Is BUB1 p.Asp65Asn (c.193G>A) pathogenic?

BUB1 p.Asp65Asn (c.193G>A) is classified Uncertain significance in BUB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-21). AlphaMissense: ambiguous (0.5116); Very rare (popmax 0.000268%, nfe).

How common is BUB1 p.Asp65Asn (c.193G>A) in the general population?

BUB1 p.Asp65Asn (c.193G>A) is very rare (popmax 0.000268%, nfe) (gnomAD).

What do computational predictors say about BUB1 p.Asp65Asn (c.193G>A)?

AlphaMissense predicts ambiguous (score 0.5116) — an in-silico prediction, not a clinical call.

BUB1 p.Asp65Asn

c.193G>A · rs2468038590 · VCV2560899

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5116 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000268%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5116	ambiguous
REVEL	0.784	moderately pathogenic-leaning
SaProt	LLR -11.15	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 40 kb · p 0.00043 · 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

Grpmax group 0.000268% European (non-Finnish) · 3/1,119,690 alleles

Filtering AF 7.1e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 2e-05%

Overall 0.000194% 3/1,546,116 alleles · very rare exomes 3/1,393,796 · genomes 0/152,320 · joint denominator

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.Asp65Asn
Coding: c.193G>A
MANE Select: NM_004336
dbSNP: rs2468038590
Type: single nucleotide variant
Location: chr2:110674118 (GRCh38)
Gene constraint: LOEUF 0.727 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.91 · 11 PDB
Residue 65: 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.Asp65Glu Uncertain significance ★ ⚠ same residue
BUB1 p.Asp65Val 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

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-asp65asn (accessed [today's date]).

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