Is RB1 p.Phe839= (c.2517C>T) pathogenic?

RB1 p.Phe839= (c.2517C>T) is classified Likely benign in RB1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-10-09). Very rare (popmax 0.00167%, amr); Associated with hereditary neoplastic syndrome.

What condition is associated with RB1 p.Phe839= (c.2517C>T)?

RB1 p.Phe839= (c.2517C>T) is associated with hereditary neoplastic syndrome, retinoblastoma (ClinVar).

How common is RB1 p.Phe839= (c.2517C>T) in the general population?

RB1 p.Phe839= (c.2517C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

RB1 p.Phe839=

c.2517C>T · rs759188465 · VCV458152

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.21	acceptor loss, 27 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 4.2	GERP 0.55, phastCons 1
Overall
CADD	14.43	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/59,828 alleles

Filtering AF 0.000303% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000219%

Overall 0.000704% 11/1,562,154 alleles · very rare exomes 9/1,410,152 · genomes 2/152,002 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00316%	31,672
Admixed Americangrpmax	0.00167%	59,828
European (non-Finnish)	0.000705%	141,837

Finnish 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.Phe839=
Coding: c.2517C>T
MANE Select: NM_000321
dbSNP: rs759188465
Type: single nucleotide variant
Location: chr13:48473387 (GRCh38)
Gene constraint: LOEUF 0.239 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.03 · 19 PDB
Residue 839: a turn; the 'interaction with limd1' region; the 'domain c; mediates interaction with e4f1' region

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.Phe839Leu 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
RB1 c.1128-2A>G Pathogenic ★★ same condition
RB1 c.1215+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-phe839 (accessed [today's date]).

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