Is CBL p.Thr745= (c.2235C>T) pathogenic?

CBL p.Thr745= (c.2235C>T) is classified Likely benign in CBL (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-09). Ultra-rare (popmax 0.0267%, eas); Associated with Cardiovascular phenotype.

What condition is associated with CBL p.Thr745= (c.2235C>T)?

CBL p.Thr745= (c.2235C>T) is associated with Cardiovascular phenotype, RASopathy (ClinVar).

How common is CBL p.Thr745= (c.2235C>T) in the general population?

CBL p.Thr745= (c.2235C>T) is ultra-rare (popmax 0.0267%, eas) (gnomAD).

CBL p.Thr745=

c.2235C>T · rs763880494 · VCV1123879

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0267%, eas)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5.9	GERP -3.3
Overall
CADD	0.175	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0267% East Asian · 12/44,872 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0121%

Overall 0.00143% 23/1,611,482 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0267%	3,739
Middle Eastern	0.0164%	6,082
South Asian	0.00439%	22,756
Remaining individualsnot grpmax-eligible	0.00321%	31,196
African / African-American	0.00267%	37,418
Admixed American	0.00167%	60,002
Finnishnot grpmax-eligible	0.00157%	63,554

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.Thr745=
Coding: c.2235C>T
MANE Select: NM_005188
dbSNP: rs763880494
Type: single nucleotide variant
Location: chr11:119297465 (GRCh38)
Gene constraint: LOEUF 0.622 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.27 · 34 PDB
Residue 745: 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

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

Also linked: RASopathy

Similar variants

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
CBL p.Tyr371Asn 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-thr745 (accessed [today's date]).

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