SPOP
protein-codingspeckle type BTB/POZ protein, the group of BTB domain containing
Gene summary
This gene encodes a protein that may modulate the transcriptional repression activities of death-associated protein 6 (DAXX), which interacts with histone deacetylase, core histones, and other histone-associated proteins. In mouse, the encoded protein binds to the putative leucine zipper domain of macroH2A1.2, a variant H2A histone that is enriched on inactivated X chromosomes. The BTB/POZ domain of this protein has been shown in other proteins to mediate transcriptional repression and to interact with components of histone deacetylase co-repressor complexes. Alternative splicing of this gene results in multiple transcript variants encoding the same protein. [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~79.3 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0032943
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0032942
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0032942
Submitter: ClinGen
*SPOP* is located on chromosome 17q21.33 and encodes Speckle-type BTB/POZ protein which forms homodimers and is involved in the ubiquitin proteasome pathway (Nabais Sa et al., 2020, PMID: 32109420). *SPOP* was first reported in relation to neurodevelopmental disorder with microcephaly and dysmorphic facies, MONDO:0032942 and neurodevelopmental disorder with relative macrocephaly and with or without cardiac or endocrine anomalies, MONDO:0032943 in 2020 (PMID: 32109420) and has a previously well-established role in cancer. Per criteria outlined by the ClinGen Lumping and Splitting Working group, while there was no difference in inheritance patterns, there were differences in molecular mechanisms and slightly differing clinical presentations for each disorder. Variants resulting in neurodevelopmental disorder with microcephaly and dysmorphic facies were found to cause disease through a gain of function mechanism and those that cause neurodevelopmental disorder with relative macrocephaly and with or without cardiac or endocrine anomalies (MONDO:0032943) cause disease through a dominant negative mechanism (PMID: 32109420). Therefore, the disease entities have been split into two. The curation for neurodevelopmental disorder with relative macrocephaly and with or without cardiac or endocrine anomalies (MONDO:0032943) has been curated separately. Neurodevelopmental disorder with microcephaly and dysmorphic facies, MONDO:0032942 is characterised by microcephaly, intellectual disability of variable severity and consistent dysmorphic features including small forehead, full nasal tip, highly arched eyebrows and a pointed chin (PMID: 32109420). 5 variants (4 missense, 1 truncating) have been reported in 5 cases across 4 publications (PMIDs: 32109420, 35892095, 36063898, 39918173) and are included in this curation. The mechanism of pathogenicity is reported to be gain of function (PMID: 32109420). This gene-disease relationship is supported by experimental evidence (biochemical function, protein interaction and functional alteration in patient cells and cell lines) (PMID: 19818702, 32109420). Other genes involved in the ubiquitin proteasome pathway (*CUL3*, *CUL7*, *CUL4B*, *UBR1*, *UBE3B*) are strongly or definitively associated with neurodevelopmental or syndromic disorders. *SPOP* interacts on a protein level with *CUL3*. *SPOP* has a MATH domain which binds substrate to be tagged for degradation and binds *CUL3* via a BTB domain (PMID: 19818708, 14528312). Cellular models in patient cells demonstrated variants acted through a gain of function mechanism with increased degradation of substrate resulting in reduced substrate amount in cells (PMID: 32109420, 28805821). In summary there is moderate evidence to support this gene-disease relationship.. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Syndromic Disorders Gene Curation Expert Panel on the meeting date November 11th, 2025 (SOP Version 11).
Inheritance Pattern: AD
Disease ID:MONDO:0032942
Submitter: Illumina
Inheritance Pattern: AD
Disease ID:MONDO:0032943
Submitter: ClinGen
*SPOP* is located on chromosome 17q21.33 and encodes Speckle-type BTB/POZ protein which forms homodimers and is involved in the ubiquitin proteasome pathway (Nabais Sa et al., 2020, PMID: 32109420). *SPOP* was first reported in relation to neurodevelopmental disorder with microcephaly and dysmorphic facies, MONDO:0032942 and neurodevelopmental disorder with relative macrocephaly and with or without cardiac or endocrine anomalies, MONDO:0032943 in 2020 (PMID: 32109420) and has a previously well-established role in cancer. Per criteria outlined by the ClinGen Lumping and Splitting Working group, while there was no difference in inheritance patterns, there were differences in molecular mechanisms and slightly differing clinical presentations for each disorder. Variants resulting in neurodevelopmental disorder with microcephaly and dysmorphic facies were found to cause disease through a gain of function mechanism and those that cause neurodevelopmental disorder with relative macrocephaly and with or without cardiac or endocrine anomalies, MONDO:0032943 cause disease through a dominant negative mechanism (PMID: 32109420). Therefore, the disease entities have been split into two. The curation for neurodevelopmental disorder with microcephaly and dysmorphic facies has been curated separately. Neurodevelopmental disorder with relative macrocephaly and with or without cardiac or endocrine anomalies, MONDO:0032943 is characterised by macrocephaly, poor growth/short stature, mild to moderate intellectual disability and consistent dysmorphic features including high/broad forehead, hypertelorism and pointed chin (PMID: 32109420). Other features such as congenital cardiac disease and endocrine abnormalities such as hypothyroidism are variably present. 