ZBTB11

protein-coding

zinc finger and BTB domain containing 11, the group of Zinc fingers C2H2-type|BTB domain containing

Gene summary

Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of DNA-templated transcription. Located in nucleoplasm. Implicated in autosomal recessive intellectual developmental disorder 69. [provided by Alliance of Genome Resources, Jul 2025]

MANE transcript

NM_014415.4

Inheritance

ClinVar variants

P:11U:130B:36

Top phenotype

Neurodevelopmental disorder with progressive movement abnormalities, cognitive decline, and brain abnormalities

gnomAD constraint

pLI —, LoF o/e 0.37

Max pathogenic AF

—

Genomic locus

chr3:101,648,889-101,677,135

External References & Databases

Ensembl (ENSG00000066422)

Transcript & Mutation Effects

hg38 • Region Span ~28.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

intellectual developmental disorder, autosomal recessive 69LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0032715

Submitter: Ambry Genetics

intellectual developmental disorder, autosomal recessive 69STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032715

Submitter: PanelApp Australia

intellectual developmental disorder, autosomal recessive 69STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032715

Submitter: Labcorp Genetics (formerly Invitae)

syndromic complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0800439

Submitter: ClinGen

*ZBTB11* was first reported in relation to autosomal recessive syndromic complex neurodevelopmental disorder in 1995 (Stromme et al., PMID: 7586637). The condition is regressive, with phenotypes usually presenting around three to five years of age and increasing in severity through life. Intellectual disability (ranging from mild to profound), along with other features, such as contractures, coordination problems, cataracts, and combined malonic and methylmalonic aciduria (CMAMMA) are common phenotypes across affected individuals. Nineteen variants (14 missense, 1 nonsense, and 4 small deletion/duplications leading to frameshift) that have been reported in 13 probands in four publications (PMIDs: 29893856, 31130284, 35104841, 38899514) are included in this curation. All de novo and unknown inheritance variants are within the C2H2 zinc finger domain. The mechanism of pathogenicity appears to be loss of function due to reduced binding to transcriptional targets (PMIDs: 35104841, 38355937). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease relationship is also supported by animal models and functional expression studies (PMID: 29893856). Other members of the ZBTB gene family (*ZBTB18, ZBTB20*) have previously been associated with intellectual disability and similar syndromic disorders (PMIDs: 24193349, 25017102), however intellectual disability and/or autism in these genes are associated with autosomal dominant inheritance. In summary, there is definitive evidence supporting the relationship between *ZBTB11* and autosomal recessive syndromic complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism GCEP on the meeting date June 2, 2026 (SOP Version 12).

intellectual developmental disorder, autosomal recessive 69STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032715

Submitter: G2P

Clinical Genomic Database (CGD)

Neurodevelopmental disorder with progressive movement abnormalities, cognitive decline, and brain abnormalitiesAR

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: 29893856

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ZBTB11 variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 116

not providedTotal: 44

Intellectual developmental disorder, autosomal recessive 69Total: 18

ZBTB11-related disorderTotal: 9

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_014415.4. 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				29 clinvar		29
missense	7 clinvar		118 clinvar	7 clinvar		132
nonsense	2 clinvar		5 clinvar			7
start loss						0
frameshift	2 clinvar		2 clinvar			4
splice donor/acceptor (+/-2bp)			5 clinvar			5
Total	11	0	130	36	0	177

Highest pathogenic variant AF is 0.000005580959

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 16 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_014415.4	RefSeq	NP_055230.2	11	MANE Select
ENST00000312938.5	Ensembl	ENSP00000326200.4	11	MANE Select
ENST00000461821.1	Ensembl	ENSP00000417369.1	2	Standard
ENST00000461821.2	Ensembl	ENSP00000417369.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

regulation of transcription by RNA polymerase II
biological_process

Molecular Function

DNA-binding transcription factor activity, RNA polymerase II-specific
molecular_function
DNA binding
metal ion binding

Cellular Component

nucleoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000312938
Coding exons: 11
Length: 28607
Individuals with no LoFs: 125709
Homozygous LoFs: 0
Heterozygous LoFs: 39
Defined: 125748
p: 0.000155

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.05	424	560	0.757	0.0000282	6858
Missense (PolyPhen)		149	255.03	0.58425		3058
Synonymous	-1.66	232	202	1.15	0.0000100	2003
Loss of Function	4.20	19	51.5	0.369	0.00000303	622

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000089	0.000087	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.00022	0.00022	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00021	0.00020	rare
South Asian	0.00016	0.00016	rare
Other	0.00017	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May be involved in transcriptional regulation.;

Recessive Scores

pRec: 0.126

Intolerance Scores

LoFtool: 0.641
RVIS EVS: -1.3
RVIS percentile EVS: 4.92

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.940

Gene Damage Prediction

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