CTNND2

Chr 5

catenin delta 2

Also known as: GT24, NPRAP

NCBI Gene: 1501 ENSG00000169862 UniProt: Q9UQB3 OMIM: 604275

The protein regulates dendritic spine and synapse formation in neurons, controls Wnt signaling through beta-catenin regulation, and functions in neuronal cell adhesion. Mutations cause autosomal recessive intellectual disability with severe speech delay, often accompanied by autism spectrum disorder and behavioral abnormalities. This gene is extremely intolerant to loss-of-function variants, indicating its critical role in neurodevelopment.

OMIM ResearchSummary from RefSeq, UniProt

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. [provided by RefSeq, Dec 2013]

OMIM ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.10

Clinical Summary— CTNND2

⚡

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.

📋

ClinVar Variants

15 unique Pathogenic / Likely Pathogenic· 164 VUS of 372 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.10LOEUF

pLI 1.000

Z-score 7.21

OE 0.03 (0.01–0.10)

Highly constrained

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

Missense Constraint?

2.77Z-score

OE missense 0.70 (0.65–0.76)

489 obs / 694.7 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.03 (0.01–0.10)

0≤0.351.4

Missense OE?0.70 (0.65–0.76)

0≤0.61.4

Synonymous OE?1.09

0≤1.21.6

LoF obs/exp: 2 / 64.4Missense obs/exp: 489 / 694.7Syn Z: -1.27

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongCTNND2-related neurodevelopmental disorderLOFAD

This gene — mechanism propensity

0.3892th %ile

GOF

0.4677th %ile

LOF

0.80top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 1 literature citation · 73% of P/LP variants are LoF · LOEUF 0.10

Literature Evidence

LOFTurner et al (2015) performed exome sequencing on 13 females with autism and identified 2 missense variants in the CTNND2 gene. To further explore variation in this gene, they sequenced CTNND2 in 362 additional autism families and identified 7 variants (additional observations of the original 2 miss1

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

References

1.PMID 25807484 ↗

ClinVar Variant Classifications

372 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4

Likely Pathogenic11

VUS164

Likely Benign88

Benign87

Conflicting8

Pathogenic

Likely Pathogenic

164

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	3	0	1	0	4
Likely Pathogenic	8	2	1	0	11
VUS	6	152	6	0	164
Likely Benign	0	26	39	23	88
Benign	1	5	71	10	87
Conflicting	—				8
Total	18	185	118	33	362

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

View in ClinVar →

105 pathogenic / likely-pathogenic (of 137) ClinVar copy-number / structural variants overlap CTNND2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →