# NM_016169.4(SUFU):c.1023G>A (p.Pro341=)

https://sugi.bio/variant/sufu-p-pro341

## Summary

**SUFU p.Pro341= (c.1023G>A)** is classified **Likely benign** in SUFU (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-28). Absent from gnomAD v4.1; Associated with nevoid basal cell carcinoma syndrome.

**At a glance:** Likely benign · review: Single submitter · rsID rs2135929726 · 1 submitter · 2 linked conditions · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the SUFU gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to nevoid basal cell carcinoma syndrome.

*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 | 22 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0007166/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.Pro341= |
| Coding change (HGVS c.) | c.1023G>A |
| MANE Select transcript | [NM_016169](https://www.ncbi.nlm.nih.gov/nuccore/NM_016169) |
| dbSNP | [rs2135929726](https://www.ncbi.nlm.nih.gov/snp/rs2135929726/) |
| Variant type | single nucleotide variant |
| Location | chr10:102615268-102615268 (GRCh38) |
| ClinVar | [VCV1089579](https://www.ncbi.nlm.nih.gov/clinvar/variation/1089579/) |

**All HGVS expressions:** `LRG_521:g.116307G>A`, `NC_000010.10:g.104375025G>A`, `NC_000010.11:g.102615268G>A`, `NG_021338.1:g.116307G>A`, `NM_001178133.2:c.1023G>A`, `NM_016169.4:c.1023G>A`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor gain** (Δ 0.24) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 2.609, GERP -0.674, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 16.39**. 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 deltas (raw): acceptor loss **0.02**, donor loss **0.00**, acceptor gain **0.24**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.24**, donor gain **0.00**.
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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 **341** lies in the 'disordered' region; a UniProt-annotated variant site (sequence variant); a UniProt-annotated variant site (found in a patient with holoprosencephaly; uncertain significance).

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.Pro341= 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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-01-28.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2022-01-28 |

## Associated conditions {#conditions}

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

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

## Same-residue context {#hotspot}

Residue **341** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [SUFU p.Pro341fs](/variant/sufu-p-pro341fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related SUFU variant pages (same residue, condition, or type): [SUFU p.Pro341Ala](/variant/sufu-p-pro341ala), [SUFU p.Pro341Arg](/variant/sufu-p-pro341arg), [SUFU p.Pro341Leu](/variant/sufu-p-pro341leu), [SUFU p.Pro341fs](/variant/sufu-p-pro341fs), [SUFU p.Pro341Ser](/variant/sufu-p-pro341ser), [SUFU c.1022+1G>A](/variant/sufu-c-1022-plus-1g-a), [SUFU c.1023-2A>T](/variant/sufu-c-1023-minus-2a-t), [SUFU c.683+1G>A](/variant/sufu-c-683-plus-1g-a).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 1089579). 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.*