UBERON:0004167	96.70	gold quality
sperm	CL:0000019	96.69	gold quality
parietal lobe	UBERON:0001872	96.58	gold quality
amygdala	UBERON:0001876	96.55	gold quality
anterior cingulate cortex	UBERON:0009835	96.45	gold quality
cranial nerve II	UBERON:0000941	96.42	gold quality
middle frontal gyrus	UBERON:0002702	96.41	gold quality
cingulate cortex	UBERON:0003027	96.41	gold quality
frontal cortex	UBERON:0001870	96.34	gold quality
temporal lobe	UBERON:0001871	96.29	gold quality
prefrontal cortex	UBERON:0000451	96.23	gold quality
neocortex	UBERON:0001950	96.17	gold quality
cerebral cortex	UBERON:0000956	96.14	gold quality
Brodmann (1909) area 9	UBERON:0013540	96.08	gold quality
entorhinal cortex	UBERON:0002728	96.01	gold quality
primary visual cortex	UBERON:0002436	95.97	gold quality
right frontal lobe	UBERON:0002810	95.97	gold quality
telencephalon	UBERON:0001893	95.59	gold quality
occipital lobe	UBERON:0002021	95.47	gold quality
caudate nucleus	UBERON:0001873	95.46	gold quality
middle temporal gyrus	UBERON:0002771	95.31	gold quality
cortical plate	UBERON:0005343	95.31	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	6816.49
E-GEOD-180759	yes	6349.80
E-GEOD-84465	yes	25.43
E-HCAD-25	yes	20.77
E-GEOD-93593	yes	10.63
E-ANND-3	yes	6.10
E-HCAD-30	no	6794.58

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CTNNB1, GATA3

miRNA regulators (miRDB)

62 targeting CTNNA2, 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-548P	99.98	72.25	3784
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-10523-5P	99.91	69.22	2038
HSA-MIR-3140-3P	99.88	68.47	2069
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-4694-3P	99.79	69.53	2640
HSA-MIR-199A-3P	99.75	70.48	929
HSA-MIR-199B-3P	99.75	70.48	929
HSA-MIR-3129-5P	99.75	70.46	914
HSA-MIR-6885-3P	99.75	70.36	3187
HSA-MIR-2116-3P	99.74	64.32	889
HSA-MIR-518A-5P	99.70	69.01	2209
HSA-MIR-527	99.70	69.01	2209
HSA-MIR-586	99.65	70.40	2051
HSA-MIR-5197-5P	99.64	69.08	1494
HSA-MIR-3679-3P	99.64	69.88	1599
HSA-MIR-4666B	99.64	68.69	1282
HSA-MIR-642A-5P	99.51	65.10	1152
HSA-MIR-5689	99.50	71.26	1154
HSA-MIR-6727-3P	99.49	65.92	1333
HSA-MIR-578	99.46	68.36	1787
HSA-MIR-372-5P	99.41	69.11	2299
HSA-MIR-4722-3P	99.35	65.22	1099
HSA-MIR-183-5P	99.31	72.27	1164
HSA-MIR-3606-5P	99.31	69.67	1168

Literature-anchored findings (GeneRIF, showing 9)

• CTNNA2 is differentially regulated by smoking in schizophrenic patients. (PMID:18163523)
• Common variants in CTNNA2 are associated with excitement-seeking and risk-taking. (PMID:22833195)
• CTNNA2 and CTNNA3 are tumor suppressor genes frequently mutated in laryngeal carcinomas. (PMID:24100690)
• CTNNA2 gene increases the risk of alcohol addiction in White women. (PMID:25041903)
• Single nucleotide polymorphism in CTNNA2 is associated with breast cancer susceptibility. (PMID:25824743)
• SNP 50-kb upstream from CTNNA2 was associated with impulsivity in Native American sample. (PMID:27167163)
• One association in the CTNNA2 gene on chromosome 2p12 [rs1567532, hazard ratio (HR) = 1.75, 95% confidence interval (CI) 1.19-2.58, P = 0.005 for homozygotes for the minor allele] and one in the last intron of the RUNX2 gene on chromosome 6p21 (rs12209785, HR = 0.88, 95% CI 0.80-0.98, P = 0.014 for heterozygotes) are of particular relevance. These loci do not coincide with those that showed the strongest associations in t (PMID:27497070)
• Single nucleotide polymorphisms in CTNNA2 show associations in Schizophrenia and general cognitive function. (PMID:28746715)
• Novel-miR-4885 can bind to 3’ untranslated region of CTNNA2 to reduce cell adhesion. (PMID:30526004)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ctnna2	ENSDARG00000024785
mus_musculus	Ctnna2	ENSMUSG00000063063
rattus_norvegicus	Ctnna2	ENSRNOG00000006003
drosophila_melanogaster	alpha-Cat	FBGN0010215
caenorhabditis_elegans		WBGENE00001978

