Is BUB1B p.Leu1012Pro (c.3035T>C) pathogenic?

BUB1B p.Leu1012Pro (c.3035T>C) is classified Uncertain significance in BUB1B (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-26). AlphaMissense: likely pathogenic (0.872); Ultra-rare (popmax 0.0184%, nfe); Associated with colorectal cancer.

What condition is associated with BUB1B p.Leu1012Pro (c.3035T>C)?

BUB1B p.Leu1012Pro (c.3035T>C) is associated with colorectal cancer, premature chromatid separation trait, mosaic variegated aneuploidy syndrome 1 (ClinVar).

How common is BUB1B p.Leu1012Pro (c.3035T>C) in the general population?

BUB1B p.Leu1012Pro (c.3035T>C) is ultra-rare (popmax 0.0184%, nfe) (gnomAD).

What do computational predictors say about BUB1B p.Leu1012Pro (c.3035T>C)?

AlphaMissense predicts likely pathogenic (score 0.872) — an in-silico prediction, not a clinical call.

BUB1B p.Leu1012Pro

c.3035T>C · rs28989185 · VCV6765

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.872 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0184%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

colorectal cancer

Computational evidence

Protein change
AlphaMissense	0.872	likely pathogenic · top 5% in BUB1B
REVEL	0.5	indeterminate
SaProt	LLR -10.17	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.4, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 60 kb · p 0.0024 · regional, not allelic
Overall
CADD	26.7	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 0.0184% European (non-Finnish) · 217/1,180,044 alleles

Filtering AF 0.0164% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0156%

Overall 0.0137% 221/1,614,122 alleles · ultra-rare exomes 219/1,461,878 · genomes 2/152,244 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0184%	5,438
South Asian	0.00329%	30,363
Remaining individualsnot grpmax-eligible	0.0016%	62,488

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.Leu1012Pro
Coding: c.3035T>C
MANE Select: NM_001211
dbSNP: rs28989185
Type: single nucleotide variant
Location: chr15:40220641 (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 1012: the protein kinase domain; a UniProt-annotated variant site (in mva1; heterozygous compound with nonsense mutation)

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.Leu1012Phe 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-leu1012pro (accessed [today's date]).

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