# NM_016169.4(SUFU):c.859_863dup (p.Ser288fs)

https://sugi.bio/variant/sufu-p-ser288fs

## Summary

**SUFU p.Ser288fs (c.859_863dup)** is classified **Pathogenic** in SUFU (ClinVar, Single submitter, 1 submitter; last evaluated 2021-03-17). No gnomAD frequency available for this variant; Associated with medulloblastoma.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2135881899 · 1 submitter · 2 linked conditions · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the SUFU gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to medulloblastoma.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Not applicable |
| Age of onset (of this condition) | All ages |
| Prevalence | 1-9 / 1 000 000 (Europe) |
| Clinical trials | 149 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | SUFU is a diagnostic-grade gene on 20 Genomics England panels |

**Commonly reported features of Medulloblastoma** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Medulloblastoma — Obligate (100%)
- Delayed cranial suture closure — Frequent (79-30%)
- Ataxia — Frequent (79-30%)
- Lethargy — Frequent (79-30%)
- Abnormal cranial nerve morphology — Frequent (79-30%)
- Dysmetria — Frequent (79-30%)
- Nausea and vomiting — Frequent (79-30%)
- Progressive cerebellar ataxia — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0007005/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [SUFU](https://sugi.bio/atlas/gene/SUFU/) |
| Protein change (HGVS p.) | p.Ser288fs |
| Coding change (HGVS c.) | c.859_863dup |
| MANE Select transcript | [NM_016169](https://www.ncbi.nlm.nih.gov/nuccore/NM_016169) |
| dbSNP | [rs2135881899](https://www.ncbi.nlm.nih.gov/snp/rs2135881899/) |
| Variant type | Duplication |
| Location | chr10:102597239-102597240 (GRCh38) |
| ClinVar | [VCV1395659](https://www.ncbi.nlm.nih.gov/clinvar/variation/1395659/) |

**All HGVS expressions:** `LRG_521:g.98281_98285dup`, `NC_000010.10:g.104356999_104357003dup`, `NC_000010.11:g.102597242_102597246dup`, `NG_021338.1:g.98281_98285dup`, `NM_001178133.2:c.859_863dup`, `NM_016169.4:c.859_863dup`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 11.819, GERP 2.93, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene (constraint LOEUF 0.214, pLI 1), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 7 of 12**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**SUFU** population constraint: LOEUF 0.214, pLI 1, missense-Z 3.1286; ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *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):

- **medulloblastoma** — Definitive (AD)
- **ciliopathy** — Limited (AR)

## Protein context {#protein}

Residue **288** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 82.95, 67% of residues very-high.

**10 experimental structure(s)** (PDB): [1M1L](https://www.rcsb.org/structure/1M1L), [4BL8](https://www.rcsb.org/structure/4BL8), [4BL9](https://www.rcsb.org/structure/4BL9), [4BLA](https://www.rcsb.org/structure/4BLA), [4BLB](https://www.rcsb.org/structure/4BLB), [4BLD](https://www.rcsb.org/structure/4BLD) — incl. mutant structure 4BL9.

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

*Describes the biological roles of SUFU (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:** SUFU's established molecular role includes protein kinase binding. p.Ser288fs falls in the disordered region.


### Pathways affected {#pathways}

SUFU participates in **5 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [GLI3 is processed to GLI3R by the proteasome](https://reactome.org/content/detail/R-HSA-5610785) | curated |
| [Hedgehog 'off' state](https://reactome.org/content/detail/R-HSA-5610787) | curated |
| [Hedgehog 'on' state](https://reactome.org/content/detail/R-HSA-5632684) | curated |
| [Degradation of GLI1 by the proteasome](https://reactome.org/content/detail/R-HSA-5610780) | electronic |
| [Degradation of GLI2 by the proteasome](https://reactome.org/content/detail/R-HSA-5610783) | electronic |

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

**Molecular function:** protein kinase binding.

**Biological process:** negative regulation of transcription by RNA polymerase II, regulation of DNA-templated transcription, negative regulation of smoothened signaling pathway.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-03-17.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2021-03-17 |

## Associated conditions {#conditions}

[medulloblastoma](https://sugi.bio/atlas/disease/medulloblastoma/), [nevoid basal cell carcinoma syndrome](https://sugi.bio/atlas/disease/nevoid-basal-cell-carcinoma-syndrome/).

**Reported phenotype names (ClinVar):** Medulloblastoma, Gorlin syndrome, MEDULLOBLASTOMA PREDISPOSITION SYNDROME, Medulloblastoma, somatic, Nevoid Basal Cell Carcinoma Syndrome, Basal cell nevus syndrome.

## Similar variants {#similar}

Related SUFU variant pages (same residue, condition, or type): [SUFU p.Ser288Cys](/variant/sufu-p-ser288cys), [SUFU p.Thr196fs](/variant/sufu-p-thr196fs), [SUFU p.Leu312_Arg313insLeu](/variant/sufu-p-leu312-arg313insleu), [SUFU p.Arg42fs](/variant/sufu-p-arg42fs), [SUFU p.Cys273fs](/variant/sufu-p-cys273fs), [SUFU p.Gly193fs](/variant/sufu-p-gly193fs), [SUFU p.Phe417fs](/variant/sufu-p-phe417fs), [SUFU p.Pro297fs](/variant/sufu-p-pro297fs).

### 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 1395659). 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.*