Is RB1 p.Val314Phe (c.940G>T) pathogenic?

RB1 p.Val314Phe (c.940G>T) is classified Uncertain significance in RB1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-03-27). AlphaMissense: likely benign (0.1467); Very rare (popmax 8.53e-05%, nfe); Associated with retinoblastoma.

What condition is associated with RB1 p.Val314Phe (c.940G>T)?

RB1 p.Val314Phe (c.940G>T) is associated with retinoblastoma (ClinVar).

How common is RB1 p.Val314Phe (c.940G>T) in the general population?

RB1 p.Val314Phe (c.940G>T) is very rare (popmax 8.53e-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.Val314Phe (c.940G>T)?

AlphaMissense predicts likely benign (score 0.1467) — an in-silico prediction, not a clinical call.

RB1 p.Val314Phe

c.940G>T · rs1566194312 · VCV584869

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1467 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.53e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

retinoblastoma

Computational evidence

Protein change
AlphaMissense	0.1467	likely benign
REVEL	0.555	indeterminate
SaProt	LLR -4.53	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	Δ0.78	acceptor loss at this position · masked 0 · deltas
Pangolin	Δ0.68	loss · gain 0.01 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.6	GERP 0.94, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 156 kb · p 9.1e-08 · regional, not allelic
Overall
CADD	21.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 8.53e-05% European (non-Finnish) · 1/1,172,978 alleles

Overall 6.24e-05% 1/1,601,878 alleles · very rare exomes 1/1,449,724 · genomes 0/152,154 · 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.Val314Phe
Coding: c.940G>T
MANE Select: NM_000321
dbSNP: rs1566194312
Type: single nucleotide variant
Location: chr13:48367494 (GRCh38)
Gene constraint: LOEUF 0.239 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.03 · 19 PDB
Residue 314: an α-helix

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.Val314Ala Uncertain significance ★★ ⚠ same residue
RB1 p.Val314Asp Conflicting classifications of pathogenicity ★ ⚠ same residue
RB1 p.Val314Ile 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-val314phe (accessed [today's date]).

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