Is BUB3 p.Ile185Val (c.553A>G) pathogenic?

BUB3 p.Ile185Val (c.553A>G) is classified Uncertain significance in BUB3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-18). AlphaMissense: likely benign (0.1738); Very rare (popmax 0.00177%, amr).

How common is BUB3 p.Ile185Val (c.553A>G) in the general population?

BUB3 p.Ile185Val (c.553A>G) is very rare (popmax 0.00177%, amr) (gnomAD).

What do computational predictors say about BUB3 p.Ile185Val (c.553A>G)?

AlphaMissense predicts likely benign (score 0.1738) — an in-silico prediction, not a clinical call.

BUB3 p.Ile185Val

c.553A>G · VCV3262319

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1738 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00177%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1738	likely benign
REVEL	0.194	benign-leaning
SaProt	LLR -5.68	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 11	GERP 2.6, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 6,079 bp · p 8.5e-11 · regional, not allelic
Overall
CADD	21.1	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 0.00177% Admixed American · 1/56,542 alleles

Filtering AF 0.000125% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.1e-05%

Overall 0.000437% 7/1,602,810 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00177%	56,542
African / African-American	0.00135%	74,098
European (non-Finnish)	0.000425%	235,371

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: BUB3
Protein: p.Ile185Val
Coding: c.553A>G
MANE Select: NM_004725
Type: single nucleotide variant
Location: chr10:123160542 (GRCh38)
Gene constraint: LOEUF 0.77 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.10

Full BUB3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BUB3 p.Ile185Leu Uncertain significance ★ ⚠ same residue
BUB3 p.Ile185Met Uncertain significance ★ ⚠ same residue
BUB3 p.Ile185Thr Uncertain significance ★ ⚠ same residue
BUB3 p.Arg314= Likely benign ★★ same type
BUB3 p.Ser197= Likely benign ★★ same type
BUB3 p.Ser198= Likely benign ★★ same type
BUB3 p.Ala131Val Uncertain significance ★ ⚠ same type
BUB3 p.Ala155Val 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/bub3-p-ile185val (accessed [today's date]).

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