Is BUB1B p.Val618Ala (c.1853T>C) pathogenic?

BUB1B p.Val618Ala (c.1853T>C) is classified Benign in BUB1B (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.112); Common (popmax 27.7%, afr) — too common for a highly-penetrant pathogenic allele; Associated with colorectal cancer.

What condition is associated with BUB1B p.Val618Ala (c.1853T>C)?

BUB1B p.Val618Ala (c.1853T>C) is associated with colorectal cancer, premature chromatid separation trait, mosaic variegated aneuploidy syndrome 1 (ClinVar).

What do computational predictors say about BUB1B p.Val618Ala (c.1853T>C)?

AlphaMissense predicts likely benign (score 0.112) — an in-silico prediction, not a clinical call.

BUB1B p.Val618Ala

Q: How common is BUB1B p.Val618Ala (c.1853T>C) in the general population?

BUB1B p.Val618Ala (c.1853T>C) is common (popmax 27.7%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1853T>C · rs1801528 · VCV133769

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.112 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 27.7%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

colorectal cancer

Computational evidence

Protein change
AlphaMissense	0.112	likely benign
REVEL	0.066	moderately benign-leaning
SaProt	LLR -6.60	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 0.27	GERP -4.1, phastCons 0.048
Regional constraint	o/e 0.91	unconstrained · MANE · 60 kb · p 0.0024 · regional, not allelic
Overall
CADD	11.28	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 27.7% African / African-American · 20,794/74,950 alleles

Filtering AF 27.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 27.3%

Overall 1.52% 24,512/1,614,076 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	27.7%	4
Remaining individualsnot grpmax-eligible	2.02%	50
Admixed American	1.77%	57
Middle Eastern	1.35%	74
Ashkenazi Jewishnot grpmax-eligible	0.564%	177
European (non-Finnish)	0.0933%	1,072
South Asian	0.0516%	1,938

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.Val618Ala
Coding: c.1853T>C
MANE Select: NM_001211
dbSNP: rs1801528
Type: single nucleotide variant
Location: chr15:40206302 (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 618: a UniProt-annotated variant site (in)

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.Val618= 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
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-val618ala (accessed [today's date]).

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