Is BUB1 p.Leu73= (c.217T>C) pathogenic?

BUB1 p.Leu73= (c.217T>C) is classified Likely benign in BUB1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-17). Very rare (popmax 0.00217%, nfe).

How common is BUB1 p.Leu73= (c.217T>C) in the general population?

BUB1 p.Leu73= (c.217T>C) is very rare (popmax 0.00217%, nfe) (gnomAD).

BUB1 p.Leu73=

c.217T>C · rs765224314 · VCV1787256

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00217%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.3	phastCons 1
Overall
CADD	8.915	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00217% European (non-Finnish) · 24/1,106,474 alleles

Filtering AF 0.00147% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00123%

Overall 0.00164% 25/1,523,386 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00217%	46,103
Remaining individualsnot grpmax-eligible	0.00168%	59,358

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.Leu73=
Coding: c.217T>C
MANE Select: NM_004336
dbSNP: rs765224314
Type: single nucleotide variant
Location: chr2:110674094 (GRCh38)
Gene constraint: LOEUF 0.727 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.91 · 11 PDB
Residue 73: the bub1 n-terminal domain; the 'necessary for kinetochore localization' region; an α-helix

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

Similar variants

BUB1 p.Leu73Phe Uncertain significance ★ ⚠ same residue
BUB1 p.Leu73Ser 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-leu73 (accessed [today's date]).

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