Is BUB1 p.Arg324Ser (c.970C>A) pathogenic?

BUB1 p.Arg324Ser (c.970C>A) is classified Uncertain significance in BUB1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-14). AlphaMissense: likely benign (0.1149); Ultra-rare (popmax 0.0258%, nfe).

How common is BUB1 p.Arg324Ser (c.970C>A) in the general population?

BUB1 p.Arg324Ser (c.970C>A) is ultra-rare (popmax 0.0258%, nfe) (gnomAD).

What do computational predictors say about BUB1 p.Arg324Ser (c.970C>A)?

AlphaMissense predicts likely benign (score 0.1149) — an in-silico prediction, not a clinical call.

BUB1 p.Arg324Ser

c.970C>A · rs200486519 · VCV1767933

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1149 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0258%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1149	likely benign
REVEL	0.062	moderately benign-leaning
SaProt	LLR -4.99	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 -1.7
Regional constraint	o/e 0.90	unconstrained · MANE · 40 kb · p 0.00043 · regional, not allelic
Overall
CADD	0.539	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 0.0258% European (non-Finnish) · 305/1,179,982 alleles

Filtering AF 0.0234% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0225%

Overall 0.02% 323/1,614,012 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0258%	3,869
Remaining individualsnot grpmax-eligible	0.008%	12,500
African / African-American	0.008%	12,502
Finnishnot grpmax-eligible	0.00625%	15,994
East Asian	0.00446%	22,446
Admixed American	0.00167%	59,996

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.Arg324Ser
Coding: c.970C>A
MANE Select: NM_004336
dbSNP: rs200486519
Type: single nucleotide variant
Location: chr2:110661829 (GRCh38)
Gene constraint: LOEUF 0.727 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.91 · 11 PDB
Residue 324: the 'disordered' region

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

Similar variants

BUB1 p.Arg324His Uncertain significance ★★ ⚠ same residue
BUB1 p.Arg324Cys Conflicting classifications of pathogenicity ★ ⚠ 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

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-arg324ser (accessed [today's date]).

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