Is RB1 p.Val450Phe (c.1348G>T) pathogenic?

RB1 p.Val450Phe (c.1348G>T) is classified Uncertain significance in RB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-11). AlphaMissense: ambiguous (0.4777); Very rare (popmax 8.48e-05%, nfe); Associated with retinoblastoma.

What condition is associated with RB1 p.Val450Phe (c.1348G>T)?

RB1 p.Val450Phe (c.1348G>T) is associated with retinoblastoma (ClinVar).

How common is RB1 p.Val450Phe (c.1348G>T) in the general population?

RB1 p.Val450Phe (c.1348G>T) is very rare (popmax 8.48e-05%, 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.Val450Phe (c.1348G>T)?

AlphaMissense predicts ambiguous (score 0.4777) — an in-silico prediction, not a clinical call.

RB1 p.Val450Phe

c.1348G>T · rs1948513969 · VCV3075345

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4777 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

retinoblastoma

Computational evidence

Protein change
AlphaMissense	0.4777	ambiguous
REVEL	0.839	moderately pathogenic-leaning
SaProt	LLR -12.47	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 1.8, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 156 kb · p 9.1e-08 · regional, not allelic
Overall
CADD	27.9	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 8.48e-05% European (non-Finnish) · 1/1,179,712 alleles

Overall 6.2e-05% 1/1,612,518 alleles · very rare exomes 0/1,460,562 · genomes 1/151,956 · 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.Val450Phe
Coding: c.1348G>T
MANE Select: NM_000321
dbSNP: rs1948513969
Type: single nucleotide variant
Location: chr13:48379609 (GRCh38)
Gene constraint: LOEUF 0.239 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.03 · 19 PDB
Residue 450: 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.Val450= Likely benign ★★ same residue
RB1 p.Val450Gly Uncertain significance ★ ⚠ same residue
RB1 p.Val450Ile Uncertain significance ★ ⚠ same residue
RB1 p.Val450fs 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
RB1 c.1050-2A>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-val450phe (accessed [today's date]).

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