Is RB1 p.Ala496Pro (c.1486G>C) pathogenic?

RB1 p.Ala496Pro (c.1486G>C) is classified Uncertain significance in RB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-10). AlphaMissense: likely pathogenic (0.9848); Very rare (popmax 8.57e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with RB1 p.Ala496Pro (c.1486G>C)?

RB1 p.Ala496Pro (c.1486G>C) is associated with hereditary neoplastic syndrome (ClinVar).

How common is RB1 p.Ala496Pro (c.1486G>C) in the general population?

RB1 p.Ala496Pro (c.1486G>C) is very rare (popmax 8.57e-05%, nfe) (gnomAD).

What do computational predictors say about RB1 p.Ala496Pro (c.1486G>C)?

AlphaMissense predicts likely pathogenic (score 0.9848) — an in-silico prediction, not a clinical call.

RB1 p.Ala496Pro

c.1486G>C · rs1366675428 · VCV1773678

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9848 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.57e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.9848	likely pathogenic · top 6% in RB1
REVEL	0.803	moderately pathogenic-leaning
SaProt	LLR -13.01	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 156 kb · p 9.1e-08 · regional, not allelic
Overall
CADD	29.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.57e-05% European (non-Finnish) · 1/1,166,576 alleles

Overall 6.26e-05% 1/1,596,812 alleles · very rare exomes 1/1,445,498 · genomes 0/151,314 · 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.Ala496Pro
Coding: c.1486G>C
MANE Select: NM_000321
dbSNP: rs1366675428
Type: single nucleotide variant
Location: chr13:48380229 (GRCh38)
Gene constraint: LOEUF 0.239 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.03 · 19 PDB
Residue 496: an α-helix; 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

Similar variants

RB1 p.Ala496Val Uncertain significance ★★ ⚠ same residue
RB1 p.Ala496Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
RB1 p.Ala496= Likely benign ★ same residue
RB1 p.Ala496Thr 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

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-ala496pro (accessed [today's date]).

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