Is BUB1 p.Cys1013Arg (c.3037T>C) pathogenic?

BUB1 p.Cys1013Arg (c.3037T>C) is classified Uncertain significance in BUB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-14). AlphaMissense: ambiguous (0.4753); Very rare (popmax 0.00017%, nfe).

How common is BUB1 p.Cys1013Arg (c.3037T>C) in the general population?

BUB1 p.Cys1013Arg (c.3037T>C) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about BUB1 p.Cys1013Arg (c.3037T>C)?

AlphaMissense predicts ambiguous (score 0.4753) — an in-silico prediction, not a clinical call.

BUB1 p.Cys1013Arg

c.3037T>C · rs2467966999 · VCV2565811

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4753 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4753	ambiguous
REVEL	0.136	moderately benign-leaning
SaProt	LLR -5.95	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>C here scores Δ0.40 · evaluated, not missing
Constraint at this position
Conservation	phyloP 11	phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 40 kb · p 0.00043 · regional, not allelic
Overall
CADD	23.9	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 0.00017% European (non-Finnish) · 2/1,179,688 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,610 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: BUB1
Protein: p.Cys1013Arg
Coding: c.3037T>C
MANE Select: NM_004336
dbSNP: rs2467966999
Type: single nucleotide variant
Location: chr2:110639767 (GRCh38)
Gene constraint: LOEUF 0.727 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.91 · 11 PDB
Residue 1013: the protein kinase domain; a β-strand

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

Similar variants

BUB1 p.Cys1013Tyr 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-cys1013arg (accessed [today's date]).

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