Is RB1 p.Pro786Ser (c.2356C>T) pathogenic?

RB1 p.Pro786Ser (c.2356C>T) is classified Conflicting classifications of pathogenicity in RB1 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-06-22). AlphaMissense: likely benign (0.321); Ultra-rare (popmax 0.0329%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with RB1 p.Pro786Ser (c.2356C>T)?

RB1 p.Pro786Ser (c.2356C>T) is associated with hereditary neoplastic syndrome, medulloblastoma, retinoblastoma (ClinVar).

How common is RB1 p.Pro786Ser (c.2356C>T) in the general population?

RB1 p.Pro786Ser (c.2356C>T) is ultra-rare (popmax 0.0329%, nfe) (gnomAD).

What do computational predictors say about RB1 p.Pro786Ser (c.2356C>T)?

AlphaMissense predicts likely benign (score 0.321) — an in-silico prediction, not a clinical call.

RB1 p.Pro786Ser

c.2356C>T · rs754507551 · VCV458145

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.321 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.321	likely benign
REVEL	0.542	indeterminate
SaProt	LLR -7.06	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 16 kb · p 0.0046 · 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 0.0329% European (non-Finnish) · 388/1,179,890 alleles

Filtering AF 0.0302% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0291%

Overall 0.0247% 399/1,613,760 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0329%	3,041
Middle Eastern	0.0164%	6,084
Remaining individualsnot grpmax-eligible	0.0144%	6,941
African / African-American	0.00134%	74,888

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.Pro786Ser
Coding: c.2356C>T
MANE Select: NM_000321
dbSNP: rs754507551
Type: single nucleotide variant
Location: chr13:48465235 (GRCh38)
Gene constraint: LOEUF 0.239 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.03 · 19 PDB
Residue 786: 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: medulloblastoma retinoblastoma

Similar variants

RB1 p.Pro786His Uncertain significance ★★ ⚠ same residue
RB1 p.Pro786Leu 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

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-pro786ser (accessed [today's date]).

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