Is RB1 p.Phe296Cys (c.887T>G) pathogenic?

RB1 p.Phe296Cys (c.887T>G) is classified Uncertain significance in RB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-23). AlphaMissense: likely pathogenic (0.8795); Absent from gnomAD v4.1; Associated with urinary bladder cancer.

What condition is associated with RB1 p.Phe296Cys (c.887T>G)?

RB1 p.Phe296Cys (c.887T>G) is associated with urinary bladder cancer (ClinVar).

How common is RB1 p.Phe296Cys (c.887T>G) in the general population?

RB1 p.Phe296Cys (c.887T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about RB1 p.Phe296Cys (c.887T>G)?

AlphaMissense predicts likely pathogenic (score 0.8795) — an in-silico prediction, not a clinical call.

RB1 p.Phe296Cys

c.887T>G · rs2542185052 · VCV3240289

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8795 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

urinary bladder cancer

Computational evidence

Protein change
AlphaMissense	0.8795	likely pathogenic
REVEL	0.856	moderately pathogenic-leaning
SaProt	LLR -10.46	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
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 0.81	unconstrained · MANE · 156 kb · p 9.1e-08 · regional, not allelic
Overall
CADD	26.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: RB1
Protein: p.Phe296Cys
Coding: c.887T>G
MANE Select: NM_000321
dbSNP: rs2542185052
Type: single nucleotide variant
Location: chr13:48364919 (GRCh38)
Gene constraint: LOEUF 0.239 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.03 · 19 PDB
Residue 296: an α-helix

Full RB1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

urinary bladder cancer — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

RB1 c.1215+1G>A Pathogenic ★★ same condition
RB1 c.2107-2A>G Pathogenic/Likely pathogenic ★★ same condition
RB1 c.539+1G>A Likely pathogenic ★★ same condition
RB1 c.607+1G>T Pathogenic ★★ same condition
RB1 p.Arg255Ter Pathogenic ★★ same condition
RB1 p.Arg445Ter Pathogenic ★★ same condition
RB1 p.Arg455Ter Pathogenic ★★ same condition
RB1 p.Arg552Ter Pathogenic ★★ 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/rb1-p-phe296cys (accessed [today's date]).

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