# NM_001007228.2(SPOP):c.273C>T (p.Val91=)

https://sugi.bio/variant/spop-p-val91

## Summary

**SPOP p.Val91= (c.273C>T)** is classified **Uncertain significance** in SPOP (ClinVar, No assertion criteria, 1 submitter). Very rare (popmax 6.2e-05%); Associated with prostate cancer.

**At a glance:** Uncertain significance · review: No assertion criteria · rsID rs2072166000 · 1 submitter · 1 linked condition · very rare (popmax 6.2e-05%)

## For patients & families {#patients}

This is a change in the SPOP gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to prostate cancer.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Clinical trials | 5866 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [SPOP](https://sugi.bio/atlas/gene/SPOP/) |
| Protein change (HGVS p.) | p.Val91= |
| Coding change (HGVS c.) | c.273C>T |
| MANE Select transcript | [NM_001007228](https://www.ncbi.nlm.nih.gov/nuccore/NM_001007228) |
| dbSNP | [rs2072166000](https://www.ncbi.nlm.nih.gov/snp/rs2072166000/) |
| Variant type | single nucleotide variant |
| Location | chr17:49619313-49619313 (GRCh38) |
| ClinVar | [VCV694223](https://www.ncbi.nlm.nih.gov/clinvar/variation/694223/) |

**All HGVS expressions:** `LRG_1412:g.63851C>T`, `LRG_1412t1:c.273C>T`, `NC_000017.10:g.47696675G>A`, `NC_000017.11:g.49619313G>A`, `NG_041815.1:g.63851C>T`, `NM_001007226.1:c.273C>T`, `NM_001007227.1:c.273C>T`, `NM_001007228.2:c.273C>T`, `NM_001007229.1:c.273C>T`, `NM_001007230.1:c.273C>T`, `NM_001370730.1:c.273C>T`, `NM_001370731.1:c.273C>T`, `NM_001370732.1:c.273C>T`, `NM_003563.3:c.273C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 5.162, GERP -0.179, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 10.84**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.41 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): global (via dbSNP) **6.2e-05%** · 1/1,614,076 alleles overall — very rare (popmax 6.2e-05%).

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**SPOP** population constraint: LOEUF 0.377, pLI 0.99995, missense-Z 5.5384. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **neurodevelopmental disorder with microcephaly and dysmorphic facies** — Moderate (AD)
- **neurodevelopmental disorder with relative macrocephaly and with or without cardiac or endocrine anomalies** — Definitive (AD)

## Protein context {#protein}

Residue **91** lies in the math domain; the 'required for nuclear localization' region; a β-strand.

AlphaFold model confidence (whole protein): pLDDT 90.38, 78% of residues very-high.

**36 experimental structure(s)** (PDB): [2CR2](https://www.rcsb.org/structure/2CR2), [3HQH](https://www.rcsb.org/structure/3HQH), [3HQI](https://www.rcsb.org/structure/3HQI), [3HQL](https://www.rcsb.org/structure/3HQL), [3HQM](https://www.rcsb.org/structure/3HQM), [3HSV](https://www.rcsb.org/structure/3HSV).

## What this gene does {#gene-function}

*Describes the biological roles of SPOP (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** SPOP's established molecular role includes ubiquitin protein ligase binding. p.Val91= falls in the math domain.


### Pathways affected {#pathways}

SPOP participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Hedgehog 'on' state](https://reactome.org/content/detail/R-HSA-5632684) | curated |
| [SPOP-mediated proteasomal degradation of PD-L1(CD274)](https://reactome.org/content/detail/R-HSA-9929491) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** ubiquitin protein ligase binding, identical protein binding, molecular function inhibitor activity.

**Biological process:** protein polyubiquitination, proteasome-mediated ubiquitin-dependent protein catabolic process.

## Clinical significance {#significance}

**Uncertain significance** — review status No assertion criteria *(no assertion criteria provided)*.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Laboratory of Virology, Microbiology,  Quality and Medical Biotechnologies, Faculty of Sciences and Techniques - Mohammedia, Hassan II University of Casablanca | Uncertain significance | no assertion criteria provided | clinical testing |  |

## Associated conditions {#conditions}

[prostate cancer](https://sugi.bio/atlas/disease/prostate-cancer/).

**Reported phenotype names (ClinVar):** Prostate cancer, Malignant tumor of prostate.

## Similar variants {#similar}

Related SPOP variant pages (same residue, condition, or type): [SPOP c.353-1G>A](/variant/spop-c-353-minus-1g-a), [SPOP p.Arg99Trp](/variant/spop-p-arg99trp), [SPOP p.Glu160Lys](/variant/spop-p-glu160lys), [SPOP c.201-1G>C](/variant/spop-c-201-minus-1g-c), [SPOP c.201-2A>G](/variant/spop-c-201-minus-2a-g), [SPOP c.353-11C>T](/variant/spop-c-353-minus-11c-t), [SPOP c.353-17T>A](/variant/spop-c-353-minus-17t-a), [SPOP c.353-17T>G](/variant/spop-c-353-minus-17t-g).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 694223). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*