Is CBL p.Phe179= (c.537T>C) pathogenic?

CBL p.Phe179= (c.537T>C) is classified Likely benign in CBL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-19). Very rare (popmax 8.47e-05%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with CBL p.Phe179= (c.537T>C)?

CBL p.Phe179= (c.537T>C) is associated with Cardiovascular phenotype (ClinVar).

How common is CBL p.Phe179= (c.537T>C) in the general population?

CBL p.Phe179= (c.537T>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

CBL p.Phe179=

c.537T>C · VCV3996064

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.055	GERP -2, phastCons 0.97
Overall
CADD	7.873	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,179,956 alleles

Overall 0.000124% 2/1,614,098 alleles · very rare exomes 2/1,461,764 · genomes 0/152,334 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604
European (non-Finnish)grpmax	8.47e-05%	1,179,956

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Phe179=
Coding: c.537T>C
MANE Select: NM_005188
Type: single nucleotide variant
Location: chr11:119271828 (GRCh38)
Gene constraint: LOEUF 0.622 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.27 · 34 PDB
Residue 179: the cbl-ptb domain; the 'sufficient for interaction with ephb1' region; the 'ef-hand-like' 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

Similar variants

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
CBL p.Ala672Asp 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-phe179 (accessed [today's date]).

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