SPOP

Chr 17AD

speckle type BTB/POZ protein

Also known as: BTBD32, NEDMACE, NEDMIDF, NSDVS1, NSDVS2, TEF2

NCBI Gene: 8405ENSG00000121067UniProt: O43791

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]

Primary Disease Associations & Inheritance

Nabais Sa-de Vries syndrome, type 1MIM #618828
AD
Nabais Sa-de Vries syndrome, type 2MIM #618829
AD
239
ClinVar variants
23
Pathogenic / LP
1.00
pLI score· haploinsufficient
3
Active trials
Clinical Summary— SPOP
🧬
Gene-Disease Validity (ClinGen)
neurodevelopmental disorder with microcephaly and dysmorphic facies · ADModerate

Moderate evidence — consider for supplementary testing

2 total gene-disease associations curated

⚡
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.
📋
ClinVar Variants
23 Pathogenic / Likely Pathogenic· 199 VUS of 239 total submissions
💊
Clinical Trials
3 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.14LOEUF
pLI 0.999
Z-score 4.21
OE 0.00 (0.00–0.14)
Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
4.14Z-score
OE missense 0.21 (0.17–0.27)
46 obs / 218.1 exp
Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.00 (0.00–0.14)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.21 (0.17–0.27)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.11
0≤1.21.6
LoF obs/exp: 0 / 20.7Missense obs/exp: 46 / 218.1Syn Z: -0.77

ClinVar Variant Classifications

239 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic10
Likely Pathogenic13
VUS199
Likely Benign10
Benign1
Conflicting6
10
Pathogenic
13
Likely Pathogenic
199
VUS
10
Likely Benign
1
Benign
6
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
10
0
10
Likely Pathogenic
2
10
1
0
13
VUS
60
91
31
17
199
Likely Benign
0
2
1
7
10
Benign
0
0
1
0
1
Conflicting
—6
Total621034424239

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

View in ClinVar →

Protein Context — Lollipop Plot

SPOP · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

SPOP-related neurodevelopmental disorder, gain of function

strong
ADGain Of FunctionAltered Gene Product Structure
Dev. Disorders
G2P ↗

SPOP-related neurodevelopmental disorder, dominant negative

strong
ADDominant NegativeAltered Gene Product Structure
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Nabais Sa-de Vries syndrome, type 1

MIM #618828

Molecular basis of disorder known

Autosomal dominant

Nabais Sa-de Vries syndrome, type 2

MIM #618829

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
The Molecular Taxonomy of Primary Prostate Cancer.
Cancer Genome Atlas Research Network·Cell
2015
CircXRN2 suppresses tumor progression driven by histone lactylation through activating the Hippo pathway in human bladder cancer.
Xie B et al.·Mol Cancer
2023
Cyclin D-CDK4 kinase destabilizes PD-L1 via cullin 3-SPOP to control cancer immune surveillance.
Zhang J et al.·Nature
2018
Distinct structural classes of activating FOXA1 alterations in advanced prostate cancer.
Parolia A et al.·Nature
2019
SPOP Is a Key Trigger of Pathological Cardiac Hypertrophy and Heart Failure.
Wu H et al.·Circ Res
2025
Ubiquitination-directed cytosolic DNA degradation governs cGAS-STING-mediated immune response to DNA damage.
Li L et al.·Cancer Cell
2026
Prostate Cancer Transcriptomic Subtypes.
Spratt DE·Adv Exp Med Biol
2019Review
Prognostic and Predictive Role of SPOP Mutations in Prostate Cancer: A Systematic Review and Meta-analysis.
Pedrani M et al.·Eur Urol Oncol
2024Meta-analysis
Prostate Cancer-associated SPOP mutations enhance cancer cell survival and docetaxel resistance by upregulating Caprin1-dependent stress granule assembly.
Shi Q et al.·Mol Cancer
2019
ILF3 is a substrate of SPOP for regulating serine biosynthesis in colorectal cancer.
Li K et al.·Cell Res
2020
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Prostate CancerNeoadjuvant TherapyAndrogen Antagonists

Neoadjuvant Degarelix With or Without Apalutamide (ARN-509) Followed by Radical Prostatectomy

ACTIVE NOT RECRUITING
NCT03080116Phase PHASE2Universitaire Ziekenhuizen KU LeuvenStarted 2019-03-28
ARN-509DegarelixPlacebo
Castration-Resistant Prostate CarcinomaMetastatic Prostate AdenocarcinomaStage IVB Prostate Cancer AJCC v8

CJNJ-67652000 and Prednisone for Treatment of Metastatic Castration-Resistant Prostate Cancer and SPOP Gene Mutations

ACTIVE NOT RECRUITING
NCT05689021Phase PHASE2Mayo ClinicStarted 2024-03-05
Abiraterone Acetate/NiraparibBiospecimen CollectionBone Scan
Castration-Resistant Prostate CarcinomaMetastatic Castration-Resistant Prostate CarcinomaRefractory Prostate Carcinoma

Testing the Effect of M1774 on Hard-to-Treat Refractory SPOP-mutant Prostate Cancer

ACTIVE NOT RECRUITING
NCT05828082Phase PHASE2National Cancer Institute (NCI)Started 2023-10-16
Biopsy ProcedureBiospecimen CollectionComputed Tomography

External Resources

Links to major genomics databases and tools