Is BUB1B p.Trp722Arg (c.2164T>C) pathogenic?

BUB1B p.Trp722Arg (c.2164T>C) is classified Uncertain significance in BUB1B (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-07). AlphaMissense: likely pathogenic (0.9027); Ultra-rare (popmax 0.0624%, eas); Associated with mosaic variegated aneuploidy syndrome 1.

What condition is associated with BUB1B p.Trp722Arg (c.2164T>C)?

BUB1B p.Trp722Arg (c.2164T>C) is associated with mosaic variegated aneuploidy syndrome 1 (ClinVar).

How common is BUB1B p.Trp722Arg (c.2164T>C) in the general population?

BUB1B p.Trp722Arg (c.2164T>C) is ultra-rare (popmax 0.0624%, eas) (gnomAD).

What do computational predictors say about BUB1B p.Trp722Arg (c.2164T>C)?

AlphaMissense predicts likely pathogenic (score 0.9027) — an in-silico prediction, not a clinical call.

BUB1B p.Trp722Arg

c.2164T>C · rs758664966 · VCV465365

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9027 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0624%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

mosaic variegated aneuploidy syndrome 1

Computational evidence

Protein change
AlphaMissense	0.9027	likely pathogenic · top 4% in BUB1B
REVEL	0.154	moderately benign-leaning
SaProt	LLR -9.30	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.21 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.9	GERP 2.1, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 60 kb · p 0.0024 · regional, not allelic
Overall
CADD	22.3	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 0.0624% East Asian · 28/44,884 alleles

Filtering AF 0.0443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0382%

Overall 0.0018% 29/1,614,052 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0624%	1,603
European (non-Finnish)	8.47e-05%	1,180,043

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.Trp722Arg
Coding: c.2164T>C
MANE Select: NM_001211
dbSNP: rs758664966
Type: single nucleotide variant
Location: chr15:40209655 (GRCh38)
Gene constraint: LOEUF 0.707 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 64.62 · 9 PDB

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

Similar variants

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
BUB1B c.2385+4G>C Uncertain significance ★★ 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-trp722arg (accessed [today's date]).

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