Is BUB1B p.Glu281Asp (c.843G>C) pathogenic?

BUB1B p.Glu281Asp (c.843G>C) is classified Uncertain significance in BUB1B (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-12-10). AlphaMissense: likely benign (0.1078); Very rare (popmax 0.00134%, afr); Associated with Inborn genetic diseases.

What condition is associated with BUB1B p.Glu281Asp (c.843G>C)?

BUB1B p.Glu281Asp (c.843G>C) is associated with Inborn genetic diseases, mosaic variegated aneuploidy syndrome 1 (ClinVar).

How common is BUB1B p.Glu281Asp (c.843G>C) in the general population?

BUB1B p.Glu281Asp (c.843G>C) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about BUB1B p.Glu281Asp (c.843G>C)?

AlphaMissense predicts likely benign (score 0.1078) — an in-silico prediction, not a clinical call.

BUB1B p.Glu281Asp

c.843G>C · rs1411409004 · VCV1444633

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1078 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1078	likely benign
REVEL	0.061	moderately benign-leaning
SaProt	LLR -7.29	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.57	GERP -3.5
Regional constraint	o/e 0.91	unconstrained · MANE · 60 kb · p 0.0024 · regional, not allelic
Overall
CADD	7.906	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00134% African / African-American · 1/74,868 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,613,838 alleles · very rare exomes 2/1,461,752 · genomes 1/152,086 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,868
European (non-Finnish)	0.00017%	589,946

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.Glu281Asp
Coding: c.843G>C
MANE Select: NM_001211
dbSNP: rs1411409004
Type: single nucleotide variant
Location: chr15:40185256 (GRCh38)
Gene constraint: LOEUF 0.707 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 64.62 · 9 PDB

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: mosaic variegated aneuploidy syndrome 1

Similar variants

BUB1B p.Glu281Ala Uncertain significance ★ ⚠ same residue
BUB1B p.Glu281Gly Uncertain significance ★ ⚠ 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
BUB1B p.Gln267Ter 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-glu281asp (accessed [today's date]).

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