Is RB1 p.Ser187Phe (c.560C>T) pathogenic?

RB1 p.Ser187Phe (c.560C>T) is classified Conflicting classifications of pathogenicity in RB1 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-09-08). AlphaMissense: likely benign (0.1528); Very rare (popmax 0.00102%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with RB1 p.Ser187Phe (c.560C>T)?

RB1 p.Ser187Phe (c.560C>T) is associated with hereditary neoplastic syndrome, retinoblastoma (ClinVar).

How common is RB1 p.Ser187Phe (c.560C>T) in the general population?

RB1 p.Ser187Phe (c.560C>T) is very rare (popmax 0.00102%, nfe) (gnomAD).

What do computational predictors say about RB1 p.Ser187Phe (c.560C>T)?

AlphaMissense predicts likely benign (score 0.1528) — an in-silico prediction, not a clinical call.

RB1 p.Ser187Phe

c.560C>T · rs770277291 · VCV825848

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1528 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00102%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1528	likely benign
REVEL	0.417	indeterminate
SaProt	LLR -9.51	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6	GERP 4, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 156 kb · p 9.1e-08 · regional, not allelic
Overall
CADD	24.4	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 0.00102% European (non-Finnish) · 12/1,172,726 alleles

Filtering AF 0.000546% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000431%

Overall 0.000749% 12/1,601,298 alleles · very rare exomes 10/1,449,948 · genomes 2/151,350 · 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.Ser187Phe
Coding: c.560C>T
MANE Select: NM_000321
dbSNP: rs770277291
Type: single nucleotide variant
Location: chr13:48348976 (GRCh38)
Gene constraint: LOEUF 0.239 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.03 · 19 PDB

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

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: retinoblastoma

Similar variants

RB1 p.Ser187Cys Uncertain significance ★★ ⚠ same residue
RB1 p.Ser187= Benign/Likely benign ★★ 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
RB1 c.1128-2A>G 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-ser187phe (accessed [today's date]).

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