Is BUB1 p.Ser752Pro (c.2254T>C) pathogenic?

BUB1 p.Ser752Pro (c.2254T>C) is classified Uncertain significance in BUB1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-06). AlphaMissense: ambiguous (0.5404); Very rare (popmax 0.00806%, nfe).

How common is BUB1 p.Ser752Pro (c.2254T>C) in the general population?

BUB1 p.Ser752Pro (c.2254T>C) is very rare (popmax 0.00806%, nfe) (gnomAD).

What do computational predictors say about BUB1 p.Ser752Pro (c.2254T>C)?

AlphaMissense predicts ambiguous (score 0.5404) — an in-silico prediction, not a clinical call.

BUB1 p.Ser752Pro

c.2254T>C · rs770939889 · VCV1788498

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5404 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00806%, nfe)

Computational evidence

Protein change
AlphaMissense	0.5404	ambiguous
REVEL	0.316	indeterminate
SaProt	LLR -13.11	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 40 kb · p 0.00043 · regional, not allelic
Overall
CADD	22.2	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 0.00806% European (non-Finnish) · 95/1,178,328 alleles

Filtering AF 0.00673% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00625%

Overall 0.00621% 100/1,611,182 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00806%	12,403
African / African-American	0.00535%	18,706
Remaining individualsnot grpmax-eligible	0.00161%	62,294

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: BUB1
Protein: p.Ser752Pro
Coding: c.2254T>C
MANE Select: NM_004336
dbSNP: rs770939889
Type: single nucleotide variant
Location: chr2:110649327 (GRCh38)
Gene constraint: LOEUF 0.727 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.91 · 11 PDB
Residue 752: an α-helix

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

Similar variants

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
BUB1 p.Ala797Gly 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-ser752pro (accessed [today's date]).

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