Is BUB1 p.Val167Ile (c.499G>A) pathogenic?

BUB1 p.Val167Ile (c.499G>A) is classified Conflicting classifications of pathogenicity in BUB1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-08-19). AlphaMissense: likely benign (0.0628); Ultra-rare (popmax 0.04%, amr).

How common is BUB1 p.Val167Ile (c.499G>A) in the general population?

BUB1 p.Val167Ile (c.499G>A) is ultra-rare (popmax 0.04%, amr) (gnomAD).

What do computational predictors say about BUB1 p.Val167Ile (c.499G>A)?

AlphaMissense predicts likely benign (score 0.0628) — an in-silico prediction, not a clinical call.

BUB1 p.Val167Ile

c.499G>A · rs772759859 · VCV2464693

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0628 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.04%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0628	likely benign
REVEL	0.016	strongly benign-leaning
SaProt	LLR -6.83	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 0.28	phastCons 0.12
Regional constraint	o/e 0.90	unconstrained · MANE · 40 kb · p 0.00043 · regional, not allelic
Overall
CADD	3.425	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 0.04% Admixed American · 24/60,002 alleles

Filtering AF 0.0276% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0234%

Overall 0.00491% 79/1,609,188 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.04%	2,500
European (non-Finnish)	0.00434%	23,057
Remaining individualsnot grpmax-eligible	0.00321%	31,157
Finnishnot grpmax-eligible	0.00157%	63,832
South Asian	0.0011%	90,942

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.Val167Ile
Coding: c.499G>A
MANE Select: NM_004336
dbSNP: rs772759859
Type: single nucleotide variant
Location: chr2:110669521 (GRCh38)
Gene constraint: LOEUF 0.727 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.91 · 11 PDB
Residue 167: the bub1 n-terminal domain

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

Similar variants

BUB1 p.Val167Leu Uncertain significance ★ ⚠ same residue
BUB1 p.Val167Phe 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-val167ile (accessed [today's date]).

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