CTNNB1

Chr 3

catenin beta 1

Also known as: CTNNB, EVR7, MRD19, NEDSDV, armadillo

NCBI Gene: 1499 ENSG00000168036 UniProt: P35222

This protein functions in cell adhesion by constituting adherens junctions necessary for epithelial cell layer formation, anchoring the actin cytoskeleton, and transmitting contact inhibition signals to regulate cell division. Autosomal dominant loss-of-function mutations cause a neurodevelopmental disorder with spastic diplegia and visual defects, as well as exudative vitreoretinopathy. The protein is extremely intolerant to loss-of-function variants, with somatic mutations also associated with various cancers including medulloblastoma.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

The protein encoded by this gene is part of a complex of proteins that constitute adherens junctions (AJs). AJs are necessary for the creation and maintenance of epithelial cell layers by regulating cell growth and adhesion between cells. The encoded protein also anchors the actin cytoskeleton and may be responsible for transmitting the contact inhibition signal that causes cells to stop dividing once the epithelial sheet is complete. Finally, this protein binds to the product of the APC gene, which is mutated in adenomatous polyposis of the colon. Mutations in this gene are a cause of colorectal cancer (CRC), pilomatrixoma (PTR), medulloblastoma (MDB), and ovarian cancer. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2016]

GeneReviews ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.13

Clinical Summary— CTNNB1

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Gene-Disease Validity (ClinGen)

CTNNB1-related neurodevelopmental disorder and/or vitreoretinopathy · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

245 unique Pathogenic / Likely Pathogenic· 325 VUS of 971 total submissions

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Clinical Trials

12 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — CTNNB1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.13LOEUF

pLI 1.000

Z-score 5.46

OE 0.03 (0.01–0.13)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

3.85Z-score

OE missense 0.47 (0.42–0.53)

199 obs / 421.1 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.03 (0.01–0.13)

0≤0.351.4

Missense OE?0.47 (0.42–0.53)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

LoF obs/exp: 1 / 36.7Missense obs/exp: 199 / 421.1Syn Z: 0.14

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveCTNNB1-related exudative vitreoretinopathyLOFAD

definitiveCTNNB1-related intellectual developmental disorderLOFAD

This gene — mechanism propensity

0.4784th %ile

GOF

0.7028th %ile

LOF

0.88top 5%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · 84% of P/LP variants are LoF · LOEUF 0.13 · ClinGen HI: Sufficient evidence for dosage pathogenicity

GOFprediction above median · 1 literature citation

DN1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNThe batface mutant expresses a unique phenotype that is a combined consequence not only of a gain in WNT-related function (15), but also, as we show here, a dominant-negative effect on adhesion-related function.1

GOFFinally, in a few MODY3 patients with HNF1A germline mutation leading to amino acid substitutions outside the POU-H domain, we identified a different subtype of HCA either with a gp130 and/or CTNNB1 activating mutation.2

LOFA new intellectual disability syndrome caused by CTNNB1 haploinsufficiency.3

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

ClinVar Variant Classifications

971 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic176

Likely Pathogenic69

VUS325

Likely Benign307

Benign24

Conflicting16

176

Pathogenic

Likely Pathogenic

325

VUS

307

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	165	6	4	1	176
Likely Pathogenic	40	23	6	0	69
VUS	4	301	15	5	325
Likely Benign	0	8	145	154	307
Benign	0	0	16	8	24
Conflicting	—				16
Total	209	338	186	168	917

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

11 pathogenic / likely-pathogenic (of 12) ClinVar copy-number / structural variants overlap CTNNB1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →

Protein Context — Lollipop Plot

CTNNB1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

External Resources

Links to major genomics databases and tools

Franklin by Genoox

AI-powered variant curation and clinical analysis

DECIPHER

Genomic variants and phenotypes in rare disease patients

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GeneReview available — CTNNB1

