Is BUB1 p.Ile103Val (c.307A>G) pathogenic?

BUB1 p.Ile103Val (c.307A>G) is classified Conflicting classifications of pathogenicity in BUB1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-01-18). AlphaMissense: likely benign (0.0592); Ultra-rare (popmax 0.0362%, sas).

How common is BUB1 p.Ile103Val (c.307A>G) in the general population?

BUB1 p.Ile103Val (c.307A>G) is ultra-rare (popmax 0.0362%, sas) (gnomAD).

What do computational predictors say about BUB1 p.Ile103Val (c.307A>G)?

AlphaMissense predicts likely benign (score 0.0592) — an in-silico prediction, not a clinical call.

BUB1 p.Ile103Val

c.307A>G · VCV3483108

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0592 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0362%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0592	likely benign
REVEL	0.064	moderately benign-leaning
SaProt	LLR -5.75	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 -12
Regional constraint	o/e 0.90	unconstrained · MANE · 40 kb · p 0.00043 · regional, not allelic
Overall
CADD	0.005	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 0.0362% South Asian · 33/91,060 alleles

Filtering AF 0.0265% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0231%

Overall 0.00527% 85/1,614,106 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0362%	2,759
Admixed American	0.005%	20,004
European (non-Finnish)	0.0039%	25,652
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604
Remaining individualsnot grpmax-eligible	0.0016%	62,502
African / African-American	0.00133%	75,036

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.Ile103Val
Coding: c.307A>G
MANE Select: NM_004336
Type: single nucleotide variant
Location: chr2:110672776 (GRCh38)
Gene constraint: LOEUF 0.727 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.91 · 11 PDB
Residue 103: the bub1 n-terminal domain; the 'necessary for kinetochore localization' region; the 'necessary for interaction with knl1' region; an α-helix

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

Similar variants

BUB1 p.Ile103Phe 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
BUB1 p.Ala705Thr 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-ile103val (accessed [today's date]).

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