Is RB1 p.Ser758Pro (c.2272T>C) pathogenic?

RB1 p.Ser758Pro (c.2272T>C) is classified Uncertain significance in RB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-16). AlphaMissense: likely pathogenic (0.9949); Absent from gnomAD v4.1.

How common is RB1 p.Ser758Pro (c.2272T>C) in the general population?

RB1 p.Ser758Pro (c.2272T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about RB1 p.Ser758Pro (c.2272T>C)?

AlphaMissense predicts likely pathogenic (score 0.9949) — an in-silico prediction, not a clinical call.

RB1 p.Ser758Pro

c.2272T>C · VCV4282069

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9949 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9949	likely pathogenic · top 3% in RB1
REVEL	0.639	indeterminate
SaProt	LLR -15.07	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.9	GERP 0.3, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 16 kb · p 0.0046 · regional, not allelic
Overall
CADD	23.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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.Ser758Pro
Coding: c.2272T>C
MANE Select: NM_000321
Type: single nucleotide variant
Location: chr13:48465058 (GRCh38)
Gene constraint: LOEUF 0.239 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.03 · 19 PDB
Residue 758: an α-helix; the 'pocket; binds t and e1a' region; the 'domain b' region

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

Similar variants

RB1 p.Ser758= Benign/Likely benign ★★ same residue
RB1 p.Ser758Leu Benign/Likely benign ★★ same residue
RB1 p.Ser758Ter Pathogenic ★ same residue
RB1 c.1049+1G>A Pathogenic/Likely pathogenic ★★ same type
RB1 c.1049+1G>T Pathogenic/Likely pathogenic ★★ same type
RB1 c.1049+3A>G Pathogenic/Likely pathogenic ★★ same type
RB1 c.1050-2A>G Pathogenic/Likely pathogenic ★★ same type
RB1 c.1128-1G>A Pathogenic ★★ same type

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-ser758pro (accessed [today's date]).

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