Is RB1 p.Arg763Ser (c.2289A>T) pathogenic?

RB1 p.Arg763Ser (c.2289A>T) is classified Conflicting classifications of pathogenicity in RB1 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2025-10-23). AlphaMissense: likely pathogenic (0.7343); Very rare (popmax 0.00314%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with RB1 p.Arg763Ser (c.2289A>T)?

RB1 p.Arg763Ser (c.2289A>T) is associated with hereditary neoplastic syndrome, urinary bladder cancer, retinoblastoma (ClinVar).

How common is RB1 p.Arg763Ser (c.2289A>T) in the general population?

RB1 p.Arg763Ser (c.2289A>T) is very rare (popmax 0.00314%, nfe) (gnomAD).

What do computational predictors say about RB1 p.Arg763Ser (c.2289A>T)?

AlphaMissense predicts likely pathogenic (score 0.7343) — an in-silico prediction, not a clinical call.

RB1 p.Arg763Ser

c.2289A>T · rs1167280920 · VCV458143

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.7343 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00314%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.7343	likely pathogenic
REVEL	0.321	indeterminate
SaProt	LLR -6.01	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.6	GERP -0.95, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 16 kb · p 0.0046 · regional, not allelic
Overall
CADD	23.0	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 0.00314% European (non-Finnish) · 37/1,179,806 alleles

Filtering AF 0.00231% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00202%

Overall 0.00236% 38/1,612,320 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00314%	31,887
Remaining individualsnot grpmax-eligible	0.0016%	62,444

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.Arg763Ser
Coding: c.2289A>T
MANE Select: NM_000321
dbSNP: rs1167280920
Type: single nucleotide variant
Location: chr13:48465075 (GRCh38)
Gene constraint: LOEUF 0.239 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.03 · 19 PDB
Residue 763: an α-helix; the 'pocket; binds t and e1a' region; the 'domain b' region; the 'interaction with limd1' region

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

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: urinary bladder cancer retinoblastoma

Similar variants

RB1 p.Arg763Lys Uncertain significance ★★ ⚠ same residue
RB1 p.Arg763Ter 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
RB1 c.1128-2A>G 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-arg763ser (accessed [today's date]).

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