Is BUB1B p.Phe196Tyr (c.587T>A) pathogenic?

BUB1B p.Phe196Tyr (c.587T>A) is classified Uncertain significance in BUB1B (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-02). AlphaMissense: ambiguous (0.5117); Very rare (popmax 0.00133%, afr); Associated with Inborn genetic diseases.

What condition is associated with BUB1B p.Phe196Tyr (c.587T>A)?

BUB1B p.Phe196Tyr (c.587T>A) is associated with Inborn genetic diseases (ClinVar).

How common is BUB1B p.Phe196Tyr (c.587T>A) in the general population?

BUB1B p.Phe196Tyr (c.587T>A) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about BUB1B p.Phe196Tyr (c.587T>A)?

AlphaMissense predicts ambiguous (score 0.5117) — an in-silico prediction, not a clinical call.

BUB1B p.Phe196Tyr

c.587T>A · rs1037175607 · VCV1750256

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5117 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5117	ambiguous
REVEL	0.259	benign-leaning
SaProt	LLR -9.79	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 60 kb · p 0.0024 · regional, not allelic
Overall
CADD	27.4	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 0.00133% African / African-American · 1/74,918 alleles

Overall 6.2e-05% 1/1,613,904 alleles · very rare exomes 0/1,461,752 · genomes 1/152,152 · 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: BUB1B
Protein: p.Phe196Tyr
Coding: c.587T>A
MANE Select: NM_001211
dbSNP: rs1037175607
Type: single nucleotide variant
Location: chr15:40183719 (GRCh38)
Gene constraint: LOEUF 0.707 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 64.62 · 9 PDB
Residue 196: the bub1 n-terminal domain; an α-helix

Full BUB1B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

BUB1B p.Phe196Leu Uncertain significance ★ ⚠ same residue
BUB1B p.Phe196Ser Uncertain significance ★ ⚠ same residue
BUB1B c.35+4G>T Uncertain significance ★★ same condition
BUB1B p.Ala1017Thr Uncertain significance ★★ ⚠ same condition
BUB1B p.Ala1046Pro Uncertain significance ★★ ⚠ same condition
BUB1B p.Ala108Thr Uncertain significance ★★ ⚠ same condition
BUB1B p.Ala171Pro Uncertain significance ★★ ⚠ same condition
BUB1B p.Ala173Thr Uncertain significance ★★ ⚠ same condition

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/bub1b-p-phe196tyr (accessed [today's date]).

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