# NM_004336.5(BUB1):c.1023A>G (p.Pro341=)

https://sugi.bio/variant/bub1-p-pro341

## Summary

**BUB1 p.Pro341= (c.1023A>G)** is classified **Benign/Likely benign** in BUB1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-15). Low-frequency (popmax 2.08%, sas).

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs200740694 · 3 submitters · low-frequency (popmax 2.08%, sas)

## For patients & families {#patients}

This is a change in the BUB1 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 3 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.Pro341= |
| Coding change (HGVS c.) | c.1023A>G |
| MANE Select transcript | [NM_004336](https://www.ncbi.nlm.nih.gov/nuccore/NM_004336) |
| dbSNP | [rs200740694](https://www.ncbi.nlm.nih.gov/snp/rs200740694/) |
| Variant type | single nucleotide variant |
| Location | chr2:110661776-110661776 (GRCh38) |
| ClinVar | [VCV790821](https://www.ncbi.nlm.nih.gov/clinvar/variation/790821/) |

**All HGVS expressions:** `NC_000002.11:g.111419353T>C`, `NC_000002.12:g.110661776T>C`, `NG_012048.1:g.21330A>G`, `NM_001278616.2:c.963A>G`, `NM_001278617.2:c.1023A>G`, `NM_004336.5:c.1023A>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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor loss** (Δ 0.40) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -0.353 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 9.591**. 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 **0.40**, donor loss **0.00**, acceptor gain **0.07**, donor gain **0.02**. Largest is acceptor loss, 2 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.07**, donor gain **0.02**.
  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 **2.08%** (sas) · FAF95 2.01% · FAF99 1.98% · 1,899/91,086 in the highest group · 2,055/1,614,254 alleles overall — low-frequency (popmax 2.08%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 2.08% | 48 |
| Remaining individuals (not grpmax-eligible) | 0.138% | 727 |
| Middle Eastern | 0.115% | 866 |
| Admixed American | 0.00833% | 12,007 |
| European (non-Finnish) | 0.00458% | 21,853 |
| African / African-American | 0.004% | 25,021 |
| Finnish (not grpmax-eligible) | 0.00156% | 64,038 |

*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}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-12-15.

**Submitter consensus:** conflicting (2 Benign, 1 Likely benign).

**Submission history:** 3 submissions (2022–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2022-02-12 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2025-12-15 |

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

## Similar variants {#similar}

Related BUB1 variant pages (same residue, condition, or type): [BUB1 p.Pro341Thr](/variant/bub1-p-pro341thr), [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 2026-10-14); 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 790821). 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.*