Paralogs (4): VCL (ENSG00000035403), CTNNA1 (ENSG00000044115), CTNNAL1 (ENSG00000119326), CTNNA3 (ENSG00000183230)

Protein

Protein identifiers

Catenin alpha-2 — P26232 (reviewed: P26232)

Alternative names: Alpha N-catenin, Alpha-catenin-related protein

All UniProt accessions (8): P26232, A0A0A0MRI5, A0A0A0MTJ6, B8ZZE7, B9A010, C9IZ88, C9J144, F6KRI5

UniProt curated annotations — full annotation on UniProt →

Function. May function as a linker between cadherin adhesion receptors and the cytoskeleton to regulate cell-cell adhesion and differentiation in the nervous system. Required for proper regulation of cortical neuronal migration and neurite growth. It acts as a negative regulator of Arp2/3 complex activity and Arp2/3-mediated actin polymerization. It thereby suppresses excessive actin branching which would impair neurite growth and stability. Regulates morphological plasticity of synapses and cerebellar and hippocampal lamination during development. Functions in the control of startle modulation.

Subunit / interactions. Interacts with CDH1 and CDH2. Interacts with ZNF639; recruits CTNNA2 to the nucleus. Interacts with F-actin.

Subcellular location. Cell membrane. Cytoplasm. Cytoskeleton. Cell junction. Adherens junction. Cell projection. Axon. Nucleus.

Tissue specificity. Expressed in neural tissues, with strongest expression in fetal and adult brain. Expressed in the developing cortical plate and marginal zone of 20-week-old human fetal brain.

Disease relevance. Cortical dysplasia, complex, with other brain malformations 9 (CDCBM9) [MIM:618174] An autosomal recessive disorder characterized by neurodevelopmental delay apparent from early infancy, acquired microcephaly, hypotonic cerebral palsy, inability to ambulate or speak, and intractable seizures. Brain imaging shows pachygyria with severe cortical gray matter thickening, paucity of gyri without an obvious posterior-anterior gradient or focal dysplasias, hypogenesis of the corpus callosum, and cerebellar hypoplasia. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the vinculin/alpha-catenin family.

Isoforms (6)

UniProt ID	Names	Canonical?
P26232-1	1, AlphaN-catenin II	yes
P26232-2	2, AlphaN-catenin I
P26232-3	3
P26232-4	4
P26232-5	5
P26232-6	6, AlphaN-catenin III

RefSeq proteins (8): NP_001158355, NP_001269526, NP_001269527, NP_001269528, NP_001269529, NP_001307739, NP_001386666, NP_004380 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000633	Vinculin_CS	Conserved_site
IPR001033	Alpha_catenin	Family
IPR006077	Vinculin/catenin	Family
IPR036723	Alpha-catenin/vinculin-like_sf	Homologous_superfamily

Pfam: PF01044

UniProt features (29 total): splice variant 6, helix 5, modified residue 5, sequence conflict 4, sequence variant 3, compositionally biased region 2, strand 2, chain 1, region of interest 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
6DUW	X-RAY DIFFRACTION	2.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P26232-F1	80.78	0.52

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 (5): 632, 640, 651, 901, 939

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-525793	Myogenesis

MSigDB gene sets: 317 (showing top): GOBP_DENDRITE_DEVELOPMENT, GOBP_HINDBRAIN_DEVELOPMENT, GOBP_REGULATION_OF_ACTIN_NUCLEATION, CMYB_01, GOBP_NEUROGENESIS, KEGG_TIGHT_JUNCTION, MOLENAAR_TARGETS_OF_CCND1_AND_CDK4_UP, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_COMPONENT_ORGANIZATION, GOBP_REGULATION_OF_ACTIN_FILAMENT_BASED_PROCESS, GOBP_CELL_CELL_ADHESION, GOBP_STARTLE_RESPONSE, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, GOBP_REGULATION_OF_CELL_PROJECTION_ORGANIZATION, GOBP_CELL_JUNCTION_ORGANIZATION, BIOCARTA_CELL2CELL_PATHWAY

