Is RB1 p.Ser402Pro (c.1204T>C) pathogenic?

RB1 p.Ser402Pro (c.1204T>C) is classified Uncertain significance in RB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-19). AlphaMissense: ambiguous (0.5574); Very rare (popmax 0.00167%, amr); Associated with retinoblastoma.

What condition is associated with RB1 p.Ser402Pro (c.1204T>C)?

RB1 p.Ser402Pro (c.1204T>C) is associated with retinoblastoma (ClinVar).

How common is RB1 p.Ser402Pro (c.1204T>C) in the general population?

RB1 p.Ser402Pro (c.1204T>C) is very rare (popmax 0.00167%, amr) (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.Ser402Pro (c.1204T>C)?

AlphaMissense predicts ambiguous (score 0.5574) — an in-silico prediction, not a clinical call.

RB1 p.Ser402Pro

c.1204T>C · rs765021598 · VCV1992979

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5574 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

retinoblastoma

Computational evidence

Protein change
AlphaMissense	0.5574	ambiguous
REVEL	0.646	pathogenic-leaning
SaProt	LLR -9.88	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.9	GERP 0.34, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 156 kb · p 9.1e-08 · regional, not allelic
Overall
CADD	23.5	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

Grpmax group 0.00167% Admixed American · 1/59,928 alleles

Overall 6.36e-05% 1/1,573,506 alleles · very rare exomes 1/1,421,234 · genomes 0/152,272 · joint denominator

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.Ser402Pro
Coding: c.1204T>C
MANE Select: NM_000321
dbSNP: rs765021598
Type: single nucleotide variant
Location: chr13:48373481 (GRCh38)
Gene constraint: LOEUF 0.239 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.03 · 19 PDB
Residue 402: 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.Ser402Phe Uncertain significance ★★ ⚠ same residue
RB1 p.Ser402= Likely benign ★★ same residue
RB1 p.Ser402Cys 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

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-ser402pro (accessed [today's date]).

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