Authoritative clinical overview · NCBI Bookshelf · Recommended first read

Open GeneReview ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

Colorectal Cancer

ASPirin Intervention for the REDuction of Colorectal Cancer Risk

ACTIVE NOT RECRUITING

NCT02394769Phase NAMassachusetts General HospitalStarted 2015-07-06

AspirinPlacebo for Aspirin

Gastric CancerHealthy

Preliminary Experimental Study on Key Technologies for Early Screening of Gastric Cancer

RECRUITING

NCT05991947Zhejiang Cancer HospitalStarted 2021-03-01

No intervention

Aggressive Fibromatosis

National Clinical-biological Prospective Cohort of Incident Cases of Aggressive Fibromatosis (ALTITUDES)

ACTIVE NOT RECRUITING

NCT02867033Phase NACentre Oscar LambretStarted 2016-03-22

biopsybiobank constitutionColoscopy

Post Traumatic Stress DisorderComplex Posttraumatic Stress DisorderStress

Building Resilience at Schools: Emotional and Biological Assessment and Treatment of Traumatic Stress

RECRUITING

NCT05701111Phase NAStanford UniversityStarted 2024-02-23

Start with the Heart StudentsStart with the Heart TeachersCue Centered Therapy Counselors

CTNNB1 Neurodevelopmental Syndrome

CTNNB1 Neurodevelopmental Syndrome - Natural History Study

RECRUITING

NCT07167732University Medical Centre LjubljanaStarted 2024-06-14

A General Medical and Neurological AssessmentWorld Health Organisation (WHO) Motor MilestonesBurke-Fahn-Marsden Dystonia Rating Scale

16P11.2 Deletion Syndrome16p11.2 Duplications1Q21.1 Deletion

Online Study of People Who Have Genetic Changes and Features of Autism: Simons Searchlight

RECRUITING

NCT01238250Simons SearchlightStarted 2010-10

CTNNB1 Neurodevelopmental Syndrome

Gene Replacement Therapy for Treatment of Paediatric Patients With CTNNB1 Neurodevelopmental Syndrome

RECRUITING

NCT07270549Phase PHASE1, PHASE2CTNNB1 FoundationStarted 2025-11-01

Urbagen gene addition therapySirolimusMethylprednisolone (Corticosteroid)

CTNNB1L-DOPA

Study of L-dopa Treatment in Patients With a Neurodevelopmental Disorder (CTNNB1 Gene)

RECRUITING

NCT07614126Phase NAUniversity Hospital, MontpellierStarted 2026-04-08

L-Dopa

Advanced Hepatocellular CarcinomaMetastatic Hepatocellular Carcinoma

A Study to Evaluate ALN-BCAT in Patients With Hepatocellular Carcinoma

RECRUITING

NCT06600321Phase PHASE1Alnylam PharmaceuticalsStarted 2024-12-30

ALN-BCATPembrolizumab

Advanced Hepatocellular CarcinomaMetastatic Hepatocellular CarcinomaStage III Hepatocellular Carcinoma AJCC v8

Testing the Addition of an Anti-cancer Drug, Sapanisertib, to the Usual Chemotherapy Treatment (Cabozantinib) in Metastatic Liver Cell Cancer With a Change in Genes for the Protein β-Catenin, The SAPHIRE Trial

RECRUITING

NCT06811116Phase PHASE1, PHASE2National Cancer Institute (NCI)Started 2025-11-17

Biospecimen CollectionCabozantinib S-malateImaging Procedure

Lung Cancer

Feasibility of Targeted Bronchial Washing for Molecular Testing by Next Generation Sequencing in Early-stage Lung Cancer

ACTIVE NOT RECRUITING

NCT06301295Phase NAPusan National University HospitalStarted 2024-05-29

Ultarthin bronchoscopy with intratumoral washing

Metastatic Colorectal Carcinoma (mCRC)Colorectal Cancer (CRC)Adenomatous Polyposis Coli (APC) Gene Mutation

Safety and Efficacy of Tegavivint in Patients With Metastatic Colorectal Carcinoma

RECRUITING

NCT07463599Phase PHASE1, PHASE2HonorHealth Research InstituteStarted 2026-02-17