Is RB1 p.Val654= (c.1962G>T) pathogenic?

RB1 p.Val654= (c.1962G>T) is classified Likely benign in RB1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-02). Ultra-rare (popmax 0.011%, sas); Associated with retinoblastoma.

What condition is associated with RB1 p.Val654= (c.1962G>T)?

RB1 p.Val654= (c.1962G>T) is associated with retinoblastoma, hereditary neoplastic syndrome (ClinVar).

How common is RB1 p.Val654= (c.1962G>T) in the general population?

RB1 p.Val654= (c.1962G>T) is ultra-rare (popmax 0.011%, sas) (gnomAD).

How is Retinoblastoma inherited?

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

RB1 p.Val654=

c.1962G>T · rs2138335792 · VCV1083163

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.011%, sas)

Conditions

retinoblastoma

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.2	GERP -2.1, phastCons 1
Overall
CADD	5.309	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.011% South Asian · 10/91,078 alleles

Filtering AF 0.00594% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00453%

Overall 0.000682% 11/1,613,958 alleles · ultra-rare exomes 11/1,461,804 · genomes 0/152,154 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.011%	9,108
Remaining individualsnot grpmax-eligible	0.0016%	62,486

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.Val654=
Coding: c.1962G>T
MANE Select: NM_000321
dbSNP: rs2138335792
Type: single nucleotide variant
Location: chr13:48459689 (GRCh38)
Gene constraint: LOEUF 0.239 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.03 · 19 PDB
Residue 654: an α-helix; the 'pocket; binds t and e1a' region; a UniProt-annotated variant site (in rb); the 'domain b' 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

Also linked: hereditary neoplastic syndrome

For Retinoblastoma (Orphanet):

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

Similar variants

RB1 p.Val654Leu Pathogenic/Likely pathogenic ★★ same residue
RB1 p.Val654Met Pathogenic ★★ ⚠ same residue
RB1 p.Val654Ala Uncertain significance ★★ ⚠ same residue
RB1 p.Val654Gly Uncertain significance ★★ ⚠ same residue
RB1 p.Val654Glu Uncertain significance ★ ⚠ same residue
RB1 p.Val654fs Pathogenic ★ same residue
RB1 p.Val654_Tyr655delinsAsp Conflicting classifications of pathogenicity ★ same residue
RB1 c.1049+1G>A Pathogenic/Likely 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-val654 (accessed [today's date]).

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