Is RB1 p.Arg451Ser (c.1351C>A) pathogenic?

RB1 p.Arg451Ser (c.1351C>A) is classified Uncertain significance in RB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-04). AlphaMissense: likely pathogenic (0.8092); Absent from gnomAD v4.1; Associated with retinoblastoma.

What condition is associated with RB1 p.Arg451Ser (c.1351C>A)?

RB1 p.Arg451Ser (c.1351C>A) is associated with retinoblastoma (ClinVar).

How common is RB1 p.Arg451Ser (c.1351C>A) in the general population?

RB1 p.Arg451Ser (c.1351C>A) is absent from gnomAD v4.1 (gnomAD).

How is Retinoblastoma inherited?

Typically Autosomal dominant, Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about RB1 p.Arg451Ser (c.1351C>A)?

AlphaMissense predicts likely pathogenic (score 0.8092) — an in-silico prediction, not a clinical call.

RB1 p.Arg451Ser

c.1351C>A · rs759079385 · VCV1999254

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8092 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

retinoblastoma

Computational evidence

Protein change
AlphaMissense	0.8092	likely pathogenic
REVEL	0.658	pathogenic-leaning
SaProt	LLR -3.47	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	Δ0.47	donor loss, 38 bp away · masked 0 · deltas
Pangolin	Δ0.35	loss · gain 0.01 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 4	GERP 1.8, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 156 kb · p 9.1e-08 · regional, not allelic
Overall
CADD	25.6	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

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.Arg451Ser
Coding: c.1351C>A
MANE Select: NM_000321
dbSNP: rs759079385
Type: single nucleotide variant
Location: chr13:48379612 (GRCh38)
Gene constraint: LOEUF 0.239 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.03 · 19 PDB
Residue 451: an α-helix; the 'pocket; binds t and e1a' region; the 'domain a' region

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

Disease context

retinoblastoma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Retinoblastoma (Orphanet):

Inheritance: Autosomal dominant, Not applicable
Onset: Antenatal, Childhood, Infancy
Prevalence: <1 / 1 000 000 (Europe)

Similar variants

RB1 p.Arg451His Uncertain significance ★★ ⚠ same residue
RB1 p.Arg451= Likely benign ★★ same residue
RB1 p.Arg451Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
RB1 p.Arg451Gly Uncertain significance ★ ⚠ same residue
RB1 p.Arg451fs Pathogenic ★ same residue
RB1 p.Arg451Leu Uncertain significance ★ ⚠ 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-arg451ser (accessed [today's date]).

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