Is RB1 p.Ser215Pro (c.643T>C) pathogenic?

RB1 p.Ser215Pro (c.643T>C) is classified Uncertain significance in RB1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-04-23). AlphaMissense: likely pathogenic (0.9075); Very rare (popmax 0.00894%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with RB1 p.Ser215Pro (c.643T>C)?

RB1 p.Ser215Pro (c.643T>C) is associated with hereditary neoplastic syndrome, retinoblastoma (ClinVar).

How common is RB1 p.Ser215Pro (c.643T>C) in the general population?

RB1 p.Ser215Pro (c.643T>C) is very rare (popmax 0.00894%, eas) (gnomAD).

What do computational predictors say about RB1 p.Ser215Pro (c.643T>C)?

AlphaMissense predicts likely pathogenic (score 0.9075) — an in-silico prediction, not a clinical call.

RB1 p.Ser215Pro

c.643T>C · rs748923368 · VCV826406

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9075 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00894%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.9075	likely pathogenic
REVEL	0.791	moderately pathogenic-leaning
SaProt	LLR -10.28	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 5.1, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 156 kb · p 9.1e-08 · regional, not allelic
Overall
CADD	25.8	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 0.00894% East Asian · 4/44,750 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.000274% 4/1,460,574 alleles · very rare

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.Ser215Pro
Coding: c.643T>C
MANE Select: NM_000321
dbSNP: rs748923368
Type: single nucleotide variant
Location: chr13:48360052 (GRCh38)
Gene constraint: LOEUF 0.239 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.03 · 19 PDB
Residue 215: an α-helix

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: retinoblastoma

Similar variants

RB1 p.Ser215Leu Uncertain significance ★★ ⚠ same residue
RB1 p.Ser215Ter Pathogenic ★ same residue
RB1 p.Ser215= Likely benign ★ 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

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-ser215pro (accessed [today's date]).

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