ZBTB18

protein-coding

zinc finger and BTB domain containing 18, the group of Zinc fingers C2H2-type|BTB domain containing

Gene summary

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]

Previous symbols:

ZNF238

MANE transcript

NM_205768.3

Inheritance

ClinVar variants

P:84U:161B:122

Top phenotype

Intellectual developmental disorder, autosomal dominant 22

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr1:244,048,547-244,057,476

External References & Databases

Ensembl (ENSG00000179456)

Transcript & Mutation Effects

hg38 • Region Span ~8.9 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

intellectual disability, autosomal dominant 22DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012869

Submitter: G2P

complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

*ZBTB18* encodes a transcriptional repressor involved in various developmental processes, including brain development. *ZBTB18* was first reported in relation to autosomal dominant complex neurodevelopmental disorder in 2014 (de Munnik et al., PMID: 24193349). Phenotypic features include global developmental delay particularly affecting speech, intellectual disability, hypotonia, microcephaly, short stature, dysmorphic features, epilepsy, corpus callosum abnormalities, congenital anomalies, and behavioral abnormalities. Eleven variants (frameshift, nonsense, and missense) that have been reported in 12 probands in 7 publications (PMIDs: 23020937, 24193349, 26740508, 27598823, 28135719, 29573576, 31238879) are included in this curation. All variants occurred *de novo*. More evidence is available in the literature but the maximum score for genetic evidence (12 points) has been reached. Nonsense and frameshift variants lead to a premature termination codon in the last (second) exon and are not expected to result in nonsense-mediated decay. The majority of disease-associated missense variants are found within the C-terminal zinc finger DNA-binding region, which is essential for transcriptional regulation. The mechanism of pathogenicity for truncating variants appears to be loss of function. The mechanism of missense variants is not well elucidated but *in vitro* functional studies of two missense variants demonstrated impaired transcriptional repression for p.Asn461Ser and potentiation of gene transcription for p.Arg495Gly (PMID: 31112317). This gene-disease relationship is also supported by experimental evidence. *Zbtb18* heterozygous knockout mice exhibit impaired learning and memory, glutamatergic synaptic dysfunction, and corpus callosum defects (PMID: 36721027). In summary, there is definitive evidence supporting the relationship between *ZBTB18* and autosomal dominant complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally evaluated by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on December 14, 2023. It was reevaluated on May 22, 2026 (SOP Version 12). As a result of this reevaluation, the classification did not change.

intellectual disability, autosomal dominant 22STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012869

Submitter: PanelApp Australia

intellectual disability, autosomal dominant 22DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012869

Submitter: Illumina

intellectual disability, autosomal dominant 22STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012869

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Intellectual developmental disorder, autosomal dominant 22AD

Manifestation: Craniofacial; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 24193349

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ZBTB18 variants in ClinVar

12 Conditions Cataloged

not providedTotal: 260

Intellectual disability, autosomal dominant 22Total: 83

Inborn genetic diseasesTotal: 59

ZBTB18-related disorderTotal: 16

Intellectual disabilityTotal: 6

ZBTB18-related intellectual disabilityTotal: 2

not specifiedTotal: 2

Marfanoid habitus and intellectual disabilityTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_205768.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			1 clinvar	87 clinvar	3 clinvar	91
missense	2 clinvar	32 clinvar	154 clinvar	19 clinvar	13 clinvar	220
nonsense	13 clinvar	4 clinvar	2 clinvar			19
start loss						0
frameshift	22 clinvar	11 clinvar	2 clinvar			35
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	37	47	161	106	16	367

Highest pathogenic variant AF is 0.0000041046296

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 22 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_205768.3	RefSeq	NP_991331.1	2	MANE Select
ENST00000358704.4	Ensembl	ENSP00000351539.4	2	MANE Select
NM_001278196.2	RefSeq	NP_001265125.1	1	Standard
NM_001421566.1	RefSeq	NP_001408495.1	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

negative regulation of transcription by RNA polymerase II
cellular response to DNA damage stimulus
skeletal muscle tissue development
negative regulation of transcription, DNA-templated
positive regulation of transcription by RNA polymerase II

Molecular Function

DNA-binding transcription factor activity, RNA polymerase II-specific
DNA binding
DNA-binding transcription factor activity
transcription coactivator activity
protein binding

Cellular Component

nuclear chromosome
nucleus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000358704
Coding exons: 2
Length: 6194
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.43	150	324	0.463	0.0000194	3542
Missense (PolyPhen)		27	127.87	0.21116		1382
Synonymous	-0.314	146	141	1.03	0.0000102	1012
Loss of Function	3.79	0	16.7	0.00	9.79e-7	203

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Transcriptional repressor that plays a role in various developmental processes such as myogenesis and brain development. Plays a key role in myogenesis by directly repressing the expression of ID2 and ID3, 2 inhibitors of skeletal myogenesis. Also involved in controlling cell division of progenitor cells and regulating the survival of postmitotic cortical neurons. Specifically binds the consensus DNA sequence 5'- [AC]ACATCTG[GT][AC]-3' which contains the E box core, and acts by recruiting chromatin remodeling multiprotein complexes. May also play a role in the organization of chromosomes in the nucleus. {ECO:0000269|PubMed:9756912}.;

Recessive Scores

pRec: 0.121

Intolerance Scores

RVIS EVS: -0.78
RVIS percentile EVS: 12.77

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium