Is RB1 p.Ser469Phe (c.1406C>T) pathogenic?

RB1 p.Ser469Phe (c.1406C>T) is classified Uncertain significance in RB1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-22). AlphaMissense: ambiguous (0.5633); Very rare (popmax 0.000397%, nfe); Associated with retinoblastoma.

What condition is associated with RB1 p.Ser469Phe (c.1406C>T)?

RB1 p.Ser469Phe (c.1406C>T) is associated with retinoblastoma, hereditary neoplastic syndrome (ClinVar).

How common is RB1 p.Ser469Phe (c.1406C>T) in the general population?

RB1 p.Ser469Phe (c.1406C>T) is very rare (popmax 0.000397%, nfe) (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.Ser469Phe (c.1406C>T)?

AlphaMissense predicts ambiguous (score 0.5633) — an in-silico prediction, not a clinical call.

RB1 p.Ser469Phe

c.1406C>T · rs1243796201 · VCV578066

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.5633 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000397%, nfe)

Conditions

retinoblastoma

Computational evidence

Protein change
AlphaMissense	0.5633	ambiguous
REVEL	0.601	indeterminate
SaProt	LLR -9.52	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	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

Grpmax group 0.000397% European (non-Finnish) · 4/1,008,694 alleles

Filtering AF 9.3e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 6.3e-05%

Overall 0.000367% 5/1,362,554 alleles · very rare exomes 3/1,215,752 · genomes 2/146,802 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00387%	25,852
European (non-Finnish)grpmax	0.000397%	252,174

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser469Phe
Coding: c.1406C>T
MANE Select: NM_000321
dbSNP: rs1243796201
Type: single nucleotide variant
Location: chr13:48380069 (GRCh38)
Gene constraint: LOEUF 0.239 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.03 · 19 PDB
Residue 469: 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

Also linked: hereditary neoplastic syndrome

For Retinoblastoma (Orphanet):

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

Similar variants

RB1 p.Ser469Ala Uncertain significance ★★ ⚠ same residue
RB1 p.Ser469Tyr Uncertain significance ★★ same residue
RB1 p.Ser469= Benign/Likely benign ★★ same residue
RB1 p.Ser469Pro Uncertain significance ★ ⚠ same residue
RB1 p.Ser469fs Likely pathogenic ★ 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

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-ser469phe (accessed [today's date]).

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