CTNNBL1

Summary

CTNNBL1 (catenin beta like 1, HGNC:15879) is a protein-coding gene on chromosome 20q11.23, encoding Beta-catenin-like protein 1 (Q8WYA6). Component of the PRP19-CDC5L complex that forms an integral part of the spliceosome and is required for activating pre-mRNA splicing. It is a common-essential gene (DepMap: required in 94.1% of cancer cell lines).

The protein encoded by this gene is a component of the pre-mRNA-processing factor 19-cell division cycle 5-like (PRP19-CDC5L) protein complex, which activates pre-mRNA splicing and is an integral part of the spliceosome. The encoded protein is also a nuclear localization sequence binding protein, and binds to activation-induced deaminase and is important for antibody diversification. This gene may also be associated with the development of obesity. Alternative splicing results in multiple transcript variants. A pseudogene of this gene has been defined on the X chromosome.

Source: NCBI Gene 56259 — RefSeq curated summary.

At a glance

• Gene–disease (curated): common variable immunodeficiency (Limited, ClinGen) — +1 more curated relationship
• GWAS associations: 5
• Clinical variants (ClinVar): 95 total
• Phenotypes (HPO): 13
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 94.1% of screened cell lines (common-essential)
• Transcription factor: yes — 31 downstream targets (CollecTRI)
• MANE Select transcript: NM_030877

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15879
Approved symbol	CTNNBL1
Name	catenin beta like 1
Location	20q11.23
Locus type	gene with protein product
Status	Approved
Aliases	FLJ21108, P14L, P14, NAP, NYD-SP19
Ensembl gene	ENSG00000132792
Ensembl biotype	protein_coding
OMIM	611537
Entrez	56259

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 8 protein_coding, 3 protein_coding_CDS_not_defined

ENST00000361383, ENST00000373469, ENST00000373473, ENST00000447935, ENST00000472237, ENST00000473857, ENST00000481674, ENST00000628103, ENST00000883421, ENST00000883422, ENST00000883423

RefSeq mRNA: 2 — MANE Select: NM_030877 NM_001281495, NM_030877

CCDS: CCDS13298, CCDS63269

Canonical transcript exons

ENST00000361383 — 16 exons

Exon	Start	End
ENSE00000661895	37737378	37737484
ENSE00000661897	37757559	37757656
ENSE00001381882	37746468	37746607
ENSE00001827583	37694030	37694152
ENSE00003477729	37840102	37840199
ENSE00003482938	37802867	37803048
ENSE00003503658	37732879	37733067
ENSE00003507293	37777345	37777417
ENSE00003509200	37859899	37860036
ENSE00003538513	37765197	37765290
ENSE00003539961	37842339	37842419
ENSE00003551229	37860272	37860344
ENSE00003610842	37777654	37777712
ENSE00003663829	37767953	37768044
ENSE00003672768	37779187	37779335
ENSE00003850668	37871925	37872118

Expression profiles

Bgee: expression breadth ubiquitous, 280 present calls, max score 95.54.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 41.0912 / max 1096.5614, expressed in 1819 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
184516	40.7762	1819
184515	0.1695	56
184525	0.0396	17
184526	0.0264	9
184527	0.0212	7
184519	0.0206	3
184522	0.0144	6
184523	0.0089	3
184518	0.0080	3
209104	0.0064	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left testis	UBERON:0004533	95.54	gold quality
right testis	UBERON:0004534	95.31	gold quality
spleen	UBERON:0002106	94.64	gold quality
testis	UBERON:0000473	94.25	gold quality
monocyte	CL:0000576	94.06	gold quality
ganglionic eminence	UBERON:0004023	93.98	gold quality
apex of heart	UBERON:0002098	93.76	gold quality
lower esophagus muscularis layer	UBERON:0035833	93.64	gold quality
leukocyte	CL:0000738	93.63	gold quality
lower esophagus	UBERON:0013473	93.63	gold quality
mononuclear cell	CL:0000842	93.59	gold quality
granulocyte	CL:0000094	93.34	gold quality
lower esophagus mucosa	UBERON:0035834	93.16	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	93.10	gold quality
ventricular zone	UBERON:0003053	92.86	gold quality
right atrium auricular region	UBERON:0006631	92.77	gold quality
muscle layer of sigmoid colon	UBERON:0035805	92.74	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	92.67	gold quality
tibial artery	UBERON:0007610	92.60	gold quality
popliteal artery	UBERON:0002250	92.59	gold quality
right lobe of liver	UBERON:0001114	92.53	gold quality
left uterine tube	UBERON:0001303	92.51	gold quality
cortical plate	UBERON:0005343	92.51	gold quality
body of stomach	UBERON:0001161	92.21	gold quality
mucosa of stomach	UBERON:0001199	91.91	gold quality
aorta	UBERON:0000947	91.87	gold quality
cardiac atrium	UBERON:0002081	91.86	gold quality
heart left ventricle	UBERON:0002084	91.68	gold quality
body of uterus	UBERON:0009853	91.64	gold quality
left coronary artery	UBERON:0001626	91.39	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-9067	yes	634.84
E-HCAD-6	yes	49.69
E-CURD-112	yes	9.56
E-GEOD-130148	yes	7.80
E-MTAB-9801	yes	6.15
E-MTAB-6678	no	3.65
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

