Is BUB1 p.Ala76Thr (c.226G>A) pathogenic?

BUB1 p.Ala76Thr (c.226G>A) is classified Uncertain significance in BUB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-19). AlphaMissense: likely benign (0.2287); Very rare (popmax 0.00757%, amr).

How common is BUB1 p.Ala76Thr (c.226G>A) in the general population?

BUB1 p.Ala76Thr (c.226G>A) is very rare (popmax 0.00757%, amr) (gnomAD).

What do computational predictors say about BUB1 p.Ala76Thr (c.226G>A)?

AlphaMissense predicts likely benign (score 0.2287) — an in-silico prediction, not a clinical call.

BUB1 p.Ala76Thr

c.226G>A · rs767955240 · VCV1788763

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2287 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00757%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2287	likely benign
REVEL	0.441	indeterminate
SaProt	LLR -8.72	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 40 kb · p 0.00043 · regional, not allelic
Overall
CADD	27.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00757% Admixed American · 4/52,854 alleles

Filtering AF 0.00257% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00149%

Overall 0.00028% 4/1,427,494 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.Ala76Thr
Coding: c.226G>A
MANE Select: NM_004336
dbSNP: rs767955240
Type: single nucleotide variant
Location: chr2:110672857 (GRCh38)
Gene constraint: LOEUF 0.727 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.91 · 11 PDB
Residue 76: 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 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-ala76thr (accessed [today's date]).

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