Is RB1 p.Ser397Ala (c.1189T>G) pathogenic?

RB1 p.Ser397Ala (c.1189T>G) is classified Uncertain significance in RB1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-11). AlphaMissense: likely benign (0.3281); Very rare (popmax 0.00134%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with RB1 p.Ser397Ala (c.1189T>G)?

RB1 p.Ser397Ala (c.1189T>G) is associated with hereditary neoplastic syndrome, retinoblastoma (ClinVar).

How common is RB1 p.Ser397Ala (c.1189T>G) in the general population?

RB1 p.Ser397Ala (c.1189T>G) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about RB1 p.Ser397Ala (c.1189T>G)?

AlphaMissense predicts likely benign (score 0.3281) — an in-silico prediction, not a clinical call.

RB1 p.Ser397Ala

c.1189T>G · rs1952784627 · VCV2129094

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3281 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.3281	likely benign
REVEL	0.8	moderately pathogenic-leaning
SaProt	LLR -10.51	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6.1	GERP 1.7, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 156 kb · p 9.1e-08 · regional, not allelic
Overall
CADD	25.0	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 0.00134% African / African-American · 1/74,392 alleles

Overall 0.000189% 3/1,588,796 alleles · very rare exomes 2/1,436,658 · genomes 1/152,138 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,392
South Asian	0.00111%	90,442
European (non-Finnish)	8.64e-05%	1,157,432

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.Ser397Ala
Coding: c.1189T>G
MANE Select: NM_000321
dbSNP: rs1952784627
Type: single nucleotide variant
Location: chr13:48373466 (GRCh38)
Gene constraint: LOEUF 0.239 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.03 · 19 PDB
Residue 397: 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.Ser397= Benign/Likely benign ★★ same residue
RB1 p.Ser397Ter 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.1128-1G>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-ser397ala (accessed [today's date]).

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