31 targets.

Target	Regulation
APC
ATP9B
BASP1
BCL2
BIRC5
BRCA1
CCND1
CDH1
CDKN1A
CDKN1B
CDKN2A
CDKN2B
CDKN2B-AS1
CHEK2
CNTN2
DAPK1
EIF3K
FMN2
GSTP1
ITGA2B
KRAS
MDM2
MGMT
MLH1
NOTCH1
NR4A1
RARA
RUNX1T1
TAT
TSC1

miRNA regulators (miRDB)

8 targeting CTNNBL1, 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-4775	99.98	75.00	6394
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-1323	99.83	69.89	2471
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-4738-3P	98.98	67.98	1846
HSA-MIR-4661-5P	93.34	67.13	400

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 94.1% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 18)

• Study suggests a novel mechanism for the development of obesity, where CTNNBL1 may play an important role. (PMID:18325910)
• The results, therefore, identify residues in AID involved in its in vivo targeting and suggest they might act through interaction with CTNNBL1, giving possible insight into the linkage between AID recruitment and target-gene transcription. (PMID:18722174)
• We detected no confirmation of the recent association of variants in CTNNBL1 with obesity in a population of Central European ancestry (PMID:19228371)
• CTNNBL1 variants associated with body weight and height, and confer the risk of developing obesity (PMID:19245693)
• There was a significantly positive correlation between LMP1 expression and abnormal expression of beta-catenin in nasopharyngeal carcinoma tissue. (PMID:21055033)
• There are abnormal expression of beta-catenin and activation of Wnt signaling pathway in human esophageal carcinoma cell line Eca-109. (PMID:21215100)
• CTNNBL1 is a novel nuclear localization sequence-binding protein that recognizes RNA-splicing factors CDC5L and Prp31 (PMID:21385873)
• From this gene expression data and fMRI experiments suggests a role for the beta-catenin-like protein 1 in human episodic memory. (PMID:22105620)
• CTNNBL1 crystal structure provides critical insights into the molecular interactions between CTNNBL1 and its protein partners. (PMID:23897482)
• Results indicate CTNNBL1 as a unique selective nuclear localization signals (NLSs)-binding protein with striking differences from karyopherin-alphas. (PMID:24269683)
• The crystal structure of CTNNBL1 shows that the protein coalphansists mainly of alpha-helices and forms an armadillo (ARM) repeat. structure (PMID:24598747)
• Variants in the gene CTNNBL1 (encoding catenin-beta-like 1, located on chromosome 20 q11.23-q12) have been found to be associated with verbal episodic memory performance. (PMID:25268258)
• The results show that CTNNBL1 enhances the association of CWC15 and CDC5L, both core Prp19 complex proteins and identify an overlap in the region of CDC5L that binds either CTNNBL1 or CWC15 suggesting the two proteins might exchange places in the complex. (PMID:26130721)
• Tthis study identified WNT5B and CTNNBL1 for peak bone mineral density and body composition in males from the Han Chinese ethnic group. (PMID:26733379)
• CTNNBL1 regulates multiple splicing events and gene expression in ovarian cancer cells (PMID:28501461)
• Disease-associated CTNNBL1 mutation impairs somatic hypermutation by decreasing nuclear AID. (PMID:32484799)
• Transcriptional Regulation of Wnt/beta-Catenin Pathway in Colorectal Cancer. (PMID:32961708)
• Regulation of UV-B-Induced Inflammatory Mediators by Activity-Dependent Neuroprotective Protein (ADNP)-Derived Peptide (NAP) in Corneal Epithelium. (PMID:37108060)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ctnnbl1	ENSDARG00000011958
mus_musculus	Ctnnbl1	ENSMUSG00000027649
rattus_norvegicus	Ctnnbl1	ENSRNOG00000012021
drosophila_melanogaster	CG11964	FBGN0037644
caenorhabditis_elegans	ctnb-1	WBGENE00019711

