# NM_005861.4(STUB1):c.477C>T (p.Ser159=)

https://sugi.bio/variant/stub1-p-ser159

## Summary

**STUB1 p.Ser159= (c.477C>T)** is classified **Uncertain significance** in STUB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-01). Very rare (popmax 0.00644%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs750520142 · 1 submitter · very rare (popmax 0.00644%, nfe)

## For patients & families {#patients}

This is a change in the STUB1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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.*

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

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [STUB1](https://sugi.bio/atlas/gene/STUB1/) |
| Protein change (HGVS p.) | p.Ser159= |
| Coding change (HGVS c.) | c.477C>T |
| MANE Select transcript | [NM_005861](https://www.ncbi.nlm.nih.gov/nuccore/NM_005861) |
| dbSNP | [rs750520142](https://www.ncbi.nlm.nih.gov/snp/rs750520142/) |
| Variant type | single nucleotide variant |
| Location | chr16:681556-681556 (GRCh38) |
| ClinVar | [VCV3067400](https://www.ncbi.nlm.nih.gov/clinvar/variation/3067400/) |

**All HGVS expressions:** `NC_000016.10:g.681556C>T`, `NC_000016.9:g.731556C>T`, `NG_034141.1:g.6446C>T`, `NG_132622.1:g.468C>T`, `NG_132622.2:g.488C>T`, `NM_001293197.2:c.261C>T`, `NM_005861.4:c.477C>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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor gain** (Δ 0.39) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP -8.219, GERP -4.39 — fast-evolving / accelerated position
- CADD: **PHRED 14.04**. 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 **0.00**, donor loss **0.01**, acceptor gain **0.01**, donor gain **0.39**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.01**, donor gain **0.39**.
- Population frequency (gnomAD v4.1): grpmax **0.00644%** (nfe) · FAF95 0.00528% · FAF99 0.00482% · 76/1,179,802 in the highest group · 84/1,611,488 alleles overall — very rare (popmax 0.00644%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00644% | 15,524 |
| Admixed American | 0.00334% | 29,982 |
| African / African-American | 0.00267% | 37,455 |
| South Asian | 0.0022% | 45,485 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,346 |
| Finnish (not grpmax-eligible) | 0.0016% | 62,686 |

*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}

**STUB1** population constraint: LOEUF 1.294, pLI 5.2088e-13, missense-Z -0.98781; ClinGen dosage — haploinsufficiency 30, triplosensitivity Not yet evaluated (0–3 scale). *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **159** lies in the 'required for interaction with mapk7' region; the 'required for interaction with and ubiquitination of myocd' region; the 'required for ubiquitination of foxo1' region; the 'required for interaction with foxo1' region.

AlphaFold model confidence (whole protein): pLDDT 89.84, 79% of residues very-high.

**27 experimental structure(s)** (PDB): [4KBQ](https://www.rcsb.org/structure/4KBQ), [6EFK](https://www.rcsb.org/structure/6EFK), [6NSV](https://www.rcsb.org/structure/6NSV), [7TB1](https://www.rcsb.org/structure/7TB1), [8EHZ](https://www.rcsb.org/structure/8EHZ), [8EI0](https://www.rcsb.org/structure/8EI0).

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

*Describes the biological roles of STUB1 (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:** STUB1's established molecular role includes G protein-coupled receptor binding. p.Ser159= falls in the required for interaction with mapk7 region.


### Pathways affected {#pathways}

STUB1 participates in **8 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Antigen processing: Ubiquitination & Proteasome degradation](https://reactome.org/content/detail/R-HSA-983168) | curated |
| [Downregulation of ERBB2 signaling](https://reactome.org/content/detail/R-HSA-8863795) | curated |
| [Downregulation of TGF-beta receptor signaling](https://reactome.org/content/detail/R-HSA-2173788) | curated |
| [RIPK1-mediated regulated necrosis](https://reactome.org/content/detail/R-HSA-5213460) | curated |
| [Regulation of PTEN stability and activity](https://reactome.org/content/detail/R-HSA-8948751) | curated |
| [Regulation of RUNX2 expression and activity](https://reactome.org/content/detail/R-HSA-8939902) | curated |
| [Regulation of TNFR1 signaling](https://reactome.org/content/detail/R-HSA-5357905) | curated |
| [Regulation of necroptotic cell death](https://reactome.org/content/detail/R-HSA-5675482) | curated |

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

**Molecular function:** G protein-coupled receptor binding, ubiquitin-protein transferase activity, enzyme binding, kinase binding, Hsp70 protein binding, TPR domain binding.

**Biological process:** protein polyubiquitination, ubiquitin-dependent protein catabolic process, protein monoubiquitination, protein quality control for misfolded or incompletely synthesized proteins, protein ubiquitination, negative regulation of transforming growth factor beta receptor signaling pathway.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-03-01.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| CeGaT Center for Human Genetics Tuebingen | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-03-01 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related STUB1 variant pages (same residue, condition, or type): [STUB1 p.Asn65Ser](/variant/stub1-p-asn65ser), [STUB1 p.Tyr49Cys](/variant/stub1-p-tyr49cys), [STUB1 p.Ala11Thr](/variant/stub1-p-ala11thr), [STUB1 p.Arg173Leu](/variant/stub1-p-arg173leu), [STUB1 p.Arg35Pro](/variant/stub1-p-arg35pro), [STUB1 p.Asn34Ser](/variant/stub1-p-asn34ser), [STUB1 p.Cys48Tyr](/variant/stub1-p-cys48tyr), [STUB1 p.Glu174Gly](/variant/stub1-p-glu174gly).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); 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 2026-07-14); 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 3067400). 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.*