Is BUB1B p.Arg416Trp (c.1246C>T) pathogenic?

BUB1B p.Arg416Trp (c.1246C>T) is classified Uncertain significance in BUB1B (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-27). AlphaMissense: likely pathogenic (0.7658); Very rare (popmax 0.00237%, nfe); Associated with Inborn genetic diseases.

What condition is associated with BUB1B p.Arg416Trp (c.1246C>T)?

BUB1B p.Arg416Trp (c.1246C>T) is associated with Inborn genetic diseases, mosaic variegated aneuploidy syndrome 1 (ClinVar).

How common is BUB1B p.Arg416Trp (c.1246C>T) in the general population?

BUB1B p.Arg416Trp (c.1246C>T) is very rare (popmax 0.00237%, nfe) (gnomAD).

What do computational predictors say about BUB1B p.Arg416Trp (c.1246C>T)?

AlphaMissense predicts likely pathogenic (score 0.7658) — an in-silico prediction, not a clinical call.

BUB1B p.Arg416Trp

c.1246C>T · rs755579898 · VCV1004921

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7658 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00237%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7658	likely pathogenic · top 9% in BUB1B
REVEL	0.285	benign-leaning
SaProt	LLR -14.26	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 2.2, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 60 kb · p 0.0024 · regional, not allelic
Overall
CADD	29.3	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 0.00237% European (non-Finnish) · 28/1,179,924 alleles

Filtering AF 0.00165% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00142%

Overall 0.0018% 29/1,613,820 alleles · very rare exomes 28/1,461,730 · genomes 1/152,090 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00237%	42,140
African / African-American	0.00134%	74,898

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.Arg416Trp
Coding: c.1246C>T
MANE Select: NM_001211
dbSNP: rs755579898
Type: single nucleotide variant
Location: chr15:40196732 (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: mosaic variegated aneuploidy syndrome 1

Similar variants

BUB1B p.Arg416= Likely benign ★★ same residue
BUB1B p.Arg416Gln Uncertain significance ★ ⚠ same residue
BUB1B p.Arg416Leu 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

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-arg416trp (accessed [today's date]).

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