Is CBL p.Ser8Asn (c.23G>A) pathogenic?

CBL p.Ser8Asn (c.23G>A) is classified Uncertain significance in CBL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-06-06). AlphaMissense: likely benign (0.1368); Very rare (popmax 0.00903%, amr); Associated with Cardiovascular phenotype.

What condition is associated with CBL p.Ser8Asn (c.23G>A)?

CBL p.Ser8Asn (c.23G>A) is associated with Cardiovascular phenotype, RASopathy (ClinVar).

How common is CBL p.Ser8Asn (c.23G>A) in the general population?

CBL p.Ser8Asn (c.23G>A) is very rare (popmax 0.00903%, amr) (gnomAD).

What do computational predictors say about CBL p.Ser8Asn (c.23G>A)?

AlphaMissense predicts likely benign (score 0.1368) — an in-silico prediction, not a clinical call.

CBL p.Ser8Asn

c.23G>A · rs930860175 · VCV543978

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1368 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00903%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.1368	likely benign
REVEL	0.169	moderately benign-leaning
SaProt	LLR -8.03	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 5.7	GERP 1.3, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 26 kb · p 0.76 · regional, not allelic
Overall
CADD	20.2	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 0.00903% Admixed American · 5/55,360 alleles

Filtering AF 0.00348% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00221%

Overall 0.000444% 7/1,577,084 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00903%	11,072
European (non-Finnish)	0.000171%	583,335

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.Ser8Asn
Coding: c.23G>A
MANE Select: NM_005188
dbSNP: rs930860175
Type: single nucleotide variant
Location: chr11:119206440 (GRCh38)
Gene constraint: LOEUF 0.622 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.27 · 34 PDB
Residue 8: the 'sufficient for interaction with ephb1' region; the 'disordered' region

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

Disease context

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

Also linked: RASopathy

Similar variants

CBL p.Ser8Gly Uncertain significance ★ ⚠ 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
CBL p.Gln367Pro Pathogenic/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-ser8asn (accessed [today's date]).

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