SPOP

Chr 17AD

speckle type BTB/POZ protein

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

NCBI Gene: 8405 ENSG00000121067 UniProt: O43791 OMIM: 602650

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.

OMIM 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]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Nabais Sa-de Vries syndrome, type 1MIM #618828

Nabais Sa-de Vries syndrome, type 2MIM #618829

Clinical highlights

Gene–disease validity (ClinGen)

Interpreting a novel variant

Gain of function is the curated mechanism (Gene2Phenotype), so a variant that simply removes the protein may not be the pathogenic class here — missense variants in functional domains often carry more weight.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

135

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.14

LOEUF· LoF intol.

Multiple*

Mechanism· G2P

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

Background carrier burden — how many people carry a rare variant somewhere in SPOP?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 640

163 rare PASS variants

Rare truncating (LoF)

1 in 7,700

19 rare PASS variants

Rare synonymous (reference)

1 in 230

182 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for SPOP. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 560	1 in 9,000
South Asian	~43k	1 in 830	≈ 1 in 21,000
Remaining (unassigned)	~30k	1 in 1,300	1 in 2,300
European (Finnish)	~27k	1 in 2,700	none seen
Admixed American	~22k	1 in 1,000	1 in 990
African / African American	~21k	1 in 920	none seen
East Asian	~20k	1 in 2,200	none seen
Ashkenazi Jewish	~13k	≈ 1 in 13,000	none seen
Middle Eastern	~2,884	≈ 1 in 2,900	≈ 1 in 1,400

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 9 coding exons well covered in gnomAD exomes and genomes.? see exons ↓