GO Biological Process (15): axonogenesis (GO:0007409), regulation of neuron projection development (GO:0010975), cell migration (GO:0016477), radial glia guided migration of Purkinje cell (GO:0021942), negative regulation of Arp2/3 complex-mediated actin nucleation (GO:0034316), dendrite morphogenesis (GO:0048813), brain morphogenesis (GO:0048854), regulation of synapse structural plasticity (GO:0051823), prepulse inhibition (GO:0060134), cell-cell adhesion (GO:0098609), modification of postsynaptic actin cytoskeleton (GO:0098885), regulation of neuron migration (GO:2001222), cytoskeleton organization (GO:0007010), cell adhesion (GO:0007155), cell differentiation (GO:0030154)

GO Molecular Function (7): structural constituent of cytoskeleton (GO:0005200), beta-catenin binding (GO:0008013), identical protein binding (GO:0042802), cadherin binding (GO:0045296), actin filament binding (GO:0051015), structural molecule activity (GO:0005198), protein binding (GO:0005515)

GO Cellular Component (21): nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829), adherens junction (GO:0005912), actin cytoskeleton (GO:0015629), basolateral plasma membrane (GO:0016323), catenin complex (GO:0016342), lamellipodium (GO:0030027), axon (GO:0030424), hippocampal mossy fiber to CA3 synapse (GO:0098686), parallel fiber to Purkinje cell synapse (GO:0098688), presynaptic active zone cytoplasmic component (GO:0098831), extrinsic component of presynaptic membrane (GO:0098888), extrinsic component of postsynaptic membrane (GO:0098890), postsynaptic density, intracellular component (GO:0099092), cytoskeleton (GO:0005856), plasma membrane (GO:0005886), postsynaptic density (GO:0014069), membrane (GO:0016020), cell projection (GO:0042995), anchoring junction (GO:0070161)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
cell morphogenesis involved in neuron differentiation	2
neuron projection morphogenesis	2
cytoskeleton	2
protein binding	2
extrinsic component of synaptic membrane	2
axon development	1
neuron projection development	1
regulation of plasma membrane bounded cell projection organization	1
cell motility	1
hindbrain radial glia guided cell migration	1
Arp2/3 complex-mediated actin nucleation	1
regulation of Arp2/3 complex-mediated actin nucleation	1
negative regulation of actin nucleation	1
dendrite development	1
brain development	1
animal organ morphogenesis	1
regulation of synapse organization	1
startle response	1
negative regulation of response to external stimulus	1
cell adhesion	1
modification of postsynaptic structure	1
neuron migration	1
regulation of cell migration	1
organelle organization	1
cellular process	1
cellular developmental process	1
structural molecule activity	1
cytoskeleton organization	1
cell adhesion molecule binding	1
actin binding	1
protein-containing complex binding	1
molecular_function	1
binding	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cytoplasm	1
cell-cell junction	1
basal plasma membrane	1
plasma membrane region	1

Protein interactions and networks

STRING

2106 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CTNNA2	LRRTM1	Q86UE6	881
CTNNA2	CTNNB1	P35222	857
CTNNA2	CDH2	P19022	842
CTNNA2	CDH17	Q12864	837
CTNNA2	LRRTM4	Q86VH4	822
CTNNA2	AFDN	P55196	675
CTNNA2	CDH1	P12830	630
CTNNA2	CDH8	P55286	575
CTNNA2	ZNF639	Q9UID6	569
CTNNA2	CTNND2	Q9UQB3	549
CTNNA2	NRXN1	Q9ULB1	546
CTNNA2	VCL	P18206	530
CTNNA2	TLN1	Q9Y490	530
CTNNA2	TLN2	Q9Y4G6	514
CTNNA2	TRAPPC10	P48553	510

IntAct

203 interactions, top by confidence:

