Is CBL p.Ser642Asn (c.1925G>A) pathogenic?

CBL p.Ser642Asn (c.1925G>A) is classified Conflicting classifications of pathogenicity in CBL (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-12-04). AlphaMissense: likely benign (0.124); Very rare (popmax 0.00533%, afr); Associated with RASopathy.

What condition is associated with CBL p.Ser642Asn (c.1925G>A)?

CBL p.Ser642Asn (c.1925G>A) is associated with RASopathy, Noonan syndrome and Noonan-related syndrome (ClinVar).

How common is CBL p.Ser642Asn (c.1925G>A) in the general population?

CBL p.Ser642Asn (c.1925G>A) is very rare (popmax 0.00533%, afr) (gnomAD).

What do computational predictors say about CBL p.Ser642Asn (c.1925G>A)?

AlphaMissense predicts likely benign (score 0.124) — an in-silico prediction, not a clinical call.

CBL p.Ser642Asn

c.1925G>A · rs571045498 · VCV1334235

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.124 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00533%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

RASopathy

Computational evidence

Protein change
AlphaMissense	0.124	likely benign
REVEL	0.256	benign-leaning
SaProt	LLR -9.59	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 2.2	GERP -3.8, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 22 kb · p 0.19 · regional, not allelic
Overall
CADD	18.88	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 0.00533% African / African-American · 4/75,046 alleles

Filtering AF 0.00174% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000434% 7/1,614,042 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00533%	18,762
Admixed American	0.00333%	30,011
European (non-Finnish)	8.47e-05%	1,180,043

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.Ser642Asn
Coding: c.1925G>A
MANE Select: NM_005188
dbSNP: rs571045498
Type: single nucleotide variant
Location: chr11:119285550 (GRCh38)
Gene constraint: LOEUF 0.622 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.27 · 34 PDB
Residue 642: the 'required for ubiquitination of spred2' region; the 'disordered' region; a modified residue (phosphoserine)

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

Disease context

RASopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Noonan syndrome and Noonan-related syndrome

Similar variants

CBL p.Ser642Cys Uncertain significance ★★ ⚠ same residue
CBL p.Ser642Ile Conflicting classifications of pathogenicity ★ ⚠ same residue
CBL c.1096-1G>C Pathogenic/Likely pathogenic ★★ same condition
CBL c.1096-1G>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
CBL p.Gln367Arg 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-ser642asn (accessed [today's date]).

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