Is CBL p.Pro688Ser (c.2062C>T) pathogenic?

CBL p.Pro688Ser (c.2062C>T) is classified Conflicting classifications of pathogenicity in CBL (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-18). AlphaMissense: likely benign (0.0669); Very rare (popmax 0.00442%, nfe); Associated with CBL-related disorder.

What condition is associated with CBL p.Pro688Ser (c.2062C>T)?

CBL p.Pro688Ser (c.2062C>T) is associated with CBL-related disorder, RASopathy (ClinVar).

How common is CBL p.Pro688Ser (c.2062C>T) in the general population?

CBL p.Pro688Ser (c.2062C>T) is very rare (popmax 0.00442%, nfe) (gnomAD).

What do computational predictors say about CBL p.Pro688Ser (c.2062C>T)?

AlphaMissense predicts likely benign (score 0.0669) — an in-silico prediction, not a clinical call.

CBL p.Pro688Ser

c.2062C>T · rs730880428 · VCV180810

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0669 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00442%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CBL-related disorder

Computational evidence

Protein change
AlphaMissense	0.0669	likely benign
REVEL	0.056	moderately benign-leaning
SaProt	LLR -6.02	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.83	GERP -1.2
Regional constraint	o/e 1.05	unconstrained · MANE · 22 kb · p 0.19 · regional, not allelic
Overall
CADD	12.15	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 0.00442% European (non-Finnish) · 52/1,175,358 alleles

Filtering AF 0.00344% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00311%

Overall 0.00329% 53/1,608,904 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00442%	22,603
African / African-American	0.00134%	74,804

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: CBL
Protein: p.Pro688Ser
Coding: c.2062C>T
MANE Select: NM_005188
dbSNP: rs730880428
Type: single nucleotide variant
Location: chr11:119296943 (GRCh38)
Gene constraint: LOEUF 0.622 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.27 · 34 PDB
Residue 688: the 'required for ubiquitination of spred2' region; the 'interaction with cd2ap' region; the 'disordered' region

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

Disease context

Also linked: RASopathy

Similar variants

CBL p.Pro688Arg Uncertain significance ★★ ⚠ same residue
CBL p.Pro688Ala Uncertain significance ★ ⚠ same residue
CBL c.1096-1G>C Pathogenic/Likely pathogenic ★★ same condition
CBL c.1096-1G>T Pathogenic ★★ same condition
CBL c.1096-2A>T Pathogenic ★★ same condition
CBL c.1228-2A>G Pathogenic/Likely pathogenic ★★ same condition
CBL p.Arg420Gln Pathogenic/Likely pathogenic ★★ same condition
CBL p.Arg420Leu 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/cbl-p-pro688ser (accessed [today's date]).

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