Is RB1 p.Arg656Trp (c.1966C>T) pathogenic?

RB1 p.Arg656Trp (c.1966C>T) is classified Conflicting classifications of pathogenicity in RB1 (ClinVar, Conflicting submitters, 19 submitters; last evaluated 2026-06-22). AlphaMissense: likely benign (0.2938); Rare (popmax 0.125%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with RB1 p.Arg656Trp (c.1966C>T)?

RB1 p.Arg656Trp (c.1966C>T) is associated with hereditary neoplastic syndrome, ovarian cancer, retinoblastoma (ClinVar).

How common is RB1 p.Arg656Trp (c.1966C>T) in the general population?

RB1 p.Arg656Trp (c.1966C>T) is rare (popmax 0.125%, nfe) (gnomAD).

What do computational predictors say about RB1 p.Arg656Trp (c.1966C>T)?

AlphaMissense predicts likely benign (score 0.2938) — an in-silico prediction, not a clinical call.

RB1 p.Arg656Trp

c.1966C>T · rs142509759 · VCV41683

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 19 submitters

AlphaMissense

likely benign

0.2938 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.125%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.2938	likely benign
REVEL	0.685	pathogenic-leaning
SaProt	LLR -8.17	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	GERP 0.75, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 156 kb · p 9.1e-08 · regional, not allelic
Overall
CADD	24.5	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 0.125% European (non-Finnish) · 1,473/1,179,952 alleles

Filtering AF 0.119% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.117%

Overall 0.101% 1,629/1,613,844 alleles · rare exomes 1,546/1,461,794 · genomes 83/152,050 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.125%	801
Finnishnot grpmax-eligible	0.103%	970
Remaining individualsnot grpmax-eligible	0.0656%	1,524
Admixed American	0.035%	2,857
African / African-American	0.0227%	4,404
South Asian	0.0121%	8,280

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.Arg656Trp
Coding: c.1966C>T
MANE Select: NM_000321
dbSNP: rs142509759
Type: single nucleotide variant
Location: chr13:48459693 (GRCh38)
Gene constraint: LOEUF 0.239 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.03 · 19 PDB
Residue 656: an α-helix; the 'pocket; binds t and e1a' region; the 'domain b' 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: ovarian cancer retinoblastoma

Similar variants

RB1 p.Arg656Gln Benign/Likely benign ★★ same residue
RB1 p.Arg656= 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-arg656trp (accessed [today's date]).

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