Protein

Protein identifiers

Beta-catenin-like protein 1 — Q8WYA6 (reviewed: Q8WYA6)

Alternative names: Nuclear-associated protein, Testis development protein NYD-SP19

All UniProt accessions (2): Q8WYA6, A2A2P1

UniProt curated annotations — full annotation on UniProt →

Function. Component of the PRP19-CDC5L complex that forms an integral part of the spliceosome and is required for activating pre-mRNA splicing. Participates in AID/AICDA-mediated somatic hypermutation (SHM) and class-switch recombination (CSR), 2 processes resulting in the production of high-affinity, mutated isotype-switched antibodies.

Subunit / interactions. Component of the PRP19-CDC5L splicing complex composed of a core complex comprising a homotetramer of PRPF19, CDC5L, PLRG1 and BCAS2, and at least three less stably associated proteins CTNNBL1, CWC15 and HSPA8. Interacts directly with CWC15 and CDC5L in the complex. Interacts with AICDA; the interaction is important for the antibody diversification activity of AICDA. Interacts with PRPF31 (via its NLS). Interacts (via its N-terminal NLS) with KPNA1 and KPNA2.

Subcellular location. Nucleus Cytoplasm.

Tissue specificity. Widely expressed with highest levels in skeletal muscle, placenta, heart, spleen, testis and thyroid.

Disease relevance. Immunodeficiency 99 with hypogammaglobulinemia and autoimmune cytopenias (IMD99) [MIM:619846] An autosomal recessive immunologic disorder characterized by recurrent sinopulmonary infections appearing in early childhood, B- and T-cell lymphopenia, and progressive severe hypogammaglobulinemia with decreased memory B cells. Patients may develop autoimmune cytopenias, such as thrombocytopenia, or autoimmune features, such as vitiligo. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The surface residues of the concave side of the superhelical ARM repeat region contribute to, but are not essential for NLS binding.

Isoforms (4)

UniProt ID	Names	Canonical?
Q8WYA6-1	1	yes
Q8WYA6-2	2, NYD-SP19
Q8WYA6-3	3
Q8WYA6-4	4

RefSeq proteins (2): NP_001268424, NP_110517* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011989	ARM-like	Homologous_superfamily
IPR013180	CTNNBL1_N	Domain
IPR016024	ARM-type_fold	Homologous_superfamily
IPR039678	CTNNBL1	Family

Pfam: PF08216

UniProt features (70 total): helix 32, repeat 7, sequence conflict 5, modified residue 4, splice variant 4, turn 4, strand 4, short sequence motif 2, sequence variant 2, mutagenesis site 2, chain 1, compositionally biased region 1, region of interest 1, coiled-coil region 1

Structure

Experimental structures (PDB)

9 structures.

PDB	Method	Resolution (Å)
4MFU	X-RAY DIFFRACTION	2.74
4CB8	X-RAY DIFFRACTION	2.9
4HNM	X-RAY DIFFRACTION	2.9
4MFV	X-RAY DIFFRACTION	2.92
4CB9	X-RAY DIFFRACTION	3
4CBA	X-RAY DIFFRACTION	3.1
4HM9	X-RAY DIFFRACTION	3.1
7ABI	ELECTRON MICROSCOPY	8
9R8V	ELECTRON MICROSCOPY	8.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8WYA6-F1	86.95	0.79

