Is BUB3 p.Leu196Ile (c.586T>A) pathogenic?

BUB3 p.Leu196Ile (c.586T>A) is classified Uncertain significance in BUB3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-11). AlphaMissense: ambiguous (0.4552); Absent from gnomAD v4.1.

How common is BUB3 p.Leu196Ile (c.586T>A) in the general population?

BUB3 p.Leu196Ile (c.586T>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BUB3 p.Leu196Ile (c.586T>A)?

AlphaMissense predicts ambiguous (score 0.4552) — an in-silico prediction, not a clinical call.

BUB3 p.Leu196Ile

c.586T>A · rs2493765762 · VCV1750189

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4552 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4552	ambiguous
REVEL	0.222	benign-leaning
SaProt	LLR -6.55	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.2	GERP -2.7
Regional constraint	o/e 0.62	unconstrained · MANE · 6,079 bp · p 8.5e-11 · regional, not allelic
Overall
CADD	17.24	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: BUB3
Protein: p.Leu196Ile
Coding: c.586T>A
MANE Select: NM_004725
dbSNP: rs2493765762
Type: single nucleotide variant
Location: chr10:123162245 (GRCh38)
Gene constraint: LOEUF 0.77 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.10

Full BUB3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BUB3 p.Arg314= Likely benign ★★ same type
BUB3 p.Ser197= Likely benign ★★ same type
BUB3 p.Ser198= Likely benign ★★ same type
BUB3 p.Ala131Val Uncertain significance ★ ⚠ same type
BUB3 p.Ala155Val Uncertain significance ★ ⚠ same type
BUB3 p.Ala187Gly Uncertain significance ★ ⚠ same type
BUB3 p.Ala239Gly Uncertain significance ★ ⚠ same type
BUB3 p.Ala292Val 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/bub3-p-leu196ile (accessed [today's date]).

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