Is BUB1 p.Arg556His (c.1667G>A) pathogenic?

BUB1 p.Arg556His (c.1667G>A) is classified Uncertain significance in BUB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-30). AlphaMissense: likely benign (0.1102); Very rare (popmax 0.0011%, sas).

How common is BUB1 p.Arg556His (c.1667G>A) in the general population?

BUB1 p.Arg556His (c.1667G>A) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about BUB1 p.Arg556His (c.1667G>A)?

AlphaMissense predicts likely benign (score 0.1102) — an in-silico prediction, not a clinical call.

BUB1 p.Arg556His

c.1667G>A · rs1393761545 · VCV1777591

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1102 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1102	likely benign
REVEL	0.047	moderately benign-leaning
SaProt	LLR -7.54	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 40 kb · p 0.00043 · regional, not allelic
Overall
CADD	23.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/90,894 alleles

Overall 0.000124% 2/1,612,810 alleles · very rare exomes 1/1,460,728 · genomes 1/152,082 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	90,894
European (non-Finnish)	8.48e-05%	1,179,352

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.Arg556His
Coding: c.1667G>A
MANE Select: NM_004336
dbSNP: rs1393761545
Type: single nucleotide variant
Location: chr2:110657067 (GRCh38)
Gene constraint: LOEUF 0.727 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.91 · 11 PDB
Residue 556: the 'disordered' region

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

Similar variants

BUB1 p.Arg556Gly 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-arg556his (accessed [today's date]).

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