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 (4): 1, 91, 389, 545

Mutagenesis-validated functional residues (2):

Position	Phenotype
16–33	nuclear and cytoplasmic localization.
521–563	no change in nls binding nor folding.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-72163	mRNA Splicing - Major Pathway
R-HSA-9918481	Dengue Virus-Host Interactions

MSigDB gene sets: 176 (showing top): OSWALD_HEMATOPOIETIC_STEM_CELL_IN_COLLAGEN_GEL_UP, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM4, BLALOCK_ALZHEIMERS_DISEASE_UP, GOBP_IMMUNOGLOBULIN_PRODUCTION, REACTOME_PROCESSING_OF_CAPPED_INTRON_CONTAINING_PRE_MRNA, GOBP_RNA_SPLICING, GOBP_SOMATIC_DIVERSIFICATION_OF_IMMUNE_RECEPTORS, GOBP_ADAPTIVE_IMMUNE_RESPONSE, REACTOME_MRNA_SPLICING, chr20q11, GRYDER_PAX3FOXO1_ENHANCERS_IN_TADS, IVANOVA_HEMATOPOIESIS_EARLY_PROGENITOR, GOBP_PRODUCTION_OF_MOLECULAR_MEDIATOR_OF_IMMUNE_RESPONSE, CHIANG_LIVER_CANCER_SUBCLASS_CTNNB1_UP, REACTOME_METABOLISM_OF_RNA

GO Biological Process (8): mRNA splicing, via spliceosome (GO:0000398), adaptive immune response (GO:0002250), somatic diversification of immunoglobulins (GO:0016445), positive regulation of apoptotic process (GO:0043065), immune system process (GO:0002376), mRNA processing (GO:0006397), RNA splicing (GO:0008380), gene expression (GO:0010467)

GO Molecular Function (2): enzyme binding (GO:0019899), protein binding (GO:0005515)

GO Cellular Component (8): Prp19 complex (GO:0000974), nucleus (GO:0005634), nucleoplasm (GO:0005654), spliceosomal complex (GO:0005681), centrosome (GO:0005813), cytosol (GO:0005829), membrane (GO:0016020), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
mRNA Splicing	1
Dengue Virus Infection	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
RNA processing	2
RNA splicing, via transesterification reactions with bulged adenosine as nucleophile	1
mRNA processing	1
immune response	1
somatic diversification of immune receptors	1
immunoglobulin production	1
apoptotic process	1
regulation of apoptotic process	1
positive regulation of programmed cell death	1
biological_process	1
mRNA metabolic process	1
macromolecule biosynthetic process	1
protein binding	1
binding	1
protein-containing complex	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
nuclear protein-containing complex	1
ribonucleoprotein complex	1
centriole	1
microtubule organizing center	1
cytoplasm	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1944 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CTNNBL1	CDC5L	Q99459	966
CTNNBL1	PRPF19	Q9UMS4	932
CTNNBL1	CWC15	Q9P013	918
CTNNBL1	BCAS2	O75934	905
CTNNBL1	HSPA8	P11142	861
CTNNBL1	AICDA	Q9GZX7	804
CTNNBL1	PLRG1	O43660	747
CTNNBL1	PTBP2	Q9UKA9	606
CTNNBL1	SUPT5H	O00267	584
CTNNBL1	MCM3AP	O60318	558
CTNNBL1	PRPF31	Q8WWY3	534
CTNNBL1	CTNNB1	P35222	499
CTNNBL1	MC4R	P32245	452
CTNNBL1	FTO	Q9C0B1	430
CTNNBL1	PSIP1	O75475	425

IntAct

119 interactions, top by confidence:

