Is RB1 p.Tyr321= (c.963C>T) pathogenic?

RB1 p.Tyr321= (c.963C>T) is classified Benign/Likely benign in RB1 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-06-24). Ultra-rare (popmax 0.0332%, mid); Associated with hereditary neoplastic syndrome.

What condition is associated with RB1 p.Tyr321= (c.963C>T)?

RB1 p.Tyr321= (c.963C>T) is associated with hereditary neoplastic syndrome, retinoblastoma (ClinVar).

How common is RB1 p.Tyr321= (c.963C>T) in the general population?

RB1 p.Tyr321= (c.963C>T) is ultra-rare (popmax 0.0332%, mid) (gnomAD).

RB1 p.Tyr321=

c.963C>T · rs377235036 · VCV725894

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0332%, mid)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.46 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.07	GERP -3, phastCons 0.97
Overall
CADD	7.009	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0332% Middle Eastern · 2/6,024 alleles

Filtering AF 0.00585% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00243%

Overall 0.00181% 29/1,603,250 alleles · ultra-rare exomes 26/1,451,360 · genomes 3/151,890 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0332%	3,012
South Asian	0.0055%	18,179
African / African-American	0.00536%	18,650
East Asian	0.00225%	44,418
Remaining individualsnot grpmax-eligible	0.00162%	61,900
European (non-Finnish)	0.00136%	73,363

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.Tyr321=
Coding: c.963C>T
MANE Select: NM_000321
dbSNP: rs377235036
Type: single nucleotide variant
Location: chr13:48367517 (GRCh38)
Gene constraint: LOEUF 0.239 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.03 · 19 PDB
Residue 321: 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.Tyr321Ter Pathogenic/Likely pathogenic ★★ same residue
RB1 p.Tyr321Cys Uncertain significance ★★ ⚠ same residue
RB1 p.Tyr321His Uncertain significance ★★ ⚠ same residue
RB1 p.Tyr321fs 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

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-tyr321 (accessed [today's date]).

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