Is BUB3 p.Glu14Lys (c.40G>A) pathogenic?

BUB3 p.Glu14Lys (c.40G>A) is classified Uncertain significance in BUB3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-09). AlphaMissense: likely benign (0.2186); Very rare (popmax 0.00102%, nfe).

How common is BUB3 p.Glu14Lys (c.40G>A) in the general population?

BUB3 p.Glu14Lys (c.40G>A) is very rare (popmax 0.00102%, nfe) (gnomAD).

What do computational predictors say about BUB3 p.Glu14Lys (c.40G>A)?

AlphaMissense predicts likely benign (score 0.2186) — an in-silico prediction, not a clinical call.

BUB3 p.Glu14Lys

c.40G>A · rs1248622589 · VCV1737837

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2186 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00102%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2186	likely benign
REVEL	0.244	benign-leaning
SaProt	LLR -8.30	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 9.9	GERP 0.47, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 2,834 bp · p 0.91 · regional, not allelic
Overall
CADD	25.0	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 0.00102% European (non-Finnish) · 12/1,180,014 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.000821% 12/1,461,830 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: BUB3
Protein: p.Glu14Lys
Coding: c.40G>A
MANE Select: NM_004725
dbSNP: rs1248622589
Type: single nucleotide variant
Location: chr10:123154957 (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.Glu14Gly Uncertain significance ★ ⚠ same residue
BUB3 p.Glu14= Likely benign ★ same residue
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

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-glu14lys (accessed [today's date]).

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