Is RBL2 p.Pro702Ser (c.2104C>T) pathogenic?

RBL2 p.Pro702Ser (c.2104C>T) is classified Uncertain significance in RBL2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-03-16). AlphaMissense: likely benign (0.0638); Ultra-rare (popmax 0.06%, amr).

How common is RBL2 p.Pro702Ser (c.2104C>T) in the general population?

RBL2 p.Pro702Ser (c.2104C>T) is ultra-rare (popmax 0.06%, amr) (gnomAD).

What do computational predictors say about RBL2 p.Pro702Ser (c.2104C>T)?

AlphaMissense predicts likely benign (score 0.0638) — an in-silico prediction, not a clinical call.

RBL2 p.Pro702Ser

c.2104C>T · VCV3776384

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0638 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.06%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.0638	likely benign
REVEL	0.351	indeterminate
SaProt	LLR -5.73	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 51 kb · p 1.1e-08 · regional, not allelic
Overall
CADD	14.15	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.06% Admixed American · 36/60,032 alleles

Filtering AF 0.0444% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0392%

Overall 0.00291% 47/1,614,238 alleles · ultra-rare exomes 27/1,461,858 · genomes 20/152,380 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.06%	1,668
Remaining individualsnot grpmax-eligible	0.0144%	6,946
African / African-American	0.00266%	37,541

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.Pro702Ser
Coding: c.2104C>T
MANE Select: NM_005611
Type: single nucleotide variant
Location: chr16:53470044 (GRCh38)
Gene constraint: LOEUF 0.602 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.12 · 2 PDB
Residue 702: the 'pocket; binds e1a' region; the 'spacer' 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.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
RBL2 p.Leu141= 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-pro702ser (accessed [today's date]).

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