Is RB1 p.Ile126= (c.378C>A) pathogenic?

RB1 p.Ile126= (c.378C>A) is classified Likely benign in RB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-02-06). Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with RB1 p.Ile126= (c.378C>A)?

RB1 p.Ile126= (c.378C>A) is associated with hereditary neoplastic syndrome (ClinVar).

How common is RB1 p.Ile126= (c.378C>A) in the general population?

RB1 p.Ile126= (c.378C>A) is absent from gnomAD v4.1 (gnomAD).

RB1 p.Ile126=

c.378C>A · rs2138084136 · VCV1734919

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,584,882)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.3	GERP -0.099, phastCons 1
Overall
CADD	13.49	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,584,882). 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.Ile126=
Coding: c.378C>A
MANE Select: NM_000321
dbSNP: rs2138084136
Type: single nucleotide variant
Location: chr13:48342712 (GRCh38)
Gene constraint: LOEUF 0.239 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.03 · 19 PDB

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.Ile126Val Likely benign ★ same residue
RB1 p.Ile126fs Pathogenic ★★ 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.1128-2A>G Pathogenic ★★ same condition
RB1 c.1215+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-ile126 (accessed [today's date]).

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