Is BUB1B p.Ser140Arg (c.418A>C) pathogenic?

BUB1B p.Ser140Arg (c.418A>C) is classified Uncertain significance in BUB1B (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-05-05). AlphaMissense: ambiguous (0.4121); Very rare (popmax 8.47e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with BUB1B p.Ser140Arg (c.418A>C)?

BUB1B p.Ser140Arg (c.418A>C) is associated with Inborn genetic diseases, mosaic variegated aneuploidy syndrome 1 (ClinVar).

How common is BUB1B p.Ser140Arg (c.418A>C) in the general population?

BUB1B p.Ser140Arg (c.418A>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about BUB1B p.Ser140Arg (c.418A>C)?

AlphaMissense predicts ambiguous (score 0.4121) — an in-silico prediction, not a clinical call.

BUB1B p.Ser140Arg

c.418A>C · rs2037225300 · VCV1023315

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4121 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4121	ambiguous
REVEL	0.221	benign-leaning
SaProt	LLR -9.02	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 60 kb · p 0.0024 · regional, not allelic
Overall
CADD	25.4	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 8.47e-05% European (non-Finnish) · 1/1,180,022 alleles

Overall 6.84e-05% 1/1,461,848 alleles · very rare

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.Ser140Arg
Coding: c.418A>C
MANE Select: NM_001211
dbSNP: rs2037225300
Type: single nucleotide variant
Location: chr15:40176510 (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 140: the bub1 n-terminal domain; an α-helix

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: mosaic variegated aneuploidy syndrome 1

Similar variants

BUB1B p.Ser140Gly 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
BUB1B p.Leu737Ter Pathogenic/Likely 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-ser140arg (accessed [today's date]).

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