Is BUB1B p.Ala784Val (c.2351C>T) pathogenic?

BUB1B p.Ala784Val (c.2351C>T) is classified Uncertain significance in BUB1B (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-10). AlphaMissense: likely benign (0.0955); Ultra-rare (popmax 0.0335%, afr); Associated with mosaic variegated aneuploidy syndrome 1.

What condition is associated with BUB1B p.Ala784Val (c.2351C>T)?

BUB1B p.Ala784Val (c.2351C>T) is associated with mosaic variegated aneuploidy syndrome 1, colorectal cancer, premature chromatid separation trait (ClinVar).

How common is BUB1B p.Ala784Val (c.2351C>T) in the general population?

BUB1B p.Ala784Val (c.2351C>T) is ultra-rare (popmax 0.0335%, afr) (gnomAD).

What do computational predictors say about BUB1B p.Ala784Val (c.2351C>T)?

AlphaMissense predicts likely benign (score 0.0955) — an in-silico prediction, not a clinical call.

BUB1B p.Ala784Val

c.2351C>T · rs142705245 · VCV403751

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0955 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0335%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

mosaic variegated aneuploidy syndrome 1

Computational evidence

Protein change
AlphaMissense	0.0955	likely benign
REVEL	0.014	strongly benign-leaning
SaProt	LLR -8.51	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 1.4	GERP 0.29, phastCons 0.8
Regional constraint	o/e 0.91	unconstrained · MANE · 60 kb · p 0.0024 · regional, not allelic
Overall
CADD	15.85	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 0.0335% African / African-American · 25/74,688 alleles

Filtering AF 0.0232% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0198%

Overall 0.00255% 41/1,610,788 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0335%	2,988
South Asian	0.00549%	18,200
Remaining individualsnot grpmax-eligible	0.00321%	31,184
East Asian	0.00223%	44,820
Admixed American	0.00167%	59,950
European (non-Finnish)	0.000594%	168,226

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.Ala784Val
Coding: c.2351C>T
MANE Select: NM_001211
dbSNP: rs142705245
Type: single nucleotide variant
Location: chr15:40210176 (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 784: the protein kinase domain

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

Disease context

mosaic variegated aneuploidy syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: colorectal cancer premature chromatid separation trait

Similar variants

BUB1B p.Ala784= Likely benign ★★ same residue
BUB1B p.Ala784Thr 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

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-ala784val (accessed [today's date]).

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