Is CBL p.Thr406= (c.1218A>G) pathogenic?

CBL p.Thr406= (c.1218A>G) is classified Likely benign in CBL (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-30). Ultra-rare (popmax 0.0692%, sas); Associated with Cardiovascular phenotype.

What condition is associated with CBL p.Thr406= (c.1218A>G)?

CBL p.Thr406= (c.1218A>G) is associated with Cardiovascular phenotype, RASopathy (ClinVar).

How common is CBL p.Thr406= (c.1218A>G) in the general population?

CBL p.Thr406= (c.1218A>G) is ultra-rare (popmax 0.0692%, sas) (gnomAD).

CBL p.Thr406=

c.1218A>G · rs761053226 · VCV702701

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0692%, sas)

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 -2.7	GERP -4.2
Overall
CADD	2.681	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0692% South Asian · 63/91,088 alleles

Filtering AF 0.0554% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0505%

Overall 0.00421% 68/1,613,996 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0692%	1,446
Middle Eastern	0.0164%	6,084
Remaining individualsnot grpmax-eligible	0.0048%	20,827
East Asian	0.00223%	44,890

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.Thr406=
Coding: c.1218A>G
MANE Select: NM_005188
dbSNP: rs761053226
Type: single nucleotide variant
Location: chr11:119278288 (GRCh38)
Gene constraint: LOEUF 0.622 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.27 · 34 PDB
Residue 406: the 'required for ubiquitination of spred2' region; an α-helix

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.Thr406Ile Uncertain significance ★★ ⚠ same residue
CBL p.Thr406Ala 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

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-thr406 (accessed [today's date]).

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