7 variants (all missense) have been reported in 13 cases across 2 publications (PMID: 32109420, 36259278), Clinvar (SCV001432745.2, SCV003852901.1, SCV006071201.1, SCV005091493.1, SCV001987200.2) and GeneDx internal data are included in this curation. Functional data was applied at the variant level from an assay where variants from patients were introduced into a cell line and demonstrated that these variants acted through a dominant negative mechanism with reduced degradation of substrate below heterozygous wild type resulting in increased substrate amount in cells (PMID: 32109420, 28805821). The mechanism of pathogenicity is reported to be dominant negative (PMID: 32109420). This gene-disease association is supported by experimental evidence (biochemical function and protein interaction) (PMID: 19818702, 32109420). Other genes involved in the ubiquitin proteasome pathway (*CUL3*, *CUL7*, *CUL4B*, *UBR1*, *UBE3B*) are strongly or definitively associated with neurodevelopmental or syndromic disorders. *SPOP* interacts on a protein level with *CUL3*. *SPOP* has a MATH domain which binds substrate to be tagged for degradation and binds *CUL3* via a BTB domain (PMID: 19818708, 14528312). In summary there is definitive evidence to support the relationship between *SPOP* and autosomal dominant neurodevelopmental disorder with relative macrocephaly and with or without cardiac or endocrine anomalies, MONDO:0032943. 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 Syndromic Disorders Gene Curation Expert Panel on December 4th, 2025 (SOP Version 11).
Inheritance Pattern: AD
Disease ID:MONDO:0032942
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0032942
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0700092
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular; Craniofacial; Endocrine; Neurologic; Ophthalmologic
Intervention: Cardiovascular; Endocrine
Rationale: The condition can include structural cardiovascular anomalies, and awareness may allow early detection and management; Endocrine abnormalities, including hypothyroidism, have been described, and awareness may allow early detection and management
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to SPOP variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001007228.2. 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 | 18 | 9 | 27 | |||
| missense | 17 | 103 | 2 | 122 | ||
| nonsense | 6 | 1 | 7 | |||
| start loss | 0 | |||||
| frameshift | 1 | 57 | 58 | |||
| splice donor/acceptor (+/-2bp) | 1 | 8 | 9 | |||
| Total | 0 | 19 | 192 | 12 | 0 | 223 |
Highest pathogenic variant AF is 0.000002052197
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001007229.1 | 9 | MANE Select | |
| Ensembl | ENSP00000425905.1 | 9 | MANE Select | |
| RefSeq | NP_001007227.1 | 9 | Standard | |
| RefSeq | NP_001007228.1 | 9 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| spop | Danio rerio | Structure: whole organism Quality: decreased size abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Hedgehog signaling pathway - Homo sapiens (human)
- HH-Ncore
- mRNA Processing
- Hedgehog Signaling Pathway
- Signal Transduction
Biological Process
- ubiquitin-dependent protein catabolic process
- protein ubiquitination
- regulation of proteolysis
- proteasome-mediated ubiquitin-dependent protein catabolic process
Molecular Function
- protein binding
- ubiquitin protein ligase binding
Cellular Component
- nucleus
- nucleoplasm
- cytoplasm
- nuclear speck
- Cul3-RING ubiquitin ligase complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000393331
- Coding exons
- 9
- Length
- 79351
- 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 | 4.14 | 46 | 218 | 0.211 | 0.0000124 | 2474 |
| Missense (PolyPhen) | 7 | 80.132 | 0.087356 | 967 | ||
| Synonymous | -0.770 | 89 | 80.2 | 1.11 | 0.00000458 | 695 |
| Loss of Function | 4.21 | 0 | 20.7 | 0.00 | 0.00000102 | 248 |
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:
- Function
- FUNCTION: Component of a cullin-RING-based BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex that mediates the ubiquitination of target proteins, leading most often to their proteasomal degradation. In complex with CUL3, involved in ubiquitination and proteasomal degradation of BRMS1, DAXX, PDX1/IPF1, GLI2 and GLI3. In complex with CUL3, involved in ubiquitination of H2AFY and BMI1; this does not lead to their proteasomal degradation. Inhibits transcriptional activation of PDX1/IPF1 targets, such as insulin, by promoting PDX1/IPF1 degradation. The cullin-RING-based BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex containing homodimeric SPOP has higher ubiquitin ligase activity than the complex that contains the heterodimer formed by SPOP and SPOPL. {ECO:0000269|PubMed:14528312, ECO:0000269|PubMed:15897469, ECO:0000269|PubMed:16524876, ECO:0000269|PubMed:19818708, ECO:0000269|PubMed:22085717, ECO:0000269|PubMed:22632832}.;
Recessive Scores
- pRec
- 0.186
Intolerance Scores
- RVIS EVS
- -0.19
- RVIS percentile EVS
- 39.68
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- S
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.993
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |