Is BUB3 p.Arg274Trp (c.820C>T) pathogenic?

BUB3 p.Arg274Trp (c.820C>T) is classified Uncertain significance in BUB3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-12). AlphaMissense: likely pathogenic (0.8796); Very rare (popmax 0.00446%, eas).

How common is BUB3 p.Arg274Trp (c.820C>T) in the general population?

BUB3 p.Arg274Trp (c.820C>T) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about BUB3 p.Arg274Trp (c.820C>T)?

AlphaMissense predicts likely pathogenic (score 0.8796) — an in-silico prediction, not a clinical call.

BUB3 p.Arg274Trp

c.820C>T · rs1004863018 · VCV2496862

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8796 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8796	likely pathogenic
REVEL	0.491	indeterminate
SaProt	LLR -14.27	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.91 · evaluated, not missing
Constraint at this position
Conservation	phyloP 6	GERP 2.6, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 6,079 bp · p 8.5e-11 · regional, not allelic
Overall
CADD	33.0	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 0.00446% East Asian · 2/44,844 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000277%

Overall 0.000894% 13/1,454,924 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,422
African / African-American	0.00269%	37,231
Finnishnot grpmax-eligible	0.00156%	64,006
South Asian	0.00112%	89,248
European (non-Finnish)	0.000594%	168,347

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: BUB3
Protein: p.Arg274Trp
Coding: c.820C>T
MANE Select: NM_004725
dbSNP: rs1004863018
Type: single nucleotide variant
Location: chr10:123162677 (GRCh38)
Gene constraint: LOEUF 0.77 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.10

Full BUB3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BUB3 p.Arg274Gln Uncertain significance ★ ⚠ same residue
BUB3 p.Arg314= Likely benign ★★ same type
BUB3 p.Ser197= Likely benign ★★ same type
BUB3 p.Ser198= Likely benign ★★ same type
BUB3 p.Ala131Val Uncertain significance ★ ⚠ same type
BUB3 p.Ala155Val Uncertain significance ★ ⚠ same type
BUB3 p.Ala187Gly Uncertain significance ★ ⚠ same type
BUB3 p.Ala239Gly Uncertain significance ★ ⚠ same type

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/bub3-p-arg274trp (accessed [today's date]).

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