Is BUB1B p.Phe68Cys (c.203T>G) pathogenic?

BUB1B p.Phe68Cys (c.203T>G) is classified Uncertain significance in BUB1B (ClinVar, Single submitter, 1 submitter; last evaluated 2019-12-18). AlphaMissense: likely benign (0.2961); Very rare (popmax 0.00133%, afr).

How common is BUB1B p.Phe68Cys (c.203T>G) in the general population?

BUB1B p.Phe68Cys (c.203T>G) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about BUB1B p.Phe68Cys (c.203T>G)?

AlphaMissense predicts likely benign (score 0.2961) — an in-silico prediction, not a clinical call.

BUB1B p.Phe68Cys

c.203T>G · rs2037144342 · VCV1320447

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2961 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.2961	likely benign
REVEL	0.487	indeterminate
SaProt	LLR -8.17	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.8	GERP 2.1, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 60 kb · p 0.0024 · regional, not allelic
Overall
CADD	26.9	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 0.00133% African / African-American · 1/74,918 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000434% 7/1,613,864 alleles · very rare exomes 6/1,461,660 · genomes 1/152,204 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,918
European (non-Finnish)	0.000509%	196,644

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.Phe68Cys
Coding: c.203T>G
MANE Select: NM_001211
dbSNP: rs2037144342
Type: single nucleotide variant
Location: chr15:40170085 (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 68: the bub1 n-terminal domain

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

Similar variants

BUB1B p.Phe68Leu Uncertain significance ★ ⚠ same residue
BUB1B p.Phe68= Likely benign ★ same residue
BUB1B p.Arg114Ter Pathogenic ★★ same type
BUB1B p.Arg120Ter Pathogenic ★★ same type
BUB1B p.Arg194Ter Pathogenic/Likely pathogenic ★★ same type
BUB1B p.Arg199Ter Pathogenic/Likely pathogenic ★★ same type
BUB1B p.Arg67Ter Pathogenic/Likely pathogenic ★★ same type
BUB1B p.Gln267Ter Pathogenic ★★ 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/bub1b-p-phe68cys (accessed [today's date]).

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