Is BUB1B p.Arg349Gln (c.1046G>A) pathogenic?

BUB1B p.Arg349Gln (c.1046G>A) is classified Benign in BUB1B (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0471); Common (popmax 82.5%, afr) — too common for a highly-penetrant pathogenic allele; Associated with mosaic variegated aneuploidy syndrome 1.

What condition is associated with BUB1B p.Arg349Gln (c.1046G>A)?

BUB1B p.Arg349Gln (c.1046G>A) is associated with mosaic variegated aneuploidy syndrome 1 (ClinVar).

What do computational predictors say about BUB1B p.Arg349Gln (c.1046G>A)?

AlphaMissense predicts likely benign (score 0.0471) — an in-silico prediction, not a clinical call.

BUB1B p.Arg349Gln

Q: How common is BUB1B p.Arg349Gln (c.1046G>A) in the general population?

BUB1B p.Arg349Gln (c.1046G>A) is common (popmax 82.5%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1046G>A · rs1801376 · VCV133780

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0471 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 82.5%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

mosaic variegated aneuploidy syndrome 1

Computational evidence

Protein change
AlphaMissense	0.0471	likely benign
REVEL	0.061	moderately benign-leaning
SaProt	LLR -5.75	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 4	GERP -0.073, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 60 kb · p 0.0024 · regional, not allelic
Overall
CADD	16.68	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 82.5% African / African-American · 61,867/74,990 alleles

Filtering AF 82% ClinGen BA1/BS1 input FAF95, joint · FAF99 81.7%

Overall 68.6% 1,106,736/1,612,848 alleles · common exomes 998,301/1,460,684 · genomes 108,435/152,164 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	84.6%	1
African / African-Americangrpmax	82.5%	1
Finnishnot grpmax-eligible	73.4%	1
European (non-Finnish)	70.6%	1
Remaining individualsnot grpmax-eligible	65.7%	2
Admixed American	62.1%	2
Ashkenazi Jewishnot grpmax-eligible	58.8%	2
South Asian	54.9%	2
Middle Eastern	54.5%	2
East Asian	34.7%	3

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg349Gln
Coding: c.1046G>A
MANE Select: NM_001211
dbSNP: rs1801376
Type: single nucleotide variant
Location: chr15:40185630 (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 349: a UniProt-annotated variant site (in)

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

Disease context

mosaic variegated aneuploidy syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

BUB1B p.Arg349= Benign ★ same residue
BUB1B p.Arg349fs Pathogenic ★ 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-arg349gln (accessed [today's date]).

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