Is BUB1B p.Ala183Pro (c.547G>C) pathogenic?

BUB1B p.Ala183Pro (c.547G>C) is classified Uncertain significance in BUB1B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-27). AlphaMissense: likely pathogenic (0.9228); Very rare (popmax 8.47e-05%, nfe); Associated with mosaic variegated aneuploidy syndrome 1.

What condition is associated with BUB1B p.Ala183Pro (c.547G>C)?

BUB1B p.Ala183Pro (c.547G>C) is associated with mosaic variegated aneuploidy syndrome 1 (ClinVar).

How common is BUB1B p.Ala183Pro (c.547G>C) in the general population?

BUB1B p.Ala183Pro (c.547G>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about BUB1B p.Ala183Pro (c.547G>C)?

AlphaMissense predicts likely pathogenic (score 0.9228) — an in-silico prediction, not a clinical call.

BUB1B p.Ala183Pro

c.547G>C · rs1442788795 · VCV1346988

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9228 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

mosaic variegated aneuploidy syndrome 1

Computational evidence

Protein change
AlphaMissense	0.9228	likely pathogenic · top 3% in BUB1B
REVEL	0.685	pathogenic-leaning
SaProt	LLR -14.01	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 60 kb · p 0.0024 · regional, not allelic
Overall
CADD	28.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,008 alleles

Overall 0.000124% 2/1,614,098 alleles · very rare exomes 2/1,461,838 · genomes 0/152,260 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00156%	64,026
European (non-Finnish)grpmax	8.47e-05%	1,180,008

Finnish shows a higher raw frequency than the grpmax group above it. 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.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: BUB1B
Protein: p.Ala183Pro
Coding: c.547G>C
MANE Select: NM_001211
dbSNP: rs1442788795
Type: single nucleotide variant
Location: chr15:40176639 (GRCh38)
Gene constraint: LOEUF 0.707 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 64.62 · 9 PDB
Residue 183: the bub1 n-terminal domain; the 'necessary for interaction with knl1' region

Full BUB1B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

mosaic variegated aneuploidy syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

BUB1B p.Ala183Thr Uncertain significance ★★ ⚠ same residue
BUB1B p.Ala183Gly Uncertain significance ★ same residue
BUB1B p.Ala183= Likely benign ★ same residue
BUB1B p.Arg114Ter Pathogenic ★★ same condition
BUB1B p.Arg120Ter Pathogenic ★★ same condition
BUB1B p.Arg194Ter Pathogenic/Likely pathogenic ★★ same condition
BUB1B p.Arg199Ter Pathogenic/Likely pathogenic ★★ same condition
BUB1B p.Arg67Ter Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/bub1b-p-ala183pro (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown