Is BUB1B p.Arg677His (c.2030G>A) pathogenic?

BUB1B p.Arg677His (c.2030G>A) is classified Conflicting classifications of pathogenicity in BUB1B (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-06-04). AlphaMissense: likely benign (0.0823); Ultra-rare (popmax 0.011%, sas); Associated with Inborn genetic diseases.

What condition is associated with BUB1B p.Arg677His (c.2030G>A)?

BUB1B p.Arg677His (c.2030G>A) is associated with Inborn genetic diseases, ovarian cancer, mosaic variegated aneuploidy syndrome 1 (ClinVar).

How common is BUB1B p.Arg677His (c.2030G>A) in the general population?

BUB1B p.Arg677His (c.2030G>A) is ultra-rare (popmax 0.011%, sas) (gnomAD).

What do computational predictors say about BUB1B p.Arg677His (c.2030G>A)?

AlphaMissense predicts likely benign (score 0.0823) — an in-silico prediction, not a clinical call.

BUB1B p.Arg677His

c.2030G>A · rs557521971 · VCV582609

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0823 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.011%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0823	likely benign
REVEL	0.035	moderately benign-leaning
SaProt	LLR -6.32	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 3.9	GERP -0.018, phastCons 0.61
Regional constraint	o/e 0.91	unconstrained · MANE · 60 kb · p 0.0024 · regional, not allelic
Overall
CADD	18.36	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 0.011% South Asian · 10/91,050 alleles

Filtering AF 0.00594% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00453%

Overall 0.0018% 29/1,613,654 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.011%	9,105
African / African-American	0.00933%	10,715
Remaining individualsnot grpmax-eligible	0.0064%	15,623
East Asian	0.00446%	22,442
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,594
Admixed American	0.00167%	59,990
European (non-Finnish)	0.000339%	294,930

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.Arg677His
Coding: c.2030G>A
MANE Select: NM_001211
dbSNP: rs557521971
Type: single nucleotide variant
Location: chr15:40208657 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: ovarian cancer mosaic variegated aneuploidy syndrome 1

Similar variants

BUB1B p.Arg677Cys Uncertain significance ★★ ⚠ same residue
BUB1B p.Arg677Gly Uncertain significance ★ ⚠ same residue
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

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-arg677his (accessed [today's date]).

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