Is CBL p.Thr273= (c.819G>A) pathogenic?

CBL p.Thr273= (c.819G>A) is classified Conflicting classifications of pathogenicity in CBL (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-07-09). Very rare (popmax 0.0078%, nfe); Associated with Noonan syndrome and Noonan-related syndrome.

What condition is associated with CBL p.Thr273= (c.819G>A)?

CBL p.Thr273= (c.819G>A) is associated with Noonan syndrome and Noonan-related syndrome, RASopathy (ClinVar).

How common is CBL p.Thr273= (c.819G>A) in the general population?

CBL p.Thr273= (c.819G>A) is very rare (popmax 0.0078%, nfe) (gnomAD).

CBL p.Thr273=

c.819G>A · rs750907780 · VCV699490

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.0078%, nfe)

Conditions

Noonan syndrome and Noonan-related syndrome

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 -2.2	GERP -4.2
Overall
CADD	4.541	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0078% European (non-Finnish) · 92/1,179,926 alleles

Filtering AF 0.00648% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.006%

Overall 0.00595% 96/1,613,984 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0078%	12,825
East Asian	0.00223%	44,878
South Asian	0.0022%	45,540
Remaining individualsnot grpmax-eligible	0.0016%	62,502

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.Thr273=
Coding: c.819G>A
MANE Select: NM_005188
dbSNP: rs750907780
Type: single nucleotide variant
Location: chr11:119274903 (GRCh38)
Gene constraint: LOEUF 0.622 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.27 · 34 PDB
Residue 273: the cbl-ptb domain; the 'sufficient for interaction with ephb1' region; the 'sh2-like' region

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

Disease context

Noonan syndrome and Noonan-related syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: RASopathy

Similar variants

CBL p.Thr273Met Uncertain significance ★★ ⚠ same residue
CBL p.Thr273Arg 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-thr273 (accessed [today's date]).

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