Is BUB1B p.Lys1033= (c.3099A>G) pathogenic?

BUB1B p.Lys1033= (c.3099A>G) is classified Benign in BUB1B (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-03). Common (popmax 28.8%, afr) — too common for a highly-penetrant pathogenic allele; Associated with colorectal cancer.

What condition is associated with BUB1B p.Lys1033= (c.3099A>G)?

BUB1B p.Lys1033= (c.3099A>G) is associated with colorectal cancer, premature chromatid separation trait, mosaic variegated aneuploidy syndrome 1 (ClinVar).

BUB1B p.Lys1033=

Q: How common is BUB1B p.Lys1033= (c.3099A>G) in the general population?

BUB1B p.Lys1033= (c.3099A>G) is common (popmax 28.8%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.3099A>G · rs35611758 · VCV257638

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Common

common (popmax 28.8%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

colorectal cancer

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.4, phastCons 1
Overall
CADD	12.62	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 28.8% African / African-American · 21,590/74,940 alleles

Filtering AF 28.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 28.4%

Overall 1.57% 25,400/1,614,064 alleles · common exomes 12,932/1,461,864 · genomes 12,468/152,200 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	28.8%	3
Remaining individualsnot grpmax-eligible	2.1%	48
Admixed American	1.82%	55
Middle Eastern	1.37%	73
Ashkenazi Jewishnot grpmax-eligible	0.564%	177
European (non-Finnish)	0.0935%	1,070
South Asian	0.0593%	1,687

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.Lys1033=
Coding: c.3099A>G
MANE Select: NM_001211
dbSNP: rs35611758
Type: single nucleotide variant
Location: chr15:40220705 (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 1033: the protein kinase domain

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

Disease context

colorectal cancer — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: premature chromatid separation trait mosaic variegated aneuploidy syndrome 1

Similar variants

BUB1B p.Lys1033Arg 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
BUB1B p.Leu737Ter 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-lys1033 (accessed [today's date]).

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