Is RB1 p.Pro23Thr (c.67C>A) pathogenic?

RB1 p.Pro23Thr (c.67C>A) is classified Uncertain significance in RB1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-08). AlphaMissense: likely benign (0.0896); Very rare (popmax 0.000973%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with RB1 p.Pro23Thr (c.67C>A)?

RB1 p.Pro23Thr (c.67C>A) is associated with hereditary neoplastic syndrome, retinoblastoma (ClinVar).

How common is RB1 p.Pro23Thr (c.67C>A) in the general population?

RB1 p.Pro23Thr (c.67C>A) is very rare (popmax 0.000973%, nfe) (gnomAD).

What do computational predictors say about RB1 p.Pro23Thr (c.67C>A)?

AlphaMissense predicts likely benign (score 0.0896) — an in-silico prediction, not a clinical call.

RB1 p.Pro23Thr

c.67C>A · rs1349657979 · VCV949259

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0896 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000973%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0896	likely benign
REVEL	0.255	benign-leaning
SaProt	LLR -9.79	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.14	GERP 0.84, phastCons 0.005
Regional constraint	o/e 0.81	unconstrained · MANE · 156 kb · p 9.1e-08 · regional, not allelic
Overall
CADD	15.26	PHRED · no single calibrated threshold — expert panels disagree

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

Grpmax group 0.000973% European (non-Finnish) · 11/1,130,484 alleles

Filtering AF 0.000522% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000382%

Overall 0.000818% 11/1,344,820 alleles · very rare

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.Pro23Thr
Coding: c.67C>A
MANE Select: NM_000321
dbSNP: rs1349657979
Type: single nucleotide variant
Location: chr13:48303979 (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.Pro23= Benign/Likely benign ★★ 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-pro23thr (accessed [today's date]).

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