Is CBL p.Cys232Ser (c.694T>A) pathogenic?

CBL p.Cys232Ser (c.694T>A) is classified Uncertain significance in CBL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-15). AlphaMissense: likely pathogenic (0.9886); Absent from gnomAD v4.1; Associated with Cardiovascular phenotype.

What condition is associated with CBL p.Cys232Ser (c.694T>A)?

CBL p.Cys232Ser (c.694T>A) is associated with Cardiovascular phenotype (ClinVar).

How common is CBL p.Cys232Ser (c.694T>A) in the general population?

CBL p.Cys232Ser (c.694T>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CBL p.Cys232Ser (c.694T>A)?

AlphaMissense predicts likely pathogenic (score 0.9886) — an in-silico prediction, not a clinical call.

CBL p.Cys232Ser

c.694T>A · VCV4613873

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9886 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.9886	likely pathogenic
REVEL	0.907	moderately pathogenic-leaning
SaProt	LLR -9.64	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.60	unconstrained · MANE · 45 kb · p 4.6e-13 · regional, not allelic
Overall
CADD	28.7	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CBL
Protein: p.Cys232Ser
Coding: c.694T>A
MANE Select: NM_005188
Type: single nucleotide variant
Location: chr11:119273971 (GRCh38)
Gene constraint: LOEUF 0.622 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.27 · 34 PDB
Residue 232: the cbl-ptb domain; the 'sufficient for interaction with ephb1' region; the 'ef-hand-like' 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

Similar variants

CBL p.Ala187Ser Uncertain significance ★★ ⚠ same condition
CBL p.Ala187Val Uncertain significance ★★ ⚠ same condition
CBL p.Ala208Thr Uncertain significance ★★ ⚠ same condition
CBL p.Ala385Gly Uncertain significance ★★ ⚠ same condition
CBL p.Ala450Val Uncertain significance ★★ ⚠ same condition
CBL p.Ala513Thr Uncertain significance ★★ ⚠ same condition
CBL p.Ala556Gly Uncertain significance ★★ ⚠ same condition
CBL p.Ala672Asp Uncertain significance ★★ ⚠ 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-cys232ser (accessed [today's date]).

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