Is RB1 p.Ala488Val (c.1463C>T) pathogenic?

RB1 p.Ala488Val (c.1463C>T) is classified Conflicting classifications of pathogenicity in RB1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-11-17). AlphaMissense: likely pathogenic (0.7381); Ultra-rare (popmax 0.0182%, mid); Associated with hereditary neoplastic syndrome.

What condition is associated with RB1 p.Ala488Val (c.1463C>T)?

RB1 p.Ala488Val (c.1463C>T) is associated with hereditary neoplastic syndrome, retinoblastoma (ClinVar).

How common is RB1 p.Ala488Val (c.1463C>T) in the general population?

RB1 p.Ala488Val (c.1463C>T) is ultra-rare (popmax 0.0182%, mid) (gnomAD).

What do computational predictors say about RB1 p.Ala488Val (c.1463C>T)?

AlphaMissense predicts likely pathogenic (score 0.7381) — an in-silico prediction, not a clinical call.

RB1 p.Ala488Val

c.1463C>T · rs780248969 · VCV458124

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.7381 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0182%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.7381	likely pathogenic
REVEL	0.872	moderately pathogenic-leaning
SaProt	LLR -11.21	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	GERP 1.8, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 156 kb · p 9.1e-08 · regional, not allelic
Overall
CADD	27.3	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0182% Middle Eastern · 1/5,494 alleles

Filtering AF 0.000885% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000476%

Overall 0.00137% 22/1,603,846 alleles · ultra-rare exomes 20/1,454,352 · genomes 2/149,494 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0182%	5,494
Admixed American	0.00336%	29,725
South Asian	0.00333%	30,017
Remaining individualsnot grpmax-eligible	0.00322%	31,032
Finnishnot grpmax-eligible	0.00159%	62,910
European (non-Finnish)	0.00111%	90,388

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.Ala488Val
Coding: c.1463C>T
MANE Select: NM_000321
dbSNP: rs780248969
Type: single nucleotide variant
Location: chr13:48380206 (GRCh38)
Gene constraint: LOEUF 0.239 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.03 · 19 PDB
Residue 488: 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

Also linked: retinoblastoma

Similar variants

RB1 p.Ala488Thr Uncertain significance ★★ ⚠ same residue
RB1 p.Ala488= 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
RB1 c.1128-2A>G 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-ala488val (accessed [today's date]).

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