Is RB1 p.Pro789Ser (c.2365C>T) pathogenic?

RB1 p.Pro789Ser (c.2365C>T) is classified Uncertain significance in RB1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-02). AlphaMissense: likely benign (0.1824); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with RB1 p.Pro789Ser (c.2365C>T)?

RB1 p.Pro789Ser (c.2365C>T) is associated with hereditary neoplastic syndrome, retinoblastoma (ClinVar).

How common is RB1 p.Pro789Ser (c.2365C>T) in the general population?

RB1 p.Pro789Ser (c.2365C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about RB1 p.Pro789Ser (c.2365C>T)?

AlphaMissense predicts likely benign (score 0.1824) — an in-silico prediction, not a clinical call.

RB1 p.Pro789Ser

c.2365C>T · rs1949432512 · VCV1021709

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1824 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1824	likely benign
REVEL	0.621	indeterminate
SaProt	LLR -9.26	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 16 kb · p 0.0046 · regional, not allelic
Overall
CADD	24.6	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: RB1
Protein: p.Pro789Ser
Coding: c.2365C>T
MANE Select: NM_000321
dbSNP: rs1949432512
Type: single nucleotide variant
Location: chr13:48465244 (GRCh38)
Gene constraint: LOEUF 0.239 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.03 · 19 PDB
Residue 789: the 'interaction with limd1' region; the 'domain c; mediates interaction with e4f1' 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.Pro789His Uncertain significance ★★ ⚠ same residue
RB1 p.Pro789Leu 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
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-pro789ser (accessed [today's date]).

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