A	B	Type	Score
CDC5L	PLRG1	psi-mi:“MI:0915”(physical association)	0.860
CTNNBL1	CWC15	psi-mi:“MI:0407”(direct interaction)	0.850
CWC15	CTNNBL1	psi-mi:“MI:0915”(physical association)	0.850
CWC15	CTNNBL1	psi-mi:“MI:0914”(association)	0.850
KIF3A	KIF3B	psi-mi:“MI:0914”(association)	0.840
CDC5L	CTNNBL1	psi-mi:“MI:0915”(physical association)	0.810
CTNNBL1	CDC5L	psi-mi:“MI:0407”(direct interaction)	0.810
BCAS2	PLRG1	psi-mi:“MI:0914”(association)	0.790
PRPF19	AQR	psi-mi:“MI:0914”(association)	0.790
PRPF19	PLRG1	psi-mi:“MI:0914”(association)	0.770
ZNF394	SCAND1	psi-mi:“MI:0914”(association)	0.740
CDC5L	HSPA8	psi-mi:“MI:0915”(physical association)	0.710
CTNNBL1	LDOC1	psi-mi:“MI:0915”(physical association)	0.670
CDCA7L	CTNNBL1	psi-mi:“MI:0915”(physical association)	0.670
LDOC1	CTNNBL1	psi-mi:“MI:0915”(physical association)	0.670
CTNNBL1	CDCA7L	psi-mi:“MI:0915”(physical association)	0.670
KPNA1	TCERG1	psi-mi:“MI:0914”(association)	0.640
CATIP	CTNNBL1	psi-mi:“MI:0915”(physical association)	0.560
MEOX2	CTNNBL1	psi-mi:“MI:0915”(physical association)	0.560
CTNNBL1	BEX3	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (283): CTNNBL1 (Two-hybrid), CTNNBL1 (Two-hybrid), CTNNBL1 (Two-hybrid), CTNNBL1 (Two-hybrid), CTNNBL1 (Two-hybrid), CTNNBL1 (Two-hybrid), CREBZF (Two-hybrid), CATIP (Two-hybrid), CTNNBL1 (Co-crystal Structure), CTNNBL1 (Reconstituted Complex), CTNNBL1 (Reconstituted Complex), CTNNBL1 (Affinity Capture-MS), CTNNBL1 (Affinity Capture-MS), CTNNBL1 (Affinity Capture-MS), CTNNBL1 (Affinity Capture-MS)

ESM2 similar proteins: A7RWP6, B2RYZ5, B5FXZ4, B5FZ63, B5XC71, B5XGH3, O00232, O23948, O35427, O62703, P0C8Y1, P46824, P91926, Q0VFD6, Q29N38, Q2KJ25, Q3KPT5, Q3ZBJ0, Q40554, Q4H3N8, Q4V8K2, Q5R7L4, Q5RBI3, Q5RJU0, Q5U3V9, Q5U4M5, Q5ZLT7, Q60482, Q66HV4, Q6DDF4, Q6DH42, Q6P7P5, Q6PD83, Q7L1Q6, Q7QG73, Q7ZVK4, Q8BUR9, Q8VHM6, Q8WYA6, Q9C9Z8

Diamond homologs: O62703, Q4V8K2, Q8WYA6, Q9CWL8, Q9UUK1

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
CTNNBL1	“form complex”	PRP19-CDC5L	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 118 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
mRNA Splicing - Major Pathway	31	19.9×	4e-30
mRNA Splicing	15	19.4×	1e-13
Processing of Capped Intron-Containing Pre-mRNA	18	17.4×	2e-15
mRNA Polyadenylation	14	14.5×	5e-11
SARS-CoV-2 modulates host translation machinery	5	13.2×	2e-03
Dengue Virus-Host Interactions	19	10.2×	2e-12
Metabolism of RNA	20	9.8×	8e-13
CHD1 and CHD2 subfamily	7	9.0×	9e-04

GO biological processes:

GO term	Partners	Fold	FDR
U2-type prespliceosome assembly	5	28.1×	2e-04
mRNA splicing, via spliceosome	28	23.1×	7e-28
ribosomal small subunit biogenesis	5	10.3×	8e-03
RNA processing	5	9.9×	9e-03
RNA splicing	12	9.5×	2e-06
mRNA processing	10	7.1×	3e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	61
Likely benign	9
Benign	5

Top pathogenic / likely-pathogenic (0)

SpliceAI

3452 predictions. Top by Δscore:

