ZMYND8

protein-coding

zinc finger MYND-type containing 8, the group of Zinc fingers MYND-type|PWWP domain containing|Bromodomain containing|PHD finger proteins

Gene summary

The protein encoded by this gene is a receptor for activated C-kinase (RACK) protein. The encoded protein has been shown to bind in vitro to activated protein kinase C beta I. In addition, this protein is a cutaneous T-cell lymphoma-associated antigen. Finally, the protein contains a bromodomain and two zinc fingers, and is thought to be a transcriptional regulator. Multiple transcript variants encoding several different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

Previous symbols:

PRKCBP1

MANE transcript

NM_001281775.3

Inheritance

ClinVar variants

P:7U:174B:27

Top phenotype

syndromic complex neurodevelopmental disorder

gnomAD constraint

pLI —, LoF o/e 0.05

Max pathogenic AF

—

Genomic locus

chr20:47,209,214-47,356,889

External References & Databases

Ensembl (ENSG00000101040)

Transcript & Mutation Effects

hg38 • Region Span ~147.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurodevelopmental disorderMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: G2P

syndromic complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0800439

Submitter: ClinGen

*ZMYND8* encodes a multidomain protein that is part of an extensive network of protein-protein interactions involved in transcription regulation, chromatin remodeling, super-enhancer regulation, DNA damage response, and tumor suppression. *ZMYND8* was first reported in relation to autosomal dominant syndromic complex neurodevelopmental disorder in 2022 (Dias et al., PMID: 35916866). Most affected individuals present with mild to moderate intellectual disability, language deficits, variable dysmorphic facial features, congenital cardiac defects, skeletal anomalies, and hearing or visual impairment (PMID: 35916866). Other more variable features include autism spectrum disorder or autistic behavior, seizures, poor growth, and respiratory tract anomalies. Thirteen variants (8 missense, 4 frameshift, and 1 nonsense) reported in 15 probands in five publications (PMIDs: 31981491, 32530565, 33057194, 35916866, 35982159) are included in this curation. All the variants with available parental information were *de novo*. The mechanism of pathogenicity is reported to be dominant negative for missense variants and loss of function for truncating variants (PMID: 35916866). All missense variants were located in functional domains or motifs; four variants were shown to affect the interaction with the neuronal actin-binding protein drebrin or with the NuRD complex subunit GATAD2A (PMID: 35916866). This gene-disease relationship is also supported by a *Drosophila* model with neuronal knockdown of *Zmynd8* that exhibits decreased habituation learning (PMID: 35916866). In summary, there is definitive evidence supporting the relationship between *ZMYND8* and autosomal dominant syndromic 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 February 19, 2025 (SOP Version 11). It was reevaluated on March 9, 2026. As a result of this reevaluation, the classification changed from strong to definitive as three years have passed from the original discovery publication date. Since no changes were made to the evidence or scoring, the SOP version remains 11.

neurodevelopmental disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: PanelApp Australia

autism spectrum disorderLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0005258

Submitter: Ambry Genetics

neurodevelopmental disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: Ambry Genetics

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ZMYND8 variants in ClinVar

8 Conditions Cataloged

not specifiedTotal: 115

not providedTotal: 78

ZMYND8-related disorderTotal: 10

Neurodevelopmental disorderTotal: 5

ZMYND8-related neurodevelopmental disorderTotal: 2

Intellectual disabilityTotal: 2

ZMYND8-associated neurodevelopmental disorderTotal: 1

See casesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001281775.3. 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			4 clinvar	11 clinvar	2 clinvar	17
missense		3 clinvar	151 clinvar	13 clinvar	1 clinvar	168
nonsense	1 clinvar		6 clinvar			7
start loss						0
frameshift	1 clinvar	2 clinvar	5 clinvar			8
splice donor/acceptor (+/-2bp)			8 clinvar			8
Total	2	5	174	24	3	208

Highest pathogenic variant AF is 0.0000013681089

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 94 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001281775.3	RefSeq	NP_001268704.1	23	MANE Select
ENST00000471951.7	Ensembl	ENSP00000420095.2	23	MANE Select
NM_001281769.2	RefSeq	NP_001268698.1	4	Standard
NM_001281771.3	RefSeq	NP_001268700.1	21	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

regulation of transcription, DNA-templated
negative regulation of cell migration
positive regulation of filopodium assembly
positive regulation of dendritic spine development
modulation of excitatory postsynaptic potential

Molecular Function

transcription corepressor activity
protein binding
zinc ion binding
protein domain specific binding
methylated histone binding

Cellular Component

nucleus
cytoplasm
dendritic spine
dendritic shaft

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000461685
Coding exons: 23
Length: 147709
Individuals with no LoFs: 125737
Homozygous LoFs: 0
Heterozygous LoFs: 10
Defined: 125747
p: 0.0000398

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	4.04	399	700	0.570	0.0000419	7862
Missense (PolyPhen)		80	234.01	0.34187		2776
Synonymous	-0.387	294	286	1.03	0.0000204	2207
Loss of Function	6.77	3	59.2	0.0507	0.00000285	719

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	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000045	0.000044	rare
South Asian	0.000098	0.000098	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May act as a transcriptional corepressor for KDM5D. Required for KDM5D-mediated down-regulation of diverse metastasis- associated genes; the function seems to involve the recognition of the dual histone signature H3K4me1-H3K14ac. Suppresses prostate cancer cell invasion. {ECO:0000269|PubMed:27477906}.;

Recessive Scores

pRec: 0.116

Intolerance Scores

LoFtool: 0.0152
RVIS EVS: -1.44
RVIS percentile EVS: 3.98

Essentials

Essential (CRISPR): E
Essential (CRISPR2): S
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.999

Gene Damage Prediction

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