Is RB1 p.Pro776His (c.2327C>A) pathogenic?

RB1 p.Pro776His (c.2327C>A) is classified Uncertain significance in RB1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-02-01). AlphaMissense: ambiguous (0.5282); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with RB1 p.Pro776His (c.2327C>A)?

RB1 p.Pro776His (c.2327C>A) is associated with hereditary neoplastic syndrome, urinary bladder cancer, retinoblastoma (ClinVar).

How common is RB1 p.Pro776His (c.2327C>A) in the general population?

RB1 p.Pro776His (c.2327C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about RB1 p.Pro776His (c.2327C>A)?

AlphaMissense predicts ambiguous (score 0.5282) — an in-silico prediction, not a clinical call.

RB1 p.Pro776His

c.2327C>A · rs912203557 · VCV486288

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.5282 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.5282	ambiguous
REVEL	0.508	indeterminate
SaProt	LLR -13.55	damaging
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	32.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: RB1
Protein: p.Pro776His
Coding: c.2327C>A
MANE Select: NM_000321
dbSNP: rs912203557
Type: single nucleotide variant
Location: chr13:48465206 (GRCh38)
Gene constraint: LOEUF 0.239 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.03 · 19 PDB
Residue 776: an α-helix; 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: urinary bladder cancer retinoblastoma

Similar variants

RB1 p.Pro776Ala Uncertain significance ★★ ⚠ same residue
RB1 p.Pro776Ser Uncertain significance ★★ same residue
RB1 p.Pro776= Likely benign ★★ same residue
RB1 p.Pro776Arg Uncertain significance ★ ⚠ same residue
RB1 p.Pro776Thr 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

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-pro776his (accessed [today's date]).

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