CTNNBIP1

Chr 1

catenin beta interacting protein 1

Also known as: ICAT

NCBI Gene: 56998 ENSG00000178585 UniProt: Q9NSA3 OMIM: 607758

The protein negatively regulates the Wnt signaling pathway by binding to CTNNB1 (beta-catenin) and preventing its interaction with TCF family transcription factors. Mutations cause neurodevelopmental disorders with intellectual disability, developmental delay, and behavioral abnormalities including autism spectrum disorder features. The condition follows an autosomal dominant inheritance pattern.

OMIM ResearchSummary from RefSeq, UniProt

The protein encoded by this gene binds CTNNB1 and prevents interaction between CTNNB1 and TCF family members. The encoded protein is a negative regulator of the Wnt signaling pathway. Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.38

Clinical Summary— CTNNBIP1

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Population Constraint (gnomAD)

Low constraint (pLI 0.02) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

10 VUS of 15 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.38LOEUF

pLI 0.025

Z-score 0.99

OE 0.54 (0.25–1.38)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.53Z-score

OE missense 0.80 (0.62–1.03)

43 obs / 53.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.54 (0.25–1.38)

0≤0.351.4

Missense OE?0.80 (0.62–1.03)

0≤0.61.4

Synonymous OE?1.30

0≤1.21.6

LoF obs/exp: 3 / 5.5Missense obs/exp: 43 / 53.9Syn Z: -1.06

This gene — mechanism propensity

0.7036th %ile

GOF

0.84top 5%

LOF

0.2969th %ile

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

GOFprediction above median

DNprediction above median

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.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

15 submitted variants in ClinVar

ClinVar

Classification Summary

VUS10

VUS

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	10	10
Likely Benign	0	0
Benign	0	0
Total	10	10

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

View in ClinVar →

34 pathogenic / likely-pathogenic (of 45) ClinVar copy-number / structural variants overlap CTNNBIP1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →