Is BUB1 p.His620Pro (c.1859A>C) pathogenic?

BUB1 p.His620Pro (c.1859A>C) is classified Conflicting classifications of pathogenicity in BUB1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-11-18). AlphaMissense: likely benign (0.0593); Rare (popmax 0.452%, afr).

How common is BUB1 p.His620Pro (c.1859A>C) in the general population?

BUB1 p.His620Pro (c.1859A>C) is rare (popmax 0.452%, afr) (gnomAD).

What do computational predictors say about BUB1 p.His620Pro (c.1859A>C)?

AlphaMissense predicts likely benign (score 0.0593) — an in-silico prediction, not a clinical call.

BUB1 p.His620Pro

c.1859A>C · rs148734139 · VCV780354

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0593 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.452%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0593	likely benign
REVEL	0.007	strongly benign-leaning
SaProt	LLR -5.38	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 0.63	phastCons 0.19
Regional constraint	o/e 0.90	unconstrained · MANE · 40 kb · p 0.00043 · regional, not allelic
Overall
CADD	7.119	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 0.452% African / African-American · 339/75,038 alleles

Filtering AF 0.412% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.397%

Overall 0.0215% 347/1,613,610 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.452%	221
Admixed American	0.01%	10,001
Remaining individualsnot grpmax-eligible	0.0032%	31,242

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.His620Pro
Coding: c.1859A>C
MANE Select: NM_004336
dbSNP: rs148734139
Type: single nucleotide variant
Location: chr2:110655756 (GRCh38)
Gene constraint: LOEUF 0.727 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.91 · 11 PDB

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

Similar variants

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
BUB1 p.Ala797Gly 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-his620pro (accessed [today's date]).

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