Is BUB1 p.Leu751Phe (c.2253A>T) pathogenic?

BUB1 p.Leu751Phe (c.2253A>T) is classified Uncertain significance in BUB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-05). AlphaMissense: ambiguous (0.5585); Absent from gnomAD v4.1.

How common is BUB1 p.Leu751Phe (c.2253A>T) in the general population?

BUB1 p.Leu751Phe (c.2253A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BUB1 p.Leu751Phe (c.2253A>T)?

AlphaMissense predicts ambiguous (score 0.5585) — an in-silico prediction, not a clinical call.

BUB1 p.Leu751Phe

c.2253A>T · rs757521205 · VCV2451238

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5585 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,596,950)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5585	ambiguous
REVEL	0.29	benign-leaning
SaProt	LLR -8.60	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 -0.42	phastCons 0.17
Regional constraint	o/e 0.90	unconstrained · MANE · 40 kb · p 0.00043 · regional, not allelic
Overall
CADD	18.16	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

No allele count reported in gnomAD v4.1 (AN 1,596,950). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: BUB1
Protein: p.Leu751Phe
Coding: c.2253A>T
MANE Select: NM_004336
dbSNP: rs757521205
Type: single nucleotide variant
Location: chr2:110649328 (GRCh38)
Gene constraint: LOEUF 0.727 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.91 · 11 PDB
Residue 751: an α-helix

Full BUB1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BUB1 p.Leu751= Likely benign ★ same residue
BUB1 c.1698+1G>T Uncertain significance ★★ same type
BUB1 p.Ala281Thr Uncertain significance ★★ ⚠ same type
BUB1 p.Ala283Thr Uncertain significance ★★ ⚠ same type
BUB1 p.Ala499Val Uncertain significance ★★ ⚠ same type
BUB1 p.Ala502Ser Uncertain significance ★★ ⚠ same type
BUB1 p.Ala630Gly Uncertain significance ★★ ⚠ same type
BUB1 p.Ala705Thr Uncertain significance ★★ ⚠ same type

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/bub1-p-leu751phe (accessed [today's date]).

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