Variant	Effect	Δscore
20:37732877:A:AG	acceptor_gain	1.0000
20:37732878:G:GA	acceptor_gain	1.0000
20:37732878:GC:G	acceptor_gain	1.0000
20:37732878:GCCC:G	acceptor_gain	1.0000
20:37732878:GCCCA:G	acceptor_gain	1.0000
20:37732999:G:GT	donor_gain	1.0000
20:37733056:G:GT	donor_gain	1.0000
20:37733062:G:GT	donor_gain	1.0000
20:37733063:AAGAG:A	donor_loss	1.0000
20:37733065:G:GT	donor_gain	1.0000
20:37733065:GAG:G	donor_gain	1.0000
20:37733067:GG:G	donor_loss	1.0000
20:37733068:G:GA	donor_loss	1.0000
20:37733069:T:A	donor_loss	1.0000
20:37737458:GAT:G	donor_gain	1.0000
20:37737480:GAGAA:G	donor_gain	1.0000
20:37737482:G:GT	donor_gain	1.0000
20:37737482:GAA:G	donor_gain	1.0000
20:37737485:G:GG	donor_gain	1.0000
20:37746463:CCTA:C	acceptor_loss	1.0000
20:37746464:CTA:C	acceptor_loss	1.0000
20:37746466:A:AC	acceptor_loss	1.0000
20:37746466:A:AG	acceptor_gain	1.0000
20:37746466:AG:A	acceptor_gain	1.0000
20:37746467:G:GG	acceptor_gain	1.0000
20:37746467:GG:G	acceptor_gain	1.0000
20:37746467:GGT:G	acceptor_gain	1.0000
20:37746467:GGTT:G	acceptor_gain	1.0000
20:37746467:GGTTC:G	acceptor_gain	1.0000
20:37746653:G:GT	donor_gain	1.0000

AlphaMissense

3764 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:37737418:T:C	L87P	1.000
20:37737446:C:A	N96K	1.000
20:37737446:C:G	N96K	1.000
20:37737457:G:C	R100P	1.000
20:37737462:A:G	K102E	1.000
20:37737464:G:C	K102N	1.000
20:37737464:G:T	K102N	1.000
20:37737465:T:C	F103L	1.000
20:37737467:T:A	F103L	1.000
20:37737467:T:G	F103L	1.000
20:37746469:T:C	F110L	1.000
20:37746470:T:C	F110S	1.000
20:37746471:C:A	F110L	1.000
20:37746471:C:G	F110L	1.000
20:37746491:T:C	L117P	1.000
20:37746524:C:A	A128D	1.000
20:37746603:T:A	N154K	1.000
20:37746603:T:G	N154K	1.000
20:37757586:T:C	L165P	1.000
20:37777684:G:A	G285E	1.000
20:37777699:T:A	L290H	1.000
20:37777699:T:C	L290P	1.000
20:37779193:A:G	K297E	1.000
20:37779195:A:C	K297N	1.000
20:37779195:A:T	K297N	1.000
20:37779242:T:C	L313P	1.000
20:37779244:T:C	F314L	1.000
20:37779246:T:A	F314L	1.000
20:37779246:T:G	F314L	1.000
20:37779293:T:C	F330S	1.000

dbSNP variants (sampled 300 via entrez): RS1000000123 (20:37841911 G>A), RS1000016523 (20:37776126 T>C,G), RS1000059623 (20:37708238 G>A), RS1000075110 (20:37831597 A>C), RS1000075800 (20:37762732 A>G), RS1000100155 (20:37848223 C>G,T), RS1000139725 (20:37853217 A>G), RS1000143586 (20:37744010 A>G), RS1000161851 (20:37701440 AAAG>A), RS1000185470 (20:37840545 C>T), RS1000199828 (20:37747416 C>G), RS1000231638 (20:37864872 C>T), RS1000239139 (20:37822127 G>T), RS1000239620 (20:37794833 T>A,C), RS1000246772 (20:37808374 A>G)

Disease associations

OMIM: gene MIM:611537 | disease phenotypes: MIM:619846, MIM:612952

GenCC curated gene-disease

Disease	Classification	Inheritance
immunodeficiency 99 with hypogammaglobulinemia and autoimmune cytopenias	Limited	Unknown

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
common variable immunodeficiency	Limited	AR

Mondo (3): immunodeficiency 99 with hypogammaglobulinemia and autoimmune cytopenias (MONDO:0030798), Aicardi-Goutieres syndrome 5 (MONDO:0013059), congenital disorder of glycosylation (MONDO:0015286)

