Is RB1 p.Asp697Glu (c.2091C>G) pathogenic?

RB1 p.Asp697Glu (c.2091C>G) is classified Conflicting classifications of pathogenicity in RB1 (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-02-02). AlphaMissense: likely pathogenic (0.8274); Very rare (popmax 0.00695%, nfe); Associated with urinary bladder cancer.

What condition is associated with RB1 p.Asp697Glu (c.2091C>G)?

RB1 p.Asp697Glu (c.2091C>G) is associated with urinary bladder cancer, retinoblastoma, hereditary neoplastic syndrome (ClinVar).

How common is RB1 p.Asp697Glu (c.2091C>G) in the general population?

RB1 p.Asp697Glu (c.2091C>G) is very rare (popmax 0.00695%, nfe) (gnomAD).

What do computational predictors say about RB1 p.Asp697Glu (c.2091C>G)?

AlphaMissense predicts likely pathogenic (score 0.8274) — an in-silico prediction, not a clinical call.

RB1 p.Asp697Glu

c.2091C>G · rs3092903 · VCV312293

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely pathogenic

0.8274 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00695%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

urinary bladder cancer

Computational evidence

Protein change
AlphaMissense	0.8274	likely pathogenic
REVEL	0.78	moderately pathogenic-leaning
SaProt	LLR -8.16	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.3	GERP -0.84
Regional constraint	o/e 0.39	unconstrained · MANE · 4,086 bp · p 7e-08 · regional, not allelic
Overall
CADD	22.0	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 0.00695% European (non-Finnish) · 82/1,179,738 alleles

Filtering AF 0.00571% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00525%

Overall 0.00539% 87/1,613,568 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.008%	12,493
European (non-Finnish)grpmax	0.00695%	14,387

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: RB1
Protein: p.Asp697Glu
Coding: c.2091C>G
MANE Select: NM_000321
dbSNP: rs3092903
Type: single nucleotide variant
Location: chr13:48459818 (GRCh38)
Gene constraint: LOEUF 0.239 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.03 · 19 PDB
Residue 697: the 'pocket; binds t and e1a' region; a UniProt-annotated variant site (in); the 'domain b' region

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

Also linked: retinoblastoma hereditary neoplastic syndrome

Similar variants

RB1 p.Asp697= Likely benign ★★ same residue
RB1 p.Asp697His Likely benign ★ ⚠ same residue
RB1 p.Asp697fs Pathogenic ★ same residue
RB1 c.1049+1G>A Pathogenic/Likely pathogenic ★★ same condition
RB1 c.1049+1G>T Pathogenic/Likely pathogenic ★★ same condition
RB1 c.1049+3A>G Pathogenic/Likely pathogenic ★★ same condition
RB1 c.1050-2A>G Pathogenic/Likely pathogenic ★★ same condition
RB1 c.1128-1G>A 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-asp697glu (accessed [today's date]).

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