# NM_004725.4(BUB3):c.420A>G (p.Val140=)

https://sugi.bio/variant/bub3-p-val140

## Summary

**BUB3 p.Val140= (c.420A>G)** is classified **Likely benign** in BUB3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-03). Very rare (popmax 0.00407%, afr).

**At a glance:** Likely benign · review: Single submitter · rsID rs1002237760 · 1 submitter · very rare (popmax 0.00407%, afr)

## 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.Val140= |
| Coding change (HGVS c.) | c.420A>G |
| MANE Select transcript | [NM_004725](https://www.ncbi.nlm.nih.gov/nuccore/NM_004725) |
| dbSNP | [rs1002237760](https://www.ncbi.nlm.nih.gov/snp/rs1002237760/) |
| Variant type | single nucleotide variant |
| Location | chr10:123160409-123160409 (GRCh38) |
| ClinVar | [VCV1738711](https://www.ncbi.nlm.nih.gov/clinvar/variation/1738711/) |

**All HGVS expressions:** `NC_000010.10:g.124919925A>G`, `NC_000010.11:g.123160409A>G`, `NG_033794.1:g.11166A>G`, `NG_033794.2:g.11009A>G`, `NM_001007793.3:c.420A>G`, `NM_004725.4:c.420A>G`

## 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 -0.305, GERP -5.15, phastCons 0.016 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 7.661**. 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 (A>T, Δ0.31 acceptor 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): grpmax **0.00407%** (afr) · FAF95 0.00108% · FAF99 0.000499% · 3/73,776 in the highest group · 10/1,595,628 alleles overall — very rare (popmax 0.00407%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00407% | 24,592 |
| Remaining individuals (not grpmax-eligible) | 0.00162% | 61,556 |
| European (non-Finnish) | 0.000511% | 195,789 |

*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 2022-03-03.

**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 | 2022-03-03 |

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

## Similar variants {#similar}

Related BUB3 variant pages (same residue, condition, or type): [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), [BUB3 p.Ala292Val](/variant/bub3-p-ala292val).

### 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 1738711). 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.*