Orphanet (2): Congenital disorder of glycosylation (Orphanet:137), Aicardi-Goutières syndrome (Orphanet:51)

HPO phenotypes

13 total (13 of 13 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001045	Vitiligo
HP:0001510	Growth delay
HP:0001888	Decreased total lymphocyte count
HP:0001973	Autoimmune thrombocytopenia
HP:0002716	Lymphadenopathy
HP:0002729	Follicular hyperplasia
HP:0004313	Decreased circulating immunoglobulin concentration
HP:0005424	Absent specific antibody response
HP:0005425	Recurrent sinopulmonary infections
HP:0011463	Childhood onset
HP:0020113	Decreased regulatory T cell proportion
HP:0030388	Decreased class-switched memory B cell proportion

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST000092_3	Bone mineral density	1.000000e-06
GCST009305_4	California verbal learning test score	5.000000e-06
GCST010989_158	Body size at age 10	2.000000e-09
GCST012047_18	Fasting glucose	4.000000e-07
GCST90012857_16	Falling risk	6.000000e-08

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004874	memory performance
EFO:0009819	comparative body size at age 10, self-reported

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D018981	Congenital Disorders of Glycosylation	C16.320.565.202.125; C18.452.648.202.125
C535608	Aicardi-Goutieres syndrome 5 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067346 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.37	Kd	4260	nM	CHEMBL5653589
5.28	ED50	5274	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 2 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148170: Binding affinity to human CTNNBL1 incubated for 45 mins by Kinobead based pull down assay	kd	4.2597	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, affects cotreatment, increases expression	2
Valproic Acid	affects expression, increases expression	2
FR900359	increases phosphorylation	1
bisphenol F	affects cotreatment, decreases expression	1
2,4,6-tribromophenol	decreases expression	1
decabromobiphenyl ether	decreases expression	1
sodium arsenite	affects cotreatment, increases abundance, increases expression	1
tetrabromobisphenol A	decreases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
2-amino-14,16-dimethyloctadecan-3-ol	decreases expression	1
(4-amino-1,4-dihydro-3-(2-pyridyl)-5-thioxo-1,2,4-triazole)copper(II)	increases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
LDN 193189	affects cotreatment, increases expression	1
(+)-JQ1 compound	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Temozolomide	decreases expression	1
Acetaminophen	increases expression	1
Arsenic	affects cotreatment, increases abundance, increases expression	1
Atrazine	increases expression	1
Benzo(a)pyrene	affects methylation	1
Dexamethasone	affects cotreatment, decreases expression	1
Dinitrochlorobenzene	affects binding	1
Indomethacin	affects cotreatment, decreases expression	1
Ivermectin	decreases expression	1
Lead	decreases expression	1
Manganese	increases expression, affects cotreatment, increases abundance	1
Phenolsulfonphthalein	affects cotreatment, increases expression	1
Phthalic Acids	increases methylation	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651212	Binding	Binding affinity to human CTNNBL1 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT07572825	PHASE1	NOT_YET_RECRUITING	Assessing the Safety and Tolerability of NMN in DHDDS-CDG
NCT02089789	Not specified	RECRUITING	Clinical and Basic Investigations Into Known and Suspected Congenital Disorders of Glycosylation
NCT02503267	Not specified	UNKNOWN	Incidence and Consequences of Disorders of Glycosylation in Patients With Conotruncal and Septal Heart Defects
NCT02955264	Not specified	COMPLETED	Using D-Galactose as a Food Supplement in Congenital Disorders of Glycosylation
NCT03250728	Not specified	COMPLETED	Role of the Endothelium in Stroke-like Episode Among CDG Patients
NCT03560570	Not specified	COMPLETED	Study of Hemostasis in Patients With Congenital Disorder of Glycosylation
NCT04198987	Not specified	COMPLETED	Dietary Monosaccharide Supplementation in Patients With Congenital Disorders of Glycosylation
NCT04199000	Not specified	RECRUITING	Clinical and Basic Investigations Into Congenital Disorders of Glycosylation
NCT04201067	Not specified	COMPLETED	Large-Scale Metabolomic Profiling for the Diagnosis of Inborn Errors of Metabolism