Is RB1 p.Pro23= (c.69G>C) pathogenic?

RB1 p.Pro23= (c.69G>C) is classified Benign/Likely benign in RB1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-06-04). Ultra-rare (popmax 0.0252%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with RB1 p.Pro23= (c.69G>C)?

RB1 p.Pro23= (c.69G>C) is associated with hereditary neoplastic syndrome, retinoblastoma (ClinVar).

How common is RB1 p.Pro23= (c.69G>C) in the general population?

RB1 p.Pro23= (c.69G>C) is ultra-rare (popmax 0.0252%, sas) (gnomAD).

RB1 p.Pro23=

c.69G>C · rs746662122 · VCV1571742

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0252%, sas)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.28	GERP -1.3, phastCons 0.002
Overall
CADD	3.721	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0252% South Asian · 20/79,518 alleles

Filtering AF 0.0166% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0139%

Overall 0.00141% 21/1,491,178 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0252%	3,976
Remaining individualsnot grpmax-eligible	0.00173%	57,742

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.Pro23=
Coding: c.69G>C
MANE Select: NM_000321
dbSNP: rs746662122
Type: single nucleotide variant
Location: chr13:48303981 (GRCh38)
Gene constraint: LOEUF 0.239 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.03 · 19 PDB
Residue 23: the 'disordered' 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: retinoblastoma

Similar variants

RB1 p.Pro23Leu Uncertain significance ★★ ⚠ same residue
RB1 p.Pro23Ser Uncertain significance ★★ ⚠ same residue
RB1 p.Pro23Thr Uncertain significance ★★ ⚠ same residue
RB1 p.Pro23Arg Uncertain significance ★ ⚠ same residue
RB1 p.Pro23Gln Uncertain significance ★ ⚠ same residue
RB1 p.Pro23fs Pathogenic ★ same residue
RB1 c.1049+1G>A Pathogenic/Likely pathogenic ★★ same condition
RB1 c.1049+1G>T 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-pro23 (accessed [today's date]).

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