Is CBLB c.2689+2del pathogenic?

CBLB c.2689+2del is classified Likely pathogenic in CBLB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-30). Very rare (popmax 0.0022%, sas); Associated with autoimmune disease, multisystem, infantile-onset, 3.

What condition is associated with CBLB c.2689+2del?

CBLB c.2689+2del is associated with autoimmune disease, multisystem, infantile-onset, 3 (ClinVar).

How common is CBLB c.2689+2del in the general population?

CBLB c.2689+2del is very rare (popmax 0.0022%, sas) (gnomAD).

CBLB c.2689+2del

VCV4849425

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

canonical splice-site (±1/±2)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Conditions

autoimmune disease, multisystem, infantile-onset, 3

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	canonical splice-site (±1/±2)	predicted loss-of-function in a LoF-intolerant gene
Splicing
Splice region	donor +2	canonical splice dinucleotide (donor +2) · inside the BP7-excluded zone
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.6	GERP 2, phastCons 1
Non-coding constraint	Z 0.72	1 kb window · o/e 0.94 · regional · uncalibrated

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0022% South Asian · 2/91,054 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000205% 3/1,460,710 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,527
Remaining individualsnot grpmax-eligible	0.0016%	62,462

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: CBLB
Coding: c.2689+2del
MANE Select: NM_170662
Type: Deletion
Location: chr3:105670231 (GRCh38)
Gene constraint: LOEUF 0.406 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 62.88 · 36 PDB

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

Disease context

autoimmune disease, multisystem, infantile-onset, 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CBLB c.2569+1609A>C Uncertain significance ★ same condition
CBLB p.Arg468Ter Pathogenic same condition
CBLB p.Cys436Trp Pathogenic ⚠ same condition
CBLB p.His257Leu Pathogenic same condition
CBLB c.2569+1del Uncertain significance ★ same type
CBLB c.1594-18del Likely benign ★ same type
CBLB c.1594-20_1594-18del Likely benign ★ same type
CBLB c.1594-21_1594-18del Likely benign ★ same type

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/cblb-c-2689-plus-2del (accessed [today's date]).

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