# NM_004725.4(BUB3):c.25C>T (p.Leu9=)

https://sugi.bio/variant/bub3-p-leu9

## Summary

**BUB3 p.Leu9= (c.25C>T)** is classified **Likely benign** in BUB3 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-08-03). Very rare (popmax 0.0011%, sas).

**At a glance:** Likely benign · review: Single submitter · rsID rs2493755155 · 1 submitter · very rare (popmax 0.0011%, sas)

## For patients & families {#patients}

This is a change in the BUB3 gene that is classified as likely benign — not considered disease-causing, 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 | [BUB3](https://sugi.bio/atlas/gene/BUB3/) |
| Protein change (HGVS p.) | p.Leu9= |
| Coding change (HGVS c.) | c.25C>T |
| MANE Select transcript | [NM_004725](https://www.ncbi.nlm.nih.gov/nuccore/NM_004725) |
| dbSNP | [rs2493755155](https://www.ncbi.nlm.nih.gov/snp/rs2493755155/) |
| Variant type | single nucleotide variant |
| Location | chr10:123154942-123154942 (GRCh38) |
| ClinVar | [VCV1793647](https://www.ncbi.nlm.nih.gov/clinvar/variation/1793647/) |

**All HGVS expressions:** `NC_000010.10:g.124914458C>T`, `NC_000010.11:g.123154942C>T`, `NG_033794.1:g.5699C>T`, `NG_033794.2:g.5542C>T`, `NM_001007793.3:c.25C>T`, `NM_004725.4:c.25C>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 **acceptor gain** (Δ 0.23) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 1.375, GERP 1.58, phastCons 1 — weakly conserved position
- CADD: **PHRED 16.86**. 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 **0.04**, donor loss **0.00**, acceptor gain **0.23**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.23**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.0011%** (sas) · 1/91,072 in the highest group · 1/1,613,952 alleles overall — very rare (popmax 0.0011%, sas).

*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}

**BUB3** population constraint: LOEUF 0.77, pLI 0.00065367, missense-Z 2.2668. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 96.10, 93% of residues very-high.

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

*Describes the biological roles of BUB3 (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.*


### Pathways affected {#pathways}

BUB3 participates in **10 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [APC-Cdc20 mediated degradation of Nek2A](https://reactome.org/content/detail/R-HSA-179409) | curated |
| [APC/C:Cdc20 mediated degradation of mitotic proteins](https://reactome.org/content/detail/R-HSA-176409) | curated |
| [Amplification  of signal from unattached  kinetochores via a MAD2  inhibitory signal](https://reactome.org/content/detail/R-HSA-141444) | curated |
| [Cdc20:Phospho-APC/C mediated degradation of Cyclin A](https://reactome.org/content/detail/R-HSA-174184) | curated |
| [EML4 and NUDC in mitotic spindle formation](https://reactome.org/content/detail/R-HSA-9648025) | curated |
| [Inactivation of APC/C via direct inhibition of the APC/C complex](https://reactome.org/content/detail/R-HSA-141430) | curated |
| [Mitotic Prometaphase](https://reactome.org/content/detail/R-HSA-68877) | curated |
| [RHO GTPases Activate Formins](https://reactome.org/content/detail/R-HSA-5663220) | curated |
| [Resolution of Sister Chromatid Cohesion](https://reactome.org/content/detail/R-HSA-2500257) | curated |
| [Separation of Sister Chromatids](https://reactome.org/content/detail/R-HSA-2467813) | curated |

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

**Biological process:** attachment of spindle microtubules to kinetochore, protein localization to kinetochore.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2019-08-03.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2019-08-03 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related BUB3 variant pages (same residue, condition, or type): [BUB3 p.Leu9Met](/variant/bub3-p-leu9met), [BUB3 p.Arg314=](/variant/bub3-p-arg314), [BUB3 p.Ser197=](/variant/bub3-p-ser197), [BUB3 p.Ser198=](/variant/bub3-p-ser198), [BUB3 p.Ala131Val](/variant/bub3-p-ala131val), [BUB3 p.Ala155Val](/variant/bub3-p-ala155val), [BUB3 p.Ala187Gly](/variant/bub3-p-ala187gly), [BUB3 p.Ala239Gly](/variant/bub3-p-ala239gly).

### 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 1793647). 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.*