ZBTB18

Chr 1

zinc finger and BTB domain containing 18

Also known as: C1DELq42q44, C1DELq43q44, C2H2-171, DEL1Q42Q44, DEL1Q43Q44, MRD22, RP58, TAZ-1

NCBI Gene: 10472 ENSG00000179456 UniProt: Q99592

The protein is a C2H2-type zinc finger transcriptional repressor that recognizes specific DNA sequence motifs and recruits chromatin components to repress genes involved in neuronal development. Mutations cause intellectual developmental disorder, autosomal dominant 22 through a loss-of-function mechanism. The condition follows autosomal dominant inheritance.

ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a C2H2-type zinc finger protein which acts a transcriptional repressor of genes involved in neuronal development. The encoded protein recognizes a specific sequence motif and recruits components of chromatin to target genes. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2013]

ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.18

Clinical Summary— ZBTB18

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Gene-Disease Validity (ClinGen)

complex neurodevelopmental disorder · 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

77 unique Pathogenic / Likely Pathogenic· 157 VUS of 374 total submissions

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

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.18LOEUF

pLI 0.997

Z-score 3.79

OE 0.00 (0.00–0.18)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

3.43Z-score

OE missense 0.46 (0.41–0.53)

150 obs / 323.7 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.18)

0≤0.351.4

Missense OE?0.46 (0.41–0.53)

0≤0.61.4

Synonymous OE?1.03

0≤1.21.6

LoF obs/exp: 0 / 16.7Missense obs/exp: 150 / 323.7Syn Z: -0.31

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveZBTB18-related intellectual developmental disorderLOFAD

This gene — mechanism propensity

0.2898th %ile

GOF

0.3094th %ile

LOF

0.82top 5%

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

LOFprediction above median · 1 literature citation · 62% of P/LP variants are LoF · LOEUF 0.18 · ClinGen HI: Sufficient evidence for dosage pathogenicity

Literature Evidence

LOFHere we provide additional evidence for haploinsufficiency or dysfunction of the ZBTB18 gene as the cause of ID in five unrelated patients with variable syndromic features who underwent whole exome sequencing revealing separate de novo pathogenic or likely pathogenic variants in ZBTB18 (two missense1

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 27598823 ↗

ClinVar Variant Classifications

374 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic38

Likely Pathogenic39

VUS157

Likely Benign101

Benign16

Conflicting14

Pathogenic

Likely Pathogenic

157

VUS

101

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	33	4	1	0	38
Likely Pathogenic	15	24	0	0	39
VUS	3	152	1	1	157
Likely Benign	0	13	1	87	101
Benign	0	13	0	3	16
Conflicting	—				14
Total	51	206	3	91	365

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

View in ClinVar →

91 pathogenic / likely-pathogenic (of 104) ClinVar copy-number / structural variants overlap ZBTB18 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →