Is BUB1 p.Ile69Phe (c.205A>T) pathogenic?

BUB1 p.Ile69Phe (c.205A>T) is classified Uncertain significance in BUB1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-12-26). AlphaMissense: ambiguous (0.3431); Very rare (popmax 9.01e-05%, nfe).

How common is BUB1 p.Ile69Phe (c.205A>T) in the general population?

BUB1 p.Ile69Phe (c.205A>T) is very rare (popmax 9.01e-05%, nfe) (gnomAD).

What do computational predictors say about BUB1 p.Ile69Phe (c.205A>T)?

AlphaMissense predicts ambiguous (score 0.3431) — an in-silico prediction, not a clinical call.

BUB1 p.Ile69Phe

c.205A>T · rs780901314 · VCV1785187

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3431 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 9.01e-05%, nfe)

Computational evidence

Protein change
AlphaMissense	0.3431	ambiguous
REVEL	0.509	indeterminate
SaProt	LLR -11.48	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	23.6	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 9.01e-05% European (non-Finnish) · 1/1,109,718 alleles

Overall 0.000657% 1/152,264 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: BUB1
Protein: p.Ile69Phe
Coding: c.205A>T
MANE Select: NM_004336
dbSNP: rs780901314
Type: single nucleotide variant
Location: chr2:110674106 (GRCh38)
Gene constraint: LOEUF 0.727 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.91 · 11 PDB
Residue 69: the bub1 n-terminal domain; the 'necessary for kinetochore localization' region; an α-helix

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

Similar variants

BUB1 p.Ile69Asn Uncertain significance ★ ⚠ same residue
BUB1 p.Ile69Leu Uncertain significance ★ ⚠ 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

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-ile69phe (accessed [today's date]).

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