# NM_004336.5(BUB1):c.2048C>T (p.Ala683Val)

https://sugi.bio/variant/bub1-p-ala683val

## Summary

**BUB1 p.Ala683Val (c.2048C>T)** is classified **Uncertain significance** in BUB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-20). AlphaMissense: likely benign (0.0847); Very rare (popmax 0.000339%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1338916768 · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.000339%, nfe)

## For patients & families {#patients}

This is a change in the BUB1 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 | [BUB1](https://sugi.bio/atlas/gene/BUB1/) |
| Protein change (HGVS p.) | p.Ala683Val |
| Coding change (HGVS c.) | c.2048C>T |
| MANE Select transcript | [NM_004336](https://www.ncbi.nlm.nih.gov/nuccore/NM_004336) |
| dbSNP | [rs1338916768](https://www.ncbi.nlm.nih.gov/snp/rs1338916768/) |
| Variant type | single nucleotide variant |
| Location | chr2:110650701-110650701 (GRCh38) |
| ClinVar | [VCV1785001](https://www.ncbi.nlm.nih.gov/clinvar/variation/1785001/) |

**All HGVS expressions:** `NC_000002.11:g.111408278G>A`, `NC_000002.12:g.110650701G>A`, `NG_012048.2:g.32362C>T`, `NM_001278616.2:c.1988C>T`, `NM_001278617.2:c.2048C>T`, `NM_004336.5:c.2048C>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.0847)
- REVEL 0.008 (strongly benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.695 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **donor loss** (Δ 0.24) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 2.29, phastCons 0.028 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 15.01**. 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.*
- Regional missense constraint: **o/e 0.90** across the covering region of the MANE Select transcript (110,637,967–110,677,995), spanning 40,028 bp. Chi-square p 0.00043. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.24**, acceptor gain **0.00**, donor gain **0.03**. Largest is donor loss, 2 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.03**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **0.000339%** (nfe) · FAF95 7.9e-05% · FAF99 5.4e-05% · 4/1,179,982 in the highest group · 4/1,614,056 alleles overall — very rare (popmax 0.000339%, nfe).

*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}


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.


### 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-10-20.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-10-20 |

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

## Similar variants {#similar}

Related BUB1 variant pages (same residue, condition, or type): [BUB1 p.Ala683=](/variant/bub1-p-ala683), [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 2026-10-14); 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 1785001). 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.*