# NM_004336.5(BUB1):c.1430dup (p.Pro478fs)

https://sugi.bio/variant/bub1-p-pro478fs

## Summary

**BUB1 p.Pro478fs (c.1430dup)** is classified **Likely pathogenic** in BUB1 (ClinVar, Single submitter, 1 submitter). Very rare (popmax 0.0022%, sas); Associated with microcephaly 30, primary, autosomal recessive.

**At a glance:** Likely pathogenic · review: Single submitter · 1 submitter · 1 linked condition · very rare (popmax 0.0022%, sas)

## For patients & families {#patients}

This is a change in the BUB1 gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to microcephaly 30, primary, autosomal recessive.

*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/0026708/index) · [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.Pro478fs |
| Coding change (HGVS c.) | c.1430dup |
| MANE Select transcript | [NM_004336](https://www.ncbi.nlm.nih.gov/nuccore/NM_004336) |
| Variant type | Duplication |
| Location | chr2:110658495-110658496 (GRCh38) |
| ClinVar | [VCV3377649](https://www.ncbi.nlm.nih.gov/clinvar/variation/3377649/) |

**All HGVS expressions:** `NC_000002.11:g.111416073dup`, `NC_000002.12:g.110658496dup`, `NG_012048.1:g.24610dup`, `NG_012048.2:g.24567dup`, `NM_001278616.2:c.1370dup`, `NM_001278617.2:c.1430dup`, `NM_004336.5:c.1430dup`

## 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 1.357, phastCons 0.999 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.727, pLI 7.3293e-13. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 13 of 25**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0022%** (sas) · FAF95 0.000365% · FAF99 0.000137% · 2/91,044 in the highest group · 2/1,461,676 alleles overall — very rare (popmax 0.0022%, sas).

*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}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*.

**Submitter consensus:** unanimous (1/1 Likely Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Neuberg Centre For Genomic Medicine, NCGM | Likely Pathogenic | criteria provided, single submitter | clinical testing |  |

## Associated conditions {#conditions}

[microcephaly 30, primary, autosomal recessive](https://sugi.bio/atlas/disease/microcephaly-30-primary-autosomal-recessive/).

**Reported phenotype names (ClinVar):** Microcephaly 30, primary, autosomal recessive.

## Similar variants {#similar}

Related BUB1 variant pages (same residue, condition, or type): [BUB1 p.Pro478Leu](/variant/bub1-p-pro478leu), [BUB1 p.Pro478Ser](/variant/bub1-p-pro478ser), [BUB1 p.Ala733fs](/variant/bub1-p-ala733fs), [BUB1 p.Ile103Phe](/variant/bub1-p-ile103phe), [BUB1 p.Met1Arg](/variant/bub1-p-met1arg), [BUB1 c.2625+1G>A](/variant/bub1-c-2625-plus-1g-a), [BUB1 p.Val558fs](/variant/bub1-p-val558fs), [BUB1 c.1277-20dup](/variant/bub1-c-1277-minus-20dup).

### 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 3377649). 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.*