SPOP

Chr 17

speckle type BTB/POZ protein

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

NCBI Gene: 8405 ENSG00000121067 UniProt: O43791

The SPOP protein functions as a component of a cullin-RING-based E3 ubiquitin ligase complex that targets specific proteins for degradation or regulation, playing essential roles in transcriptional regulation, DNA replication, and cell proliferation. Mutations cause Nabais Sa-de Vries syndrome types 1 and 2 with autosomal dominant inheritance. This gene is highly constrained against loss-of-function variation in the population, indicating that such mutations are likely to have significant clinical consequences.

ResearchSummary from RefSeq, OMIM, UniProt

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]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.14

Clinical Summary— SPOP

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Gene-Disease Validity (ClinGen)

neurodevelopmental disorder with microcephaly and dysmorphic facies · ADModerate

Moderate evidence — consider for supplementary testing

2 total gene-disease associations curated

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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.

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ClinVar Variants

12 unique Pathogenic / Likely Pathogenic· 198 VUS of 243 total submissions

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Clinical Trials

3 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

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?

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?

LoF OE?0.00 (0.00–0.14)

0≤0.351.4

Missense OE?0.21 (0.17–0.27)

0≤0.61.4

Synonymous OE?1.11

0≤1.21.6

LoF obs/exp: 0 / 20.7Missense obs/exp: 46 / 218.1Syn Z: -0.77

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongSPOP-related neurodevelopmental disorder, gain of functionGOFAD

strongSPOP-related neurodevelopmental disorder, dominant negativeDNAD

This gene — mechanism propensity

0.3494th %ile

GOF

0.3690th %ile

LOF

0.75top 10%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 17% of P/LP variants are LoF · LOEUF 0.14

GOF1 literature citation · 83% of P/LP are missense

DN1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNRecurrent somatic variants in SPOP are cancer specific; endometrial and prostate cancers result from gain-of-function and dominant-negative effects toward BET proteins, respectively.1

GOFRecurrent somatic variants in SPOP are cancer specific; endometrial and prostate cancers result from gain-of-function and dominant-negative effects toward BET proteins, respectively.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 32109420 ↗

ClinVar Variant Classifications

243 submitted variants in ClinVar

ClinVar

Classification Summary

Likely Pathogenic12

VUS198

Likely Benign11

Benign1

Conflicting6

Likely Pathogenic

198

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	2	10	0	0	12
VUS	67	92	22	17	198
Likely Benign	1	2	1	7	11
Benign	0	0	1	0	1
Conflicting	—				6
Total	70	104	24	24	228

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

View in ClinVar →

11 pathogenic / likely-pathogenic (of 12) ClinVar copy-number / structural variants overlap SPOP — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →