Is BUB1B p.Leu258Phe (c.772C>T) pathogenic?

BUB1B p.Leu258Phe (c.772C>T) is classified Likely benign in BUB1B (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-12-30). AlphaMissense: likely benign (0.0681); Rare (popmax 0.267%, afr); Associated with mosaic variegated aneuploidy syndrome 1.

What condition is associated with BUB1B p.Leu258Phe (c.772C>T)?

BUB1B p.Leu258Phe (c.772C>T) is associated with mosaic variegated aneuploidy syndrome 1 (ClinVar).

How common is BUB1B p.Leu258Phe (c.772C>T) in the general population?

BUB1B p.Leu258Phe (c.772C>T) is rare (popmax 0.267%, afr) (gnomAD).

What do computational predictors say about BUB1B p.Leu258Phe (c.772C>T)?

AlphaMissense predicts likely benign (score 0.0681) — an in-silico prediction, not a clinical call.

BUB1B p.Leu258Phe

c.772C>T · rs146387899 · VCV403745

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0681 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.267%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

mosaic variegated aneuploidy syndrome 1

Computational evidence

Protein change
AlphaMissense	0.0681	likely benign
REVEL	0.028	moderately benign-leaning
SaProt	LLR -7.09	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 0.11	GERP -1.8, phastCons 0.62
Regional constraint	o/e 0.91	unconstrained · MANE · 60 kb · p 0.0024 · regional, not allelic
Overall
CADD	8.711	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 0.267% African / African-American · 200/75,016 alleles

Filtering AF 0.236% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.225%

Overall 0.0139% 224/1,613,990 alleles · rare exomes 107/1,461,790 · genomes 117/152,200 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.267%	375
Remaining individualsnot grpmax-eligible	0.0208%	4,808
Admixed American	0.0167%	6,002
European (non-Finnish)	8.47e-05%	1,179,952

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.Leu258Phe
Coding: c.772C>T
MANE Select: NM_001211
dbSNP: rs146387899
Type: single nucleotide variant
Location: chr15:40185185 (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

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

Similar variants

BUB1B p.Leu258= Likely benign ★★ 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-leu258phe (accessed [today's date]).

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