Is CBL p.Ile673Phe (c.2017A>T) pathogenic?

CBL p.Ile673Phe (c.2017A>T) is classified Uncertain significance in CBL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-31). AlphaMissense: likely pathogenic (0.6388); Absent from gnomAD v4.1; Associated with Cardiovascular phenotype.

What condition is associated with CBL p.Ile673Phe (c.2017A>T)?

CBL p.Ile673Phe (c.2017A>T) is associated with Cardiovascular phenotype (ClinVar).

How common is CBL p.Ile673Phe (c.2017A>T) in the general population?

CBL p.Ile673Phe (c.2017A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CBL p.Ile673Phe (c.2017A>T)?

AlphaMissense predicts likely pathogenic (score 0.6388) — an in-silico prediction, not a clinical call.

CBL p.Ile673Phe

c.2017A>T · VCV4219882

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6388 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.6388	likely pathogenic
REVEL	0.447	indeterminate
SaProt	LLR -7.24	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.7, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 22 kb · p 0.19 · regional, not allelic
Overall
CADD	26.4	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.Ile673Phe
Coding: c.2017A>T
MANE Select: NM_005188
Type: single nucleotide variant
Location: chr11:119287927 (GRCh38)
Gene constraint: LOEUF 0.622 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.27 · 34 PDB
Residue 673: the 'required for ubiquitination of spred2' region; the 'interaction with cd2ap' 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.Ile673Val Uncertain significance ★★ ⚠ same residue
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

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-ile673phe (accessed [today's date]).

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