Is RB1 p.Pro28Ser (c.82C>T) pathogenic?

RB1 p.Pro28Ser (c.82C>T) is classified Uncertain significance in RB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-05). AlphaMissense: likely benign (0.0886); Absent from gnomAD v4.1; Associated with retinoblastoma.

What condition is associated with RB1 p.Pro28Ser (c.82C>T)?

RB1 p.Pro28Ser (c.82C>T) is associated with retinoblastoma (ClinVar).

How common is RB1 p.Pro28Ser (c.82C>T) in the general population?

RB1 p.Pro28Ser (c.82C>T) is absent from gnomAD v4.1 (gnomAD).

How is Retinoblastoma inherited?

Typically Autosomal dominant, Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about RB1 p.Pro28Ser (c.82C>T)?

AlphaMissense predicts likely benign (score 0.0886) — an in-silico prediction, not a clinical call.

RB1 p.Pro28Ser

c.82C>T · rs1020342293 · VCV2990152

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0886 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,497,762)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

retinoblastoma

Computational evidence

Protein change
AlphaMissense	0.0886	likely benign
REVEL	0.134	moderately benign-leaning
SaProt	LLR -8.93	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP -0.69, phastCons 0.062
Regional constraint	o/e 0.81	unconstrained · MANE · 156 kb · p 9.1e-08 · regional, not allelic
Overall
CADD	8.06	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

No allele count reported in gnomAD v4.1 (AN 1,497,762). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: RB1
Protein: p.Pro28Ser
Coding: c.82C>T
MANE Select: NM_000321
dbSNP: rs1020342293
Type: single nucleotide variant
Location: chr13:48303994 (GRCh38)
Gene constraint: LOEUF 0.239 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.03 · 19 PDB
Residue 28: the 'disordered' region

Full RB1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

retinoblastoma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Retinoblastoma (Orphanet):

Inheritance: Autosomal dominant, Not applicable
Onset: Antenatal, Childhood, Infancy
Prevalence: <1 / 1 000 000 (Europe)

Similar variants

RB1 p.Pro28Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
RB1 p.Pro28Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
RB1 p.Pro28_Pro29dup Uncertain significance ★★ same residue
RB1 p.Pro28fs Pathogenic ★ same residue
RB1 p.Pro28_Pro29del Likely benign ★ same residue
RB1 p.Pro28Ala Uncertain significance ★ ⚠ same residue
RB1 p.Pro28His Uncertain significance ★ ⚠ same residue
RB1 p.Pro28Thr Uncertain significance ★ ⚠ same residue

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-pro28ser (accessed [today's date]).

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