Is BUB1 p.Arg1070Cys (c.3208C>T) pathogenic?

BUB1 p.Arg1070Cys (c.3208C>T) is classified Uncertain significance in BUB1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-08-24). AlphaMissense: likely benign (0.1776); Ultra-rare (popmax 0.0181%, eas).

How common is BUB1 p.Arg1070Cys (c.3208C>T) in the general population?

BUB1 p.Arg1070Cys (c.3208C>T) is ultra-rare (popmax 0.0181%, eas) (gnomAD).

What do computational predictors say about BUB1 p.Arg1070Cys (c.3208C>T)?

AlphaMissense predicts likely benign (score 0.1776) — an in-silico prediction, not a clinical call.

BUB1 p.Arg1070Cys

c.3208C>T · rs191292475 · VCV2464519

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1776 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0181%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1776	likely benign
REVEL	0.096	moderately benign-leaning
SaProt	LLR -11.66	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.3	phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 40 kb · p 0.00043 · regional, not allelic
Overall
CADD	25.5	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 0.0181% East Asian · 8/44,268 alleles

Filtering AF 0.00894% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00648%

Overall 0.00157% 25/1,593,842 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0181%	5,534
Remaining individualsnot grpmax-eligible	0.00162%	61,602
European (non-Finnish)	0.00137%	73,195

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: BUB1
Protein: p.Arg1070Cys
Coding: c.3208C>T
MANE Select: NM_004336
dbSNP: rs191292475
Type: single nucleotide variant
Location: chr2:110638014 (GRCh38)
Gene constraint: LOEUF 0.727 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.91 · 11 PDB
Residue 1070: the protein kinase domain; an α-helix

Full BUB1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BUB1 p.Arg1070His Uncertain significance ★ ⚠ same residue
BUB1 p.Arg1070Leu Uncertain significance ★ ⚠ same residue
BUB1 p.Arg1070Pro Uncertain significance ★ ⚠ same residue
BUB1 p.Arg1070= Likely benign ★ same residue
BUB1 c.1698+1G>T Uncertain significance ★★ same type
BUB1 p.Ala281Thr Uncertain significance ★★ ⚠ same type
BUB1 p.Ala283Thr Uncertain significance ★★ ⚠ same type
BUB1 p.Ala499Val 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/bub1-p-arg1070cys (accessed [today's date]).

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