A	B	Type	Score
CTNNBIP1	APC	psi-mi:“MI:0914”(association)	0.740
TAX1BP3	ARVCF	psi-mi:“MI:0914”(association)	0.690
CTNNA2	TAX1BP3	psi-mi:“MI:0407”(direct interaction)	0.690
CTNNB1	CTNNA2	psi-mi:“MI:0915”(physical association)	0.670
ZNF639	CTNNA2	psi-mi:“MI:0915”(physical association)	0.600
ZNF639	CTNNA2	psi-mi:“MI:0403”(colocalization)	0.600
CDH8	ARVCF	psi-mi:“MI:0914”(association)	0.530
ATP6V0A1	ATP6AP2	psi-mi:“MI:0914”(association)	0.530
CTNNA1	CTNNA2	psi-mi:“MI:0914”(association)	0.530
PVR	ORC4	psi-mi:“MI:0914”(association)	0.530
CTNNA2	NHERF4	psi-mi:“MI:0407”(direct interaction)	0.440
CTNNA2	DLG3	psi-mi:“MI:0407”(direct interaction)	0.440
CTNNA2	TAMALIN	psi-mi:“MI:0407”(direct interaction)	0.440
CTNNA2	TIAM2	psi-mi:“MI:0407”(direct interaction)	0.440
APBA3	CTNNA2	psi-mi:“MI:0407”(direct interaction)	0.440
CTNNA2	PDZD7	psi-mi:“MI:0407”(direct interaction)	0.440
LDB3	CTNNA2	psi-mi:“MI:0407”(direct interaction)	0.440
CTNNA2	APBA2	psi-mi:“MI:0407”(direct interaction)	0.440
CTNNA2	PDZRN4	psi-mi:“MI:0407”(direct interaction)	0.440
CTNNA2	PICK1	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (76): CTNNA2 (Affinity Capture-MS), CTNNA2 (Affinity Capture-MS), CTNNA2 (Affinity Capture-MS), CTNNA2 (Affinity Capture-MS), CTNNB1 (Co-fractionation), JUP (Co-fractionation), CTNNA2 (Affinity Capture-MS), CTNNA2 (Affinity Capture-MS), CTNNA2 (Affinity Capture-MS), CTNNA2 (Affinity Capture-MS), CTNNA2 (Affinity Capture-MS), CTNNA2 (Affinity Capture-MS), CTNNA2 (Proximity Label-MS), CTNNA2 (Affinity Capture-MS), CTNNA2 (Affinity Capture-MS)

ESM2 similar proteins: A0A3B6UES5, A2A5R2, A4IGI7, B1AY13, B7ZC77, D4A631, G3X9K3, G8JYB2, O46037, O46382, O88327, O95273, P12003, P18206, P19826, P26231, P26232, P26234, P30997, P35220, P35221, P85972, P90947, Q04615, Q13576, Q17162, Q2KIZ9, Q3MHM6, Q3TVC7, Q3UQ44, Q4R809, Q59I72, Q5R416, Q5RC06, Q5RFN4, Q5U4I3, Q61301, Q62717, Q64727, Q65CL1

Diamond homologs: A4IGI7, B7ZC77, P26231, P26232, P30997, P35220, P35221, P90947, Q04615, Q3MHM6, Q59I72, Q5R416, Q61301, Q65CL1, Q6GLP0, Q9PVF8, Q9UI47, G8JYB2, O88327, Q5RC06, Q9UBT7, A0A3B6UES5, O46037, P12003, P18206, P19826, P26234, P85972, Q17162, Q54MH2, Q64727

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
CTNNA2	down-regulates	YAP1	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 158 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	27.7×	8e-05
Unblocking of NMDA receptors, glutamate binding and activation	5	26.4×	8e-05
Negative regulation of NMDA receptor-mediated neuronal transmission	5	26.4×	8e-05
Long-term potentiation	5	23.1×	1e-04
Assembly and cell surface presentation of NMDA receptors	9	22.2×	5e-08
Neurexins and neuroligins	10	19.1×	5e-08
Adherens junctions interactions	7	16.9×	3e-05
Protein-protein interactions at synapses	6	15.5×	1e-04

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	10	39.5×	4e-11
receptor clustering	8	34.0×	2e-08
protein localization to synapse	6	31.3×	6e-06
regulation of postsynaptic membrane neurotransmitter receptor levels	8	27.0×	1e-07
adherens junction organization	6	20.8×	5e-05
cell-cell adhesion mediated by cadherin	6	16.8×	2e-04
cell-cell junction assembly	5	15.1×	1e-03
bicellular tight junction assembly	6	13.5×	5e-04

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 7 cancer types — CHOL, HCC, HNSC, LUAD, MEL, PAAD, PRAD.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	8
Likely pathogenic	3
Uncertain significance	155
Likely benign	30
Benign	41

Top pathogenic / likely-pathogenic (11)

