Is RB1 p.Ala14= (c.42C>T) pathogenic?

RB1 p.Ala14= (c.42C>T) is classified Benign/Likely benign in RB1 (ClinVar, Multiple submitters, 14 submitters; last evaluated 2026-06-23). Rare (popmax 0.386%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with RB1 p.Ala14= (c.42C>T)?

RB1 p.Ala14= (c.42C>T) is associated with hereditary neoplastic syndrome, retinoblastoma (ClinVar).

How common is RB1 p.Ala14= (c.42C>T) in the general population?

RB1 p.Ala14= (c.42C>T) is rare (popmax 0.386%, nfe) (gnomAD).

RB1 p.Ala14=

c.42C>T · rs148980395 · VCV237673

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 14 submitters

gnomAD v4.1

Rare

rare (popmax 0.386%, nfe)

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 -3.3	GERP -1.7
Overall
CADD	7.579	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.386% European (non-Finnish) · 4,390/1,136,262 alleles

Filtering AF 0.377% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.373%

Overall 0.302% 4,546/1,503,378 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.386%	259
Remaining individualsnot grpmax-eligible	0.154%	648
African / African-American	0.0639%	1,564
Finnishnot grpmax-eligible	0.0336%	2,972
Ashkenazi Jewishnot grpmax-eligible	0.0145%	6,914
Admixed American	0.0104%	9,641
South Asian	0.00123%	81,432

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.Ala14=
Coding: c.42C>T
MANE Select: NM_000321
dbSNP: rs148980395
Type: single nucleotide variant
Location: chr13:48303954 (GRCh38)
Gene constraint: LOEUF 0.239 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.03 · 19 PDB
Residue 14: the 'disordered' 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: retinoblastoma

Similar variants

RB1 p.Ala14Val Uncertain significance ★ ⚠ same residue
RB1 p.Ala14Leu Uncertain significance ★★ same residue
RB1 p.Ala14_Ala15insThrAlaAla 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
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-ala14 (accessed [today's date]).

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