# NM_004336.5(BUB1):c.318G>C (p.Ala106=)

https://sugi.bio/variant/bub1-p-ala106

## Summary

**BUB1 p.Ala106= (c.318G>C)** is classified **Likely benign** in BUB1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-30). Rare (popmax 0.108%, amr).

**At a glance:** Likely benign · review: Multiple submitters · rsID rs370559107 · 4 submitters · rare (popmax 0.108%, amr)

## For patients & families {#patients}

This is a change in the BUB1 gene that is classified as likely benign — not considered disease-causing, submitted by 4 submitters.

*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 | [BUB1](https://sugi.bio/atlas/gene/BUB1/) |
| Protein change (HGVS p.) | p.Ala106= |
| Coding change (HGVS c.) | c.318G>C |
| MANE Select transcript | [NM_004336](https://www.ncbi.nlm.nih.gov/nuccore/NM_004336) |
| dbSNP | [rs370559107](https://www.ncbi.nlm.nih.gov/snp/rs370559107/) |
| Variant type | single nucleotide variant |
| Location | chr2:110672765-110672765 (GRCh38) |
| ClinVar | [VCV1728648](https://www.ncbi.nlm.nih.gov/clinvar/variation/1728648/) |

**All HGVS expressions:** `NC_000002.11:g.111430342C>G`, `NC_000002.12:g.110672765C>G`, `NG_012048.1:g.10343G>C`, `NG_012048.2:g.10298G>C`, `NM_001278616.2:c.258G>C`, `NM_001278617.2:c.318G>C`, `NM_004336.4:c.318G>C`, `NM_004336.5:c.318G>C`

## 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 -12.708 — fast-evolving / accelerated position
- CADD: **PHRED 0.022**. 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 (C>T, Δ0.23 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 **0.108%** (amr) · FAF95 0.0872% · FAF99 0.0796% · 65/59,964 in the highest group · 589/1,613,956 alleles overall — rare (popmax 0.108%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.108% | 923 |
| European (non-Finnish) | 0.0431% | 2,323 |
| Remaining individuals (not grpmax-eligible) | 0.0176% | 5,680 |
| African / African-American | 0.00667% | 14,983 |

*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}

**BUB1** population constraint: LOEUF 0.727, pLI 7.3293e-13, missense-Z 1.4894. *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):

- **colorectal cancer** — Limited (AD)

## Protein context {#protein}

Residue **106** lies in the bub1 n-terminal domain; the 'necessary for kinetochore localization' region; the 'necessary for interaction with knl1' region; an α-helix.

AlphaFold model confidence (whole protein): pLDDT 63.91, 31% of residues very-high.

**11 experimental structure(s)** (PDB): [2LAH](https://www.rcsb.org/structure/2LAH), [4A1G](https://www.rcsb.org/structure/4A1G), [4QPM](https://www.rcsb.org/structure/4QPM), [4R8Q](https://www.rcsb.org/structure/4R8Q), [5DMZ](https://www.rcsb.org/structure/5DMZ), [6F7B](https://www.rcsb.org/structure/6F7B).

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

*Describes the biological roles of BUB1 (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:** BUB1's established molecular role includes protein kinase activity. p.Ala106= falls in the bub1 n-terminal domain.


### Pathways affected {#pathways}

BUB1 participates in **6 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Amplification  of signal from unattached  kinetochores via a MAD2  inhibitory signal](https://reactome.org/content/detail/R-HSA-141444) | curated |
| [EML4 and NUDC in mitotic spindle formation](https://reactome.org/content/detail/R-HSA-9648025) | 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}

**Molecular function:** protein kinase activity, protein serine/threonine kinase activity, histone H2A kinase activity.

**Biological process:** regulation of sister chromatid cohesion, mitotic spindle assembly checkpoint signaling, regulation of chromosome segregation, positive regulation of maintenance of mitotic sister chromatid cohesion, centromeric.

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-12-30.

**Submitter consensus:** unanimous (4/4 Likely benign).

**Submission history:** 4 submissions (2019–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2022-02-12 |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2019-12-23 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-12-30 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2025-11-01 |

**Reported phenotype names (ClinVar):** not provided, BUB1-related disorder, not specified, BUB1-related condition, AllHighlyPenetrant, none provided.

## Similar variants {#similar}

Related BUB1 variant pages (same residue, condition, or type): [BUB1 p.Ala106Val](/variant/bub1-p-ala106val), [BUB1 c.1698+1G>T](/variant/bub1-c-1698-plus-1g-t), [BUB1 p.Ala281Thr](/variant/bub1-p-ala281thr), [BUB1 p.Ala283Thr](/variant/bub1-p-ala283thr), [BUB1 p.Ala499Val](/variant/bub1-p-ala499val), [BUB1 p.Ala502Ser](/variant/bub1-p-ala502ser), [BUB1 p.Ala630Gly](/variant/bub1-p-ala630gly), [BUB1 p.Ala705Thr](/variant/bub1-p-ala705thr).

### 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 1728648). 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.*