Is CBL p.Thr377= (c.1131A>C) pathogenic?

CBL p.Thr377= (c.1131A>C) is classified Likely benign in CBL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-03). Very rare (popmax 8.49e-05%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with CBL p.Thr377= (c.1131A>C)?

CBL p.Thr377= (c.1131A>C) is associated with Cardiovascular phenotype (ClinVar).

How common is CBL p.Thr377= (c.1131A>C) in the general population?

CBL p.Thr377= (c.1131A>C) is very rare (popmax 8.49e-05%, nfe) (gnomAD).

CBL p.Thr377=

c.1131A>C · VCV3827796

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 8.49e-05%, nfe)

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 -2.5	GERP -4.2
Overall
CADD	1.629	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.49e-05% European (non-Finnish) · 1/1,177,410 alleles

Overall 6.21e-05% 1/1,611,276 alleles · very rare exomes 1/1,458,968 · genomes 0/152,308 · joint denominator

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.Thr377=
Coding: c.1131A>C
MANE Select: NM_005188
Type: single nucleotide variant
Location: chr11:119278201 (GRCh38)
Gene constraint: LOEUF 0.622 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.27 · 34 PDB
Residue 377: the 'required for ubiquitination of spred2' region; an α-helix; the 'linker' 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

Similar variants

CBL p.Thr377Lys Uncertain significance ★ ⚠ same residue
CBL p.Thr377Ala Uncertain significance ★★ ⚠ same residue
CBL p.Thr377Ile Uncertain significance ★ ⚠ same residue
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

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-thr377 (accessed [today's date]).

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