Is RB1 p.Arg376Ser (c.1128G>C) pathogenic?

RB1 p.Arg376Ser (c.1128G>C) is classified Conflicting classifications of pathogenicity in RB1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-05-12). AlphaMissense: likely pathogenic (0.9412); Very rare (popmax 0.00542%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with RB1 p.Arg376Ser (c.1128G>C)?

RB1 p.Arg376Ser (c.1128G>C) is associated with hereditary neoplastic syndrome, urinary bladder cancer, retinoblastoma (ClinVar).

How common is RB1 p.Arg376Ser (c.1128G>C) in the general population?

RB1 p.Arg376Ser (c.1128G>C) is very rare (popmax 0.00542%, afr) (gnomAD).

What do computational predictors say about RB1 p.Arg376Ser (c.1128G>C)?

AlphaMissense predicts likely pathogenic (score 0.9412) — an in-silico prediction, not a clinical call.

RB1 p.Arg376Ser

c.1128G>C · rs908738769 · VCV848110

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9412 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00542%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.9412	likely pathogenic
REVEL	0.638	indeterminate
SaProt	LLR -5.12	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	Δ0.30	acceptor loss at this position · masked 0 · deltas
Constraint at this position
Conservation	phyloP 5.1	GERP -0.06, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 156 kb · p 9.1e-08 · regional, not allelic
Overall
CADD	23.4	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 0.00542% African / African-American · 4/73,800 alleles

Filtering AF 0.00176% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00105%

Overall 0.000255% 4/1,568,726 alleles · very rare exomes 3/1,416,868 · genomes 1/151,858 · 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.Arg376Ser
Coding: c.1128G>C
MANE Select: NM_000321
dbSNP: rs908738769
Type: single nucleotide variant
Location: chr13:48373405 (GRCh38)
Gene constraint: LOEUF 0.239 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.03 · 19 PDB
Residue 376: the 'pocket; binds t and e1a' region; the 'domain a' 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: urinary bladder cancer retinoblastoma

Similar variants

RB1 p.Arg376Lys Uncertain significance ★★ ⚠ same residue
RB1 p.Arg376Gly 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-arg376ser (accessed [today's date]).

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