Is CBL p.Pro547= (c.1641T>C) pathogenic?

CBL p.Pro547= (c.1641T>C) is classified Benign/Likely benign in CBL (ClinVar, Multiple submitters, 15 submitters; last evaluated 2026-01-30). Rare (popmax 0.429%, mid); Associated with CBL-related disorder.

What condition is associated with CBL p.Pro547= (c.1641T>C)?

CBL p.Pro547= (c.1641T>C) is associated with CBL-related disorder, juvenile myelomonocytic leukemia, Noonan syndrome and Noonan-related syndrome (ClinVar).

How common is CBL p.Pro547= (c.1641T>C) in the general population?

CBL p.Pro547= (c.1641T>C) is rare (popmax 0.429%, mid) (gnomAD).

CBL p.Pro547=

c.1641T>C · rs61755280 · VCV45202

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 15 submitters

gnomAD v4.1

Rare

rare (popmax 0.429%, mid)

Conditions

CBL-related disorder

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 1.8	GERP 0.85, phastCons 1
Overall
CADD	9.757	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.429% Middle Eastern · 26/6,062 alleles

Filtering AF 0.301% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.258%

Overall 0.0608% 981/1,613,986 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.429%	233
Ashkenazi Jewishnot grpmax-eligible	0.193%	519
Admixed American	0.145%	690
African / African-American	0.144%	694
Remaining individualsnot grpmax-eligible	0.107%	933
European (non-Finnish)	0.0521%	1,919
South Asian	0.0209%	4,793
Finnishnot grpmax-eligible	0.00313%	31,998

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.Pro547=
Coding: c.1641T>C
MANE Select: NM_005188
dbSNP: rs61755280
Type: single nucleotide variant
Location: chr11:119285266 (GRCh38)
Gene constraint: LOEUF 0.622 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.27 · 34 PDB
Residue 547: the 'required for ubiquitination of spred2' region; the 'disordered' region

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

Disease context

Also linked: juvenile myelomonocytic leukemia Noonan syndrome and Noonan-related syndrome RASopathy

Similar variants

CBL c.1096-1G>C Pathogenic/Likely pathogenic ★★ same condition
CBL c.1096-1G>T Pathogenic ★★ same condition
CBL c.1096-2A>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

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-pro547 (accessed [today's date]).

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