Variant ID	HGVS	Classification
2577041	NC_000002.11:g.(?79740059)(80875994_?)del	Pathogenic
2637657	NM_001282597.3(CTNNA2):c.1938_1939del (p.Asp646fs)	Pathogenic
4279151	GRCh37/hg19 2p12(chr2:80167230-80732448)x1	Pathogenic
590259	NM_001282597.3(CTNNA2):c.2788C>T (p.Arg930Ter)	Pathogenic
590260	NM_001282597.3(CTNNA2):c.2341C>T (p.Arg781Ter)	Pathogenic
590261	NM_001282597.3(CTNNA2):c.1480C>T (p.Arg494Ter)	Pathogenic
685860	GRCh37/hg19 2p13.1-12(chr2:74972080-83043893)x1	Pathogenic
981838	NM_001282597.3(CTNNA2):c.103-1G>A	Pathogenic
2582433	NM_001282597.3(CTNNA2):c.718del (p.Arg240fs)	Likely pathogenic
3358212	NM_001282597.3(CTNNA2):c.1372dup (p.Leu458fs)	Likely pathogenic
3390860	NM_001282597.3(CTNNA2):c.544G>T (p.Glu182Ter)	Likely pathogenic

SpliceAI

5828 predictions. Top by Δscore:

Variant	Effect	Δscore
2:79185431:GGT:G	donor_loss	1.0000
2:79185432:G:GG	donor_gain	1.0000
2:79185433:T:A	donor_loss	1.0000
2:79651546:CCATA:C	acceptor_loss	1.0000
2:79651548:ATAG:A	acceptor_gain	1.0000
2:79651549:TAG:T	acceptor_loss	1.0000
2:79651549:TAGGG:T	acceptor_gain	1.0000
2:79651550:A:AC	acceptor_loss	1.0000
2:79651550:A:AG	acceptor_gain	1.0000
2:79651550:AG:A	acceptor_gain	1.0000
2:79651550:AGG:A	acceptor_gain	1.0000
2:79651550:AGGGA:A	acceptor_gain	1.0000
2:79651551:G:GT	acceptor_gain	1.0000
2:79651551:GG:G	acceptor_gain	1.0000
2:79651551:GGG:G	acceptor_gain	1.0000
2:79651551:GGGA:G	acceptor_gain	1.0000
2:79651551:GGGAG:G	acceptor_gain	1.0000
2:79651656:CAG:C	donor_gain	1.0000
2:79651657:AG:A	donor_gain	1.0000
2:79651658:GG:G	donor_gain	1.0000
2:79651659:G:GA	donor_loss	1.0000
2:79651659:G:GG	donor_gain	1.0000
2:79651660:T:A	donor_loss	1.0000
2:79652166:GTTA:G	donor_gain	1.0000
2:79652167:TTAT:T	donor_gain	1.0000
2:79744579:CAAGG:C	donor_loss	1.0000
2:79744580:AAGG:A	donor_loss	1.0000
2:79744581:AGGTA:A	donor_loss	1.0000
2:79744583:G:GC	donor_loss	1.0000
2:79744584:T:G	donor_loss	1.0000

AlphaMissense

6288 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:79651590:T:A	W12R	1.000
2:79651590:T:C	W12R	1.000
2:79651612:T:A	I19N	1.000
2:79651612:T:C	I19T	1.000
2:79651612:T:G	I19S	1.000
2:79651636:T:C	L27P	1.000
2:79651639:T:C	L28S	1.000
2:79651639:T:G	L28W	1.000
2:79651648:T:A	L31H	1.000
2:79651648:T:C	L31P	1.000
2:79651651:T:A	V32D	1.000
2:79744397:T:A	L38H	1.000
2:79744397:T:C	L38P	1.000
2:79744483:G:C	A67P	1.000
2:79744496:T:C	F71S	1.000
2:79744507:G:C	G75R	1.000
2:79744508:G:A	G75D	1.000
2:79744558:G:C	A92P	1.000
2:79858042:T:C	F110L	1.000
2:79858043:T:C	F110S	1.000
2:79858043:T:G	F110C	1.000
2:79858044:T:A	F110L	1.000
2:79858044:T:G	F110L	1.000
2:79858072:C:A	R120S	1.000
2:79858073:G:C	R120P	1.000
2:79858090:G:C	A126P	1.000
2:79858093:G:C	A127P	1.000
2:79858094:C:A	A127E	1.000
2:79858097:G:C	R128T	1.000
2:79858097:G:T	R128M	1.000

