CTBP2

Chr 10

C-terminal binding protein 2

NCBI Gene: 1488 ENSG00000175029 UniProt: P56545

This gene encodes a transcriptional repressor and a synaptic ribbon component essential for specialized synapses, both containing NAD+ binding domains. Mutations cause autosomal recessive developmental and epileptic encephalopathy with onset in infancy, characterized by severe intellectual disability, seizures, and visual impairment. The gene shows moderate constraint against loss-of-function variants, suggesting some tolerance to complete gene loss.

ResearchSummary from RefSeq, UniProt

This gene produces alternative transcripts encoding two distinct proteins. One protein is a transcriptional repressor, while the other isoform is a major component of specialized synapses known as synaptic ribbons. Both proteins contain a NAD+ binding domain similar to NAD+-dependent 2-hydroxyacid dehydrogenases. A portion of the 3' untranslated region was used to map this gene to chromosome 21q21.3; however, it was noted that similar loci elsewhere in the genome are likely. Blast analysis shows that this gene is present on chromosome 10. Several transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Feb 2014]

ResearchGenerating clinical summary…

DNmechanismLOEUF 0.53

Clinical Summary— CTBP2

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.33) despite low pLI — interpret in context.

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ClinVar Variants

3 unique Pathogenic / Likely Pathogenic· 7 VUS of 81 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.53LOEUF

pLI 0.001

Z-score 3.79

OE 0.33 (0.21–0.53)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.06Z-score

OE missense 0.88 (0.82–0.95)

581 obs / 657.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.33 (0.21–0.53)

0≤0.351.4

Missense OE?0.88 (0.82–0.95)

0≤0.61.4

Synonymous OE?1.08

0≤1.21.6

LoF obs/exp: 12 / 36.8Missense obs/exp: 581 / 657.4Syn Z: -1.07

This gene — mechanism propensity

0.6938th %ile

GOF

0.6249th %ile

LOF

0.4233th %ile

The highest-scoring mechanism for this gene is dominant-negative.

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

81 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic3

VUS7

Likely Benign31

Benign23

Pathogenic

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	3	0	0	3
Likely Pathogenic	0	0	0	0	0
VUS	2	5	0	0	7
Likely Benign	2	10	2	17	31
Benign	1	12	1	9	23
Total	5	30	3	26	64

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

View in ClinVar →

61 pathogenic / likely-pathogenic (of 68) ClinVar copy-number / structural variants overlap CTBP2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →