# NM_001211.6(BUB1B):c.1261C>T (p.Arg421Trp)

https://sugi.bio/variant/bub1b-p-arg421trp

## Summary

**BUB1B p.Arg421Trp (c.1261C>T)** is classified **Conflicting classifications of pathogenicity** in BUB1B (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-11-17). AlphaMissense: likely benign (0.1145); Ultra-rare (popmax 0.0233%, amr); Associated with mosaic variegated aneuploidy syndrome 1.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs201251790 · 3 submitters · 1 linked condition · AlphaMissense likely benign · ultra-rare (popmax 0.0233%, amr)

## For patients & families {#patients}

This is a change in the BUB1B gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 3 submitters, and is linked to mosaic variegated aneuploidy syndrome 1.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0024694/index) · [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.Arg421Trp |
| Coding change (HGVS c.) | c.1261C>T |
| MANE Select transcript | [NM_001211](https://www.ncbi.nlm.nih.gov/nuccore/NM_001211) |
| dbSNP | [rs201251790](https://www.ncbi.nlm.nih.gov/snp/rs201251790/) |
| Variant type | single nucleotide variant |
| Location | chr15:40196747-40196747 (GRCh38) |
| ClinVar | [VCV465359](https://www.ncbi.nlm.nih.gov/clinvar/variation/465359/) |

**All HGVS expressions:** `LRG_489:g.40739C>T`, `LRG_489t1:c.1261C>T`, `NC_000015.10:g.40196747C>T`, `NC_000015.9:g.40488948C>T`, `NG_016338.1:g.40739C>T`, `NM_001211.6:c.1261C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1145)
- REVEL 0.076 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -8.602 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 2.671, GERP 1.17, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 22.7**. 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: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0233%** (amr) · FAF95 0.0141% · FAF99 0.0112% · 14/59,990 in the highest group · 199/1,613,792 alleles overall — ultra-rare (popmax 0.0233%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Ashkenazi Jewish (not grpmax-eligible) | 0.355% | 282 |
| Remaining individuals (not grpmax-eligible) | 0.0384% | 2,604 |
| Admixed American (grpmax) | 0.0233% | 4,285 |
| Middle Eastern | 0.0165% | 6,060 |
| South Asian | 0.0143% | 7,005 |
| African / African-American | 0.008% | 12,497 |
| East Asian | 0.00446% | 22,435 |
| European (non-Finnish) | 0.00288% | 34,701 |

Ashkenazi Jewish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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 30, triplosensitivity 0 (0–3 scale). *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}


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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-11-17.

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

**Submission history:** 3 submissions (2021–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-11-03 |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2022-04-01 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-11-17 |

## Associated conditions {#conditions}

[mosaic variegated aneuploidy syndrome 1](https://sugi.bio/atlas/disease/mosaic-variegated-aneuploidy-syndrome-1/).

**Reported phenotype names (ClinVar):** Mosaic variegated aneuploidy syndrome 1, not provided, BUB1B-related disorder, BUB1B-related condition, none provided, Warburton-Anyane-Yeboa syndrome.

## Similar variants {#similar}

Related BUB1B variant pages (same residue, condition, or type): [BUB1B p.Arg421Gln](/variant/bub1b-p-arg421gln), [BUB1B p.Arg421Leu](/variant/bub1b-p-arg421leu), [BUB1B p.Arg421=](/variant/bub1b-p-arg421), [BUB1B p.Arg114Ter](/variant/bub1b-p-arg114ter), [BUB1B p.Arg120Ter](/variant/bub1b-p-arg120ter), [BUB1B p.Arg194Ter](/variant/bub1b-p-arg194ter), [BUB1B p.Arg199Ter](/variant/bub1b-p-arg199ter), [BUB1B p.Arg67Ter](/variant/bub1b-p-arg67ter).

### 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 465359). 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.*