dbSNP variants (sampled 300 via entrez): RS1000003009 (2:79643318 C>T), RS1000005779 (2:80158648 G>A), RS1000006209 (2:80274913 A>G), RS1000008715 (2:79854727 C>T), RS1000009224 (2:79877228 G>A,T), RS1000010621 (2:79396509 T>C), RS1000011927 (2:80202731 A>T), RS1000013125 (2:79761335 T>C), RS1000014709 (2:79815449 A>G), RS1000015153 (2:80507880 A>C), RS1000015504 (2:79921858 T>C), RS1000016003 (2:79509143 A>G), RS1000025144 (2:79810589 C>CAT), RS1000026026 (2:79333990 G>C), RS1000027969 (2:80033753 A>G)

Disease associations

OMIM: gene MIM:114025 | disease phenotypes: MIM:618174

GenCC curated gene-disease

Disease	Classification	Inheritance
cortical dysplasia, complex, with other brain malformations 9	Strong	Autosomal recessive

Mondo (2): cortical dysplasia, complex, with other brain malformations 9 (MONDO:0032578), hereditary breast ovarian cancer syndrome (MONDO:0003582)

Orphanet (1): Hereditary breast and/or ovarian cancer syndrome (Orphanet:145)

HPO phenotypes

33 total (30 of 33 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000238	Hydrocephalus
HP:0000256	Macrocephaly
HP:0000648	Optic atrophy
HP:0000729	Autistic behavior
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001276	Hypertonia
HP:0001302	Pachygyria
HP:0001321	Cerebellar hypoplasia
HP:0001344	Absent speech
HP:0001347	Hyperreflexia
HP:0001776	Bilateral talipes equinovarus
HP:0002079	Hypoplasia of the corpus callosum
HP:0002089	Pulmonary hypoplasia
HP:0002194	Delayed gross motor development
HP:0002353	EEG abnormality
HP:0002365	Hypoplasia of the brainstem
HP:0002510	Spastic tetraplegia
HP:0002521	Hypsarrhythmia
HP:0002540	Inability to walk
HP:0003593	Infantile onset
HP:0004322	Short stature
HP:0005484	Secondary microcephaly
HP:0010819	Atonic seizure
HP:0010862	Delayed fine motor development
HP:0010864	Severe intellectual disability
HP:0011344	Severe global developmental delay
HP:0012434	Delayed early-childhood social milestone development

GWAS associations

34 associations (top):

Study	Trait	p-value
GCST000189_36	Protein quantitative trait loci	5.000000e-07
GCST000387_11	Bipolar disorder	3.000000e-06
GCST001915_3	Alzheimer’s disease (cognitive decline)	1.000000e-08
GCST002209_1	Orthostatic hypotension	5.000000e-08
GCST002238_2	Contrast sensitivity	1.000000e-07
GCST002345_6	Response to cytadine analogues (cytosine arabinoside)	7.000000e-06
GCST002735_2	Breast cancer	1.000000e-07
GCST002774_2	Cognitive function	7.000000e-06
GCST002783_609	Body mass index	3.000000e-07
GCST003124_21	Mild influenza (H1N1) infection	2.000000e-08
GCST003134_17	Cerebrospinal fluid clusterin levels	7.000000e-06
GCST003381_6	Bone mineral density (femoral neck)	5.000000e-08
GCST004485_29	Survival in pancreatic cancer	4.000000e-06
GCST004886_5	Alcohol consumption	4.000000e-08
GCST005951_41	Body mass index	4.000000e-08
GCST006248_3	Response to lurasidone in schizophrenia	5.000000e-07
GCST006248_7	Response to lurasidone in schizophrenia	2.000000e-06
GCST007509_1	Cleft palate	7.000000e-09
GCST007509_2	Cleft palate	7.000000e-09
GCST008275_4	Cerebral microbleeds	5.000000e-06
GCST008512_5	Multisite chronic pain	4.000000e-08
GCST008645_3	Alcohol dependence or heroin dependence or methamphetamine dependence	5.000000e-09
GCST009891_1	Schizophrenia (MTAG)	2.000000e-06
GCST010002_395	Refractive error	3.000000e-12
GCST010137_6	Cooked vegetable consumption	1.000000e-08
GCST010138_9	Raw vegetable consumption	1.000000e-08
GCST010142_20	Fish- and plant-related diet	4.000000e-10
GCST010916_7	Proportion of activated microglia (inferior temporal cortex)	8.000000e-06
GCST010988_182	Adult body size	1.000000e-09
GCST011741_48	LDL cholesterol levels in HIV infection	8.000000e-06

