Is RB1 p.Pro298Leu (c.893C>T) pathogenic?

RB1 p.Pro298Leu (c.893C>T) is classified Uncertain significance in RB1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-12). AlphaMissense: likely benign (0.2808); Very rare (popmax 0.00356%, amr); Associated with hereditary neoplastic syndrome.

What condition is associated with RB1 p.Pro298Leu (c.893C>T)?

RB1 p.Pro298Leu (c.893C>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is RB1 p.Pro298Leu (c.893C>T) in the general population?

RB1 p.Pro298Leu (c.893C>T) is very rare (popmax 0.00356%, amr) (gnomAD).

What do computational predictors say about RB1 p.Pro298Leu (c.893C>T)?

AlphaMissense predicts likely benign (score 0.2808) — an in-silico prediction, not a clinical call.

RB1 p.Pro298Leu

c.893C>T · rs759675910 · VCV2450508

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2808 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00356%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.2808	likely benign
REVEL	0.676	pathogenic-leaning
SaProt	LLR -11.12	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 156 kb · p 9.1e-08 · regional, not allelic
Overall
CADD	25.7	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 0.00356% Admixed American · 2/56,124 alleles

Filtering AF 0.000591% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000221%

Overall 0.000192% 3/1,565,742 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00356%	28,062
European (non-Finnish)	8.68e-05%	1,151,556

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.Pro298Leu
Coding: c.893C>T
MANE Select: NM_000321
dbSNP: rs759675910
Type: single nucleotide variant
Location: chr13:48364925 (GRCh38)
Gene constraint: LOEUF 0.239 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.03 · 19 PDB
Residue 298: an α-helix

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

Similar variants

RB1 p.Pro298His Uncertain significance ★★ same residue
RB1 p.Pro298Thr Uncertain significance ★★ ⚠ same residue
RB1 p.Pro298= Likely benign ★★ same residue
RB1 p.Pro298Ser Uncertain significance ★ ⚠ 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

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-pro298leu (accessed [today's date]).

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