Is BUB1 p.Ala226Val (c.677C>T) pathogenic?

BUB1 p.Ala226Val (c.677C>T) is classified Benign/Likely benign in BUB1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-05-01). AlphaMissense: likely benign (0.0999); Rare (popmax 0.373%, nfe).

How common is BUB1 p.Ala226Val (c.677C>T) in the general population?

BUB1 p.Ala226Val (c.677C>T) is rare (popmax 0.373%, nfe) (gnomAD).

What do computational predictors say about BUB1 p.Ala226Val (c.677C>T)?

AlphaMissense predicts likely benign (score 0.0999) — an in-silico prediction, not a clinical call.

BUB1 p.Ala226Val

c.677C>T · rs61730706 · VCV710415

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0999 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.373%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0999	likely benign
REVEL	0.042	moderately benign-leaning
SaProt	LLR -6.61	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 3.9	phastCons 0.93
Regional constraint	o/e 0.90	unconstrained · MANE · 40 kb · p 0.00043 · regional, not allelic
Overall
CADD	23.2	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 0.373% European (non-Finnish) · 4,399/1,179,950 alleles

Filtering AF 0.364% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.36%

Overall 0.306% 4,945/1,613,912 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.373%	268
Finnishnot grpmax-eligible	0.331%	302
Remaining individualsnot grpmax-eligible	0.274%	365
South Asian	0.0791%	1,264
Admixed American	0.0684%	1,463
African / African-American	0.0613%	1,631
Middle Eastern	0.0495%	2,020
East Asian	0.00223%	44,860

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.Ala226Val
Coding: c.677C>T
MANE Select: NM_004336
dbSNP: rs61730706
Type: single nucleotide variant
Location: chr2:110667649 (GRCh38)
Gene constraint: LOEUF 0.727 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.91 · 11 PDB

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

Similar variants

BUB1 p.Ala226Glu Uncertain significance ★ ⚠ same residue
BUB1 p.Ala226Pro Uncertain significance ★ ⚠ same residue
BUB1 p.Ala226Thr Uncertain significance ★ ⚠ same residue
BUB1 p.Ala226= 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

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-ala226val (accessed [today's date]).

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