EFO canonical traits (14, from GWAS)

EFO ID	Trait name
EFO:0004750	interleukin 10 measurement
EFO:0005419	contrast sensitivity measurement
EFO:0004337	intelligence
EFO:0004340	body mass index
EFO:1001488	influenza A (H1N1)
EFO:0007785	femoral neck bone mineral density
EFO:0000638	overall survival
EFO:0010059	cerebral microbleeds
EFO:0010100	multisite chronic pain
EFO:0008111	diet measurement
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004531	urate measurement
EFO:0009270	heel bone mineral density
EFO:0007874	gut microbiome measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D061325	Hereditary Breast and Ovarian Cancer Syndrome	C04.588.180.483; C04.588.322.455.431; C04.700.517; C12.050.351.500.056.630.705.431; C12.050.351.937.418.685.431; C12.100.250.056.630.705.431; C12.900.418.685.431; C16.320.700.517; C17.800.090.500.483; C19.344.410.431; C19.391.630.705.431

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs11126740	Efficacy	3	Tumor necrosis factor alpha (TNF-alpha) inhibitors	Psoriasis

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs11126740	CTNNA2	3	3.00	1	Tumor necrosis factor alpha (TNF-alpha) inhibitors

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, affects expression, decreases methylation	3
bisphenol A	affects cotreatment, decreases expression, affects methylation	2
sodium arsenite	affects methylation, increases expression	2
entinostat	decreases expression, affects cotreatment	2
Benzo(a)pyrene	affects methylation, decreases methylation, increases mutagenesis	2
Cadmium Chloride	increases palmitoylation, decreases expression, decreases reaction, increases abundance	2
FR900359	increases phosphorylation	1
bisphenol F	decreases methylation, affects cotreatment	1
TAK-243	affects sumoylation	1
2,4,6-tribromophenol	increases expression	1
methylmercuric chloride	decreases expression	1
pyrogallol 1,3-dimethyl ether	increases expression, affects cotreatment, decreases expression, affects localization	1
11-nor-delta(9)-tetrahydrocannabinol-9-carboxylic acid	affects methylation, increases abundance	1
tetrabromobisphenol A	increases expression	1
2-bromopalmitate	decreases reaction, increases abundance, increases palmitoylation	1
CGP 52608	increases reaction, affects binding	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
hexabrominated diphenyl ether 153	increases expression	1
bisphenol S	increases methylation	1
apatinib	affects cotreatment, increases expression	1
Arsenic Trioxide	affects cotreatment, increases expression	1
Fulvestrant	affects methylation, decreases methylation, affects cotreatment	1
Acetaminophen	decreases expression	1
Cadmium	decreases reaction, increases abundance, increases palmitoylation	1
Caffeine	affects phosphorylation	1
Calcitriol	affects cotreatment, increases expression	1
Cannabinoids	affects methylation, increases abundance	1
Diethylhexyl Phthalate	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02562170	PHASE4	COMPLETED	Protexa® Versus TiLoopBra® in Immediate Breast Reconstruction- A Pilot Study
NCT00673335	PHASE3	COMPLETED	Letrozole in Preventing Breast Cancer in Postmenopausal Women With a BRCA1 or BRCA2 Mutation
NCT00685256	PHASE3	COMPLETED	Standard Genetic Counseling With or Without a Decision Guide in Improving Communication Between Mothers Undergoing BRCA1/2 Testing and Their Minor-Age Children
NCT03162276	PHASE3	UNKNOWN	Trial of Inquiry Based Stress Reduction (IBSR) Program for BRCA1/2 Mutation Carriers
NCT00253539	PHASE2	COMPLETED	Arzoxifene or Tamoxifen in Preventing Breast Cancer in Premenopausal Women at High Risk for Breast Cancer
NCT00305695	PHASE2	COMPLETED	Zoledronate or Observation in Maintaining Bone Mineral Density in Patients Who Are Undergoing Surgery to Remove Both Ovaries
