Is BUB1 p.Val738= (c.2214T>C) pathogenic?

BUB1 p.Val738= (c.2214T>C) is classified Uncertain significance in BUB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-20). Very rare (popmax 0.000256%, nfe).

How common is BUB1 p.Val738= (c.2214T>C) in the general population?

BUB1 p.Val738= (c.2214T>C) is very rare (popmax 0.000256%, nfe) (gnomAD).

BUB1 p.Val738=

c.2214T>C · VCV4706150

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000256%, 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 0.97	phastCons 0.99
Overall
CADD	7.05	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000256% European (non-Finnish) · 3/1,171,298 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000189% 3/1,591,268 alleles · very rare exomes 2/1,439,514 · genomes 1/151,754 · joint denominator

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.Val738=
Coding: c.2214T>C
MANE Select: NM_004336
Type: single nucleotide variant
Location: chr2:110649367 (GRCh38)
Gene constraint: LOEUF 0.727 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.91 · 11 PDB
Residue 738: a β-strand

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

Similar variants

BUB1 p.Val738Ala Uncertain significance ★★ ⚠ same residue
BUB1 p.Val738Gly Uncertain significance ★ same residue
BUB1 p.Val738Ile Uncertain significance ★ ⚠ same residue
BUB1 p.Val738Leu 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

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-val738 (accessed [today's date]).

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