# NM_001211.6(BUB1B):c.581G>C (p.Arg194Pro)

https://sugi.bio/variant/bub1b-p-arg194pro

## Summary

**BUB1B p.Arg194Pro (c.581G>C)** is classified **Uncertain significance** in BUB1B (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-16). AlphaMissense: likely pathogenic (0.9364); Absent from gnomAD v4.1; Associated with premature chromatid separation trait.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs567916146 · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the BUB1B gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to premature chromatid separation trait.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [BUB1B](https://sugi.bio/atlas/gene/BUB1B/) |
| Protein change (HGVS p.) | p.Arg194Pro |
| Coding change (HGVS c.) | c.581G>C |
| MANE Select transcript | [NM_001211](https://www.ncbi.nlm.nih.gov/nuccore/NM_001211) |
| dbSNP | [rs567916146](https://www.ncbi.nlm.nih.gov/snp/rs567916146/) |
| Variant type | single nucleotide variant |
| Location | chr15:40176673-40176673 (GRCh38) |
| ClinVar | [VCV2680364](https://www.ncbi.nlm.nih.gov/clinvar/variation/2680364/) |

**All HGVS expressions:** `LRG_489:g.20665G>C`, `LRG_489t1:c.581G>C`, `NC_000015.10:g.40176673G>C`, `NC_000015.9:g.40468874G>C`, `NG_016338.1:g.20665G>C`, `NM_001211.6:c.581G>C`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely pathogenic** (0.9364)
- REVEL 0.198 (benign-leaning) — differs from AlphaMissense
- SaProt LLR -15.132 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt call this damaging; REVEL does not
- SpliceAI predicts **donor loss** (Δ 0.81) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 11.58, GERP 2.07, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 3%** most-pathogenic-predicted substitutions in BUB1B (of 6,173 modeled).
- CADD: **PHRED 35.0**. 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 0.91** across the covering region of the MANE Select transcript (40,161,221–40,220,756), spanning 59,535 bp. Chi-square p 0.0024. 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 **0.81**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.81**, acceptor gain **0.00**, donor gain **0.00**.
- Pangolin: Δ**0.76** (loss), gain 0.01 / loss 0.76. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**BUB1B** population constraint: LOEUF 0.707, pLI 2.5766e-14, missense-Z 1.7805; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity 0/3. *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):

- **mosaic variegated aneuploidy syndrome 1** — Definitive (AR)

## Protein context {#protein}

Residue **194** lies in the bub1 n-terminal domain; an α-helix.

AlphaFold model confidence (whole protein): pLDDT 64.62, 15% of residues very-high.

**9 experimental structure(s)** (PDB): [2WVI](https://www.rcsb.org/structure/2WVI), [3SI5](https://www.rcsb.org/structure/3SI5), [4GGD](https://www.rcsb.org/structure/4GGD), [5JJA](https://www.rcsb.org/structure/5JJA), [5K6S](https://www.rcsb.org/structure/5K6S), [5KHU](https://www.rcsb.org/structure/5KHU) — incl. mutant structure 5KHU.

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

*Describes the biological roles of BUB1B (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}

BUB1B 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:** mitotic spindle assembly checkpoint signaling.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-10-16.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Baylor Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-10-16 |

## Associated conditions {#conditions}

[premature chromatid separation trait](https://sugi.bio/atlas/disease/premature-chromatid-separation-trait/).

**Reported phenotype names (ClinVar):** Premature chromatid separation trait, TOTAL PREMATURE CHROMATID SEPARATION TRAIT.

## Same-residue context {#hotspot}

Residue **194** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [BUB1B p.Arg194Ter](/variant/bub1b-p-arg194ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related BUB1B variant pages (same residue, condition, or type): [BUB1B p.Arg194Ter](/variant/bub1b-p-arg194ter), [BUB1B p.Arg194Gln](/variant/bub1b-p-arg194gln), [BUB1B p.Arg194Gly](/variant/bub1b-p-arg194gly), [BUB1B p.Arg194=](/variant/bub1b-p-arg194), [BUB1B p.Ala348Val](/variant/bub1b-p-ala348val), [BUB1B p.Ala388Val](/variant/bub1b-p-ala388val), [BUB1B p.Ala784Val](/variant/bub1b-p-ala784val), [BUB1B p.Arg199Gln](/variant/bub1b-p-arg199gln).

### 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 2680364). 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.*