NCT00321633	PHASE2	COMPLETED	Carboplatin or Docetaxel in Treating Women With Metastatic Genetic Breast Cancer
NCT01333748	PHASE2	COMPLETED	Search Allelic Imbalance of Expression of BRCA Genes in Hereditary Risk of Breast and/or Ovarian Cancer
NCT01367639	PHASE2	COMPLETED	Trial of Inquiry Based Stress Reduction (IBSR) Program for BRCA1/2 Mutation Carriers
NCT00535119	PHASE1	COMPLETED	Veliparib, Carboplatin, and Paclitaxel in Treating Patients With Advanced Solid Cancer
NCT00892736	PHASE1	COMPLETED	Veliparib in Treating Patients With Malignant Solid Tumors That Do Not Respond to Previous Therapy
NCT03832985	EARLY_PHASE1	COMPLETED	Pediatric Reporting of Adult-Onset Genomic Results
NCT00005095	Not specified	RECRUITING	Specimen and Data Study for Ovarian Cancer Early Detection and Prevention
NCT00609505	Not specified	COMPLETED	Telemedicine vs. Face-to-Face Cancer Genetic Counseling
NCT01273909	Not specified	UNKNOWN	Outcomes After Perforator Flap Reconstruction for Breast Reconstruction and/or Lymphedema Treatment
NCT01445275	Not specified	WITHDRAWN	Cost of Cancer Risk Management in Women at Elevated Genetic Risk for Ovarian Cancer Who Participated on GOG-0199
NCT01608074	Not specified	ACTIVE_NOT_RECRUITING	Radical Fimbriectomy for Young BRCA Mutation Carriers
NCT02087592	Not specified	COMPLETED	Feasibility of Lifestyle Intervention in BRCA1/2 Mutation Carriers
NCT02302742	Not specified	RECRUITING	Triple Negative Breast Cancer and Germline Hereditary Breast and Ovarian Cancer Mutation Carrier Registry
NCT02324062	Not specified	COMPLETED	Cancer Genetics Hereditary Cancer Panel Testing
NCT02516540	Not specified	UNKNOWN	Efficacy of Lifestyle Intervention in BRCA1/2 Mutation Carriers
NCT02653105	Not specified	ACTIVE_NOT_RECRUITING	Women at Risk of Breast Cancer and OLFM4
NCT02705924	Not specified	TERMINATED	Impact of a Psychoeducational Intervention on Expectations and Coping in Young Women Exposed to a High HBOC Risk
NCT02760849	Not specified	ACTIVE_NOT_RECRUITING	Surgery in Preventing Ovarian Cancer in Patients With Genetic Mutations
NCT02786147	Not specified	COMPLETED	Identification and Referral of Women at Risk for Hereditary Breast/Ovarian Cancer
NCT02956681	Not specified	COMPLETED	Statewide Communication to Reach Diverse Low Income Women
NCT03015376	Not specified	UNKNOWN	Inherited Susceptible Genes Among Epithelial Ovarian Cancer
NCT03050268	Not specified	RECRUITING	Familial Investigations of Childhood Cancer Predisposition
NCT03075540	Not specified	COMPLETED	Enhancing At-risk Latina Women’s Use of Genetic Counseling for Hereditary Breast and Ovarian Cancer
NCT03124212	Not specified	RECRUITING	Cascade Genetic Testing for Hereditary Breast/Ovarian Cancer and Lynch Syndrome in Switzerland
NCT03246841	Not specified	ACTIVE_NOT_RECRUITING	Investigation of Tumour Spectrum of Germline Mutations in Breast and Ovarian Cancer Genes.
NCT03294343	Not specified	UNKNOWN	Risk-Reducing Surgeries for Hereditary Ovarian Cancer
NCT03421327	Not specified	COMPLETED	Genetic Risk: Whether, When, and How to Tell Adolescents
NCT03510689	Not specified	COMPLETED	Genetics and Heart Health After Cancer Therapy
NCT03511690	Not specified	COMPLETED	Testing an Intelligent Tutoring System to Enhance Genetic Risk Assessment
NCT03784859	Not specified	COMPLETED	Tissue Expansion in Breast Reconstruction Without Drains
NCT03979612	Not specified	UNKNOWN	Evaluation of the Adhesion to the GENEPY Network
NCT04197856	Not specified	ACTIVE_NOT_RECRUITING	Direct Information to At-risk Relatives
NCT04407611	Not specified	COMPLETED	Scalable Communication Modalities for Returning Genetic Research Results
NCT04508764	Not specified	TERMINATED	Implementation of the Families Accelerating Cascade Testing Toolkit (FACTT) for Hereditary Breast and Ovarian Cancer and Lynch Syndrome