Is BUB1B p.Cys399Arg (c.1195T>C) pathogenic?

BUB1B p.Cys399Arg (c.1195T>C) is classified Uncertain significance in BUB1B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-09). AlphaMissense: likely pathogenic (0.7277); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with BUB1B p.Cys399Arg (c.1195T>C)?

BUB1B p.Cys399Arg (c.1195T>C) is associated with Inborn genetic diseases (ClinVar).

How common is BUB1B p.Cys399Arg (c.1195T>C) in the general population?

BUB1B p.Cys399Arg (c.1195T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BUB1B p.Cys399Arg (c.1195T>C)?

AlphaMissense predicts likely pathogenic (score 0.7277) — an in-silico prediction, not a clinical call.

BUB1B p.Cys399Arg

c.1195T>C · VCV3993721

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7277 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7277	likely pathogenic · top 10% in BUB1B
REVEL	0.412	indeterminate
SaProt	LLR -3.38	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>G here scores Δ0.74 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.8	GERP 2.2, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 60 kb · p 0.0024 · regional, not allelic
Overall
CADD	25.7	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.Cys399Arg
Coding: c.1195T>C
MANE Select: NM_001211
Type: single nucleotide variant
Location: chr15:40196681 (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.Cys399Phe Uncertain significance ★ ⚠ 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-cys399arg (accessed [today's date]).

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