Is BUB1B p.Pro721Arg (c.2162C>G) pathogenic?

BUB1B p.Pro721Arg (c.2162C>G) is classified Uncertain significance in BUB1B (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-19). AlphaMissense: ambiguous (0.4169); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with BUB1B p.Pro721Arg (c.2162C>G)?

BUB1B p.Pro721Arg (c.2162C>G) is associated with Inborn genetic diseases (ClinVar).

How common is BUB1B p.Pro721Arg (c.2162C>G) in the general population?

BUB1B p.Pro721Arg (c.2162C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BUB1B p.Pro721Arg (c.2162C>G)?

AlphaMissense predicts ambiguous (score 0.4169) — an in-silico prediction, not a clinical call.

BUB1B p.Pro721Arg

c.2162C>G · rs2542571599 · VCV1786929

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4169 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4169	ambiguous
REVEL	0.083	moderately benign-leaning
SaProt	LLR -7.91	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>T here scores Δ0.25 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.7	GERP 2.1, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 60 kb · p 0.0024 · regional, not allelic
Overall
CADD	19.72	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: BUB1B
Protein: p.Pro721Arg
Coding: c.2162C>G
MANE Select: NM_001211
dbSNP: rs2542571599
Type: single nucleotide variant
Location: chr15:40209653 (GRCh38)
Gene constraint: LOEUF 0.707 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 64.62 · 9 PDB

Full BUB1B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

BUB1B p.Pro721= Likely benign ★★ same residue
BUB1B c.35+4G>T Uncertain significance ★★ same condition
BUB1B p.Ala1017Thr Uncertain significance ★★ ⚠ same condition
BUB1B p.Ala1046Pro Uncertain significance ★★ ⚠ same condition
BUB1B p.Ala108Thr Uncertain significance ★★ ⚠ same condition
BUB1B p.Ala171Pro Uncertain significance ★★ ⚠ same condition
BUB1B p.Ala173Thr Uncertain significance ★★ ⚠ same condition
BUB1B p.Ala183Thr Uncertain significance ★★ ⚠ same condition

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/bub1b-p-pro721arg (accessed [today's date]).

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