Is BUB1B p.Gln457= (c.1371A>G) pathogenic?

BUB1B p.Gln457= (c.1371A>G) is classified Conflicting classifications of pathogenicity in BUB1B (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-09-15). Rare (popmax 0.123%, afr); Associated with Inborn genetic diseases.

What condition is associated with BUB1B p.Gln457= (c.1371A>G)?

BUB1B p.Gln457= (c.1371A>G) is associated with Inborn genetic diseases, colorectal cancer, premature chromatid separation trait (ClinVar).

How common is BUB1B p.Gln457= (c.1371A>G) in the general population?

BUB1B p.Gln457= (c.1371A>G) is rare (popmax 0.123%, afr) (gnomAD).

BUB1B p.Gln457=

c.1371A>G · rs141013408 · VCV238661

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

rare (popmax 0.123%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.037	GERP -3.8, phastCons 0.014
Overall
CADD	5.039	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.123% African / African-American · 92/75,050 alleles

Filtering AF 0.102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0948%

Overall 0.00824% 133/1,613,908 alleles · rare exomes 84/1,461,578 · genomes 49/152,330 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.123%	816
Remaining individualsnot grpmax-eligible	0.0448%	2,232
Admixed American	0.00833%	12,004
South Asian	0.0011%	91,072
European (non-Finnish)	0.000593%	168,548

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.Gln457=
Coding: c.1371A>G
MANE Select: NM_001211
dbSNP: rs141013408
Type: single nucleotide variant
Location: chr15:40199697 (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 457: the 'disordered' region

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: colorectal cancer premature chromatid separation trait mosaic variegated aneuploidy syndrome 1

Similar variants

BUB1B p.Gln457His Uncertain significance ★ ⚠ same residue
BUB1B p.Gln457Pro 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-gln457 (accessed [today's date]).

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