Is BUB1 p.Arg1070His (c.3209G>A) pathogenic?

BUB1 p.Arg1070His (c.3209G>A) is classified Uncertain significance in BUB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-14). AlphaMissense: likely benign (0.1228); Ultra-rare (popmax 0.0512%, mid).

How common is BUB1 p.Arg1070His (c.3209G>A) in the general population?

BUB1 p.Arg1070His (c.3209G>A) is ultra-rare (popmax 0.0512%, mid) (gnomAD).

What do computational predictors say about BUB1 p.Arg1070His (c.3209G>A)?

AlphaMissense predicts likely benign (score 0.1228) — an in-silico prediction, not a clinical call.

BUB1 p.Arg1070His

c.3209G>A · rs765636832 · VCV1728892

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1228 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0512%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1228	likely benign
REVEL	0.165	moderately benign-leaning
SaProt	LLR -6.80	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 1.1	phastCons 0.53
Regional constraint	o/e 0.90	unconstrained · MANE · 40 kb · p 0.00043 · regional, not allelic
Overall
CADD	23.5	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 0.0512% Middle Eastern · 3/5,860 alleles

Filtering AF 0.0139% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00742%

Overall 0.000485% 7/1,441,822 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0512%	1,953
East Asian	0.00226%	44,302
Admixed American	0.00177%	56,490
South Asian	0.00115%	86,856
European (non-Finnish)	8.54e-05%	1,171,245

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.Arg1070His
Coding: c.3209G>A
MANE Select: NM_004336
dbSNP: rs765636832
Type: single nucleotide variant
Location: chr2:110638013 (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.Arg1070Cys 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-arg1070his (accessed [today's date]).

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