Is BUB1 p.Arg146Cys (c.436C>T) pathogenic?

BUB1 p.Arg146Cys (c.436C>T) is classified Uncertain significance in BUB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-21). AlphaMissense: likely benign (0.191); Very rare (popmax 0.005%, nfe).

How common is BUB1 p.Arg146Cys (c.436C>T) in the general population?

BUB1 p.Arg146Cys (c.436C>T) is very rare (popmax 0.005%, nfe) (gnomAD).

What do computational predictors say about BUB1 p.Arg146Cys (c.436C>T)?

AlphaMissense predicts likely benign (score 0.191) — an in-silico prediction, not a clinical call.

BUB1 p.Arg146Cys

c.436C>T · rs368925928 · VCV2464509

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.191 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.191	likely benign
REVEL	0.319	indeterminate
SaProt	LLR -11.68	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.23	loss · gain 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 8.6	phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 40 kb · p 0.00043 · regional, not allelic
Overall
CADD	25.0	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 0.005% European (non-Finnish) · 59/1,179,916 alleles

Filtering AF 0.00394% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00361%

Overall 0.00415% 67/1,613,922 alleles · very rare exomes 63/1,461,744 · genomes 4/152,178 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.005%	19,999
Remaining individualsnot grpmax-eligible	0.0048%	20,827
Admixed American	0.00333%	29,997
African / African-American	0.00267%	37,464
South Asian	0.0011%	91,086

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.Arg146Cys
Coding: c.436C>T
MANE Select: NM_004336
dbSNP: rs368925928
Type: single nucleotide variant
Location: chr2:110670555 (GRCh38)
Gene constraint: LOEUF 0.727 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.91 · 11 PDB
Residue 146: the bub1 n-terminal domain; the 'necessary for kinetochore localization' region

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

Similar variants

BUB1 p.Arg146His 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-arg146cys (accessed [today's date]).

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