Is BUB1B p.Arg194Pro (c.581G>C) pathogenic?

BUB1B p.Arg194Pro (c.581G>C) is classified Uncertain significance in BUB1B (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-16). AlphaMissense: likely pathogenic (0.9364); Absent from gnomAD v4.1; Associated with premature chromatid separation trait.

What condition is associated with BUB1B p.Arg194Pro (c.581G>C)?

BUB1B p.Arg194Pro (c.581G>C) is associated with premature chromatid separation trait (ClinVar).

How common is BUB1B p.Arg194Pro (c.581G>C) in the general population?

BUB1B p.Arg194Pro (c.581G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BUB1B p.Arg194Pro (c.581G>C)?

AlphaMissense predicts likely pathogenic (score 0.9364) — an in-silico prediction, not a clinical call.

BUB1B p.Arg194Pro

c.581G>C · rs567916146 · VCV2680364

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9364 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

premature chromatid separation trait

Computational evidence

Protein change
AlphaMissense	0.9364	likely pathogenic · top 3% in BUB1B
REVEL	0.198	benign-leaning
SaProt	LLR -15.13	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	Δ0.81	donor loss · deltas
Pangolin	Δ0.76	loss · gain 0.01 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 60 kb · p 0.0024 · regional, not allelic
Overall
CADD	35.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: BUB1B
Protein: p.Arg194Pro
Coding: c.581G>C
MANE Select: NM_001211
dbSNP: rs567916146
Type: single nucleotide variant
Location: chr15:40176673 (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 194: the bub1 n-terminal domain; an α-helix

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

Disease context

premature chromatid separation trait — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

BUB1B p.Arg194Ter Pathogenic/Likely pathogenic ★★ same residue
BUB1B p.Arg194Gln Uncertain significance ★★ ⚠ same residue
BUB1B p.Arg194Gly Uncertain significance ★ ⚠ same residue
BUB1B p.Arg194= Likely benign ★ same residue
BUB1B p.Ala348Val Uncertain significance ★★ ⚠ same condition
BUB1B p.Ala388Val Uncertain significance ★★ ⚠ same condition
BUB1B p.Ala784Val Uncertain significance ★★ ⚠ same condition
BUB1B p.Arg199Gln 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-arg194pro (accessed [today's date]).

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