Is RBL2 p.Pro418Ser (c.1252C>T) pathogenic?

RBL2 p.Pro418Ser (c.1252C>T) is classified Uncertain significance in RBL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-24). AlphaMissense: likely benign (0.3029); Ultra-rare (popmax 0.0801%, afr).

How common is RBL2 p.Pro418Ser (c.1252C>T) in the general population?

RBL2 p.Pro418Ser (c.1252C>T) is ultra-rare (popmax 0.0801%, afr) (gnomAD).

What do computational predictors say about RBL2 p.Pro418Ser (c.1252C>T)?

AlphaMissense predicts likely benign (score 0.3029) — an in-silico prediction, not a clinical call.

RBL2 p.Pro418Ser

c.1252C>T · rs149055093 · VCV2346337

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3029 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0801%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3029	likely benign
REVEL	0.882	moderately pathogenic-leaning
SaProt	LLR -8.84	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 1.8, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 51 kb · p 1.1e-08 · regional, not allelic
Overall
CADD	23.6	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 0.0801% African / African-American · 60/74,892 alleles

Filtering AF 0.0638% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.058%

Overall 0.00428% 69/1,612,556 alleles · ultra-rare exomes 38/1,460,328 · genomes 31/152,228 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0801%	1,248
Admixed American	0.0101%	9,936
Remaining individualsnot grpmax-eligible	0.0032%	31,221
European (non-Finnish)	8.48e-05%	1,179,458

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: RBL2
Protein: p.Pro418Ser
Coding: c.1252C>T
MANE Select: NM_005611
dbSNP: rs149055093
Type: single nucleotide variant
Location: chr16:53459523 (GRCh38)
Gene constraint: LOEUF 0.602 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.12 · 2 PDB
Residue 418: the 'pocket; binds e1a' region; the 'domain a' region; a UniProt-annotated variant site (in bruwag)

Full RBL2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

RBL2 p.Pro699Ser Uncertain significance ★★ ⚠ same type
RBL2 p.Pro702Ser Uncertain significance ★★ ⚠ same type
RBL2 p.Ser929Arg Uncertain significance ★★ ⚠ same type
RBL2 p.Thr423Met Uncertain significance ★★ ⚠ same type
RBL2 p.Tyr111Cys Uncertain significance ★★ ⚠ same type
RBL2 p.Arg829Ser Benign ★★ same type
RBL2 p.Arg852= Benign/Likely benign ★★ same type
RBL2 p.Asn549Ile Benign ★★ same type

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/rbl2-p-pro418ser (accessed [today's date]).

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