combined immunodeficiency due to LRBA deficiency

Summary

combined immunodeficiency due to LRBA deficiency (MONDO:0013863) is a disease caused by LRBA (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: LRBA (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 2,150

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		23	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	combined immunodeficiency due to LRBA deficiency
Mondo ID	MONDO:0013863
OMIM	614700
Orphanet	445018
DOID	DOID:0081151
NCIT	C17680
UMLS	C3553512
MedGen	766426
GARD	0013565
Is cancer (heuristic)	no

Also known as: CID due to LRBA deficiency · combined immunodeficiency due to LRBA deficiency · CVID8 · immunodeficiency, common variable, 8, with autoimmunity

Data availability: 2,150 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › syndromic agammaglobulinemia › common variable immunodeficiency › combined immunodeficiency due to LRBA deficiency

Related subtypes (15): immune deficiency, familial variable, immunodeficiency, common variable, 2, immunodeficiency, common variable, 1, immunodeficiency, common variable, 3, immunodeficiency, common variable, 4, immunodeficiency, common variable, 5, immunodeficiency, common variable, 6, immunodeficiency, common variable, 7, immunodeficiency, common variable, 10, IL21-related infantile inflammatory bowel disease, immunodeficiency, common variable, 12, pancytopenia due to IKZF1 mutations, immunodeficiency, common variable, 14, immunodeficiency, common variable, due to APRIL deficiency, immunodeficiency, common variable, 15

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

346 uncertain significance, 204 likely benign, 24 pathogenic, 9 benign, 8 conflicting classifications of pathogenicity, 5 benign/likely benign, 4 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1069622	NM_001364905.1(LRBA):c.5125_5152dup (p.Gln1718delinsArgTer)	LRBA	Pathogenic	criteria provided, single submitter
1070799	NM_001364905.1(LRBA):c.5980C>T (p.Arg1994Ter)	LRBA	Pathogenic	criteria provided, single submitter
1072644	NM_001364905.1(LRBA):c.6909G>A (p.Trp2303Ter)	LRBA	Pathogenic	criteria provided, single submitter
1072918	NM_001364905.1(LRBA):c.3830C>G (p.Ser1277Ter)	LRBA	Pathogenic	criteria provided, single submitter
1074569	NC_000004.11:g.(?151604683)(151604889_?)del	LRBA	Pathogenic	criteria provided, single submitter
1074570	NC_000004.11:g.(?151336570)(151520303_?)del	LRBA	Pathogenic	criteria provided, single submitter
1176175	NM_001364905.1(LRBA):c.7009C>T (p.Arg2337Ter)	LRBA	Pathogenic	criteria provided, multiple submitters, no conflicts
1177585	NM_001364905.1(LRBA):c.4261A>G (p.Ser1421Gly)	LRBA	Pathogenic	no assertion criteria provided
1361756	NM_001364905.1(LRBA):c.448+1G>T	LRBA	Pathogenic	criteria provided, single submitter
1376199	NM_001364905.1(LRBA):c.6235del (p.Ser2079fs)	LRBA	Pathogenic	criteria provided, single submitter
1391949	NM_001364905.1(LRBA):c.1697del (p.Lys566fs)	LRBA	Pathogenic	criteria provided, single submitter
1392922	NM_001364905.1(LRBA):c.6269_6270delinsAA (p.Ser2090Ter)	LRBA	Pathogenic	criteria provided, single submitter
1415306	NM_001364905.1(LRBA):c.893del (p.Lys298fs)	LRBA	Pathogenic	criteria provided, single submitter
1419646	NC_000004.11:g.(?151814184)(151814321_?)del	LRBA	Pathogenic	criteria provided, single submitter
1419984	NM_001364905.1(LRBA):c.5060_5067del (p.Asn1687fs)	LRBA	Pathogenic	criteria provided, single submitter
1424023	NM_001364905.1(LRBA):c.488del (p.Asn163fs)	LRBA	Pathogenic	criteria provided, single submitter
1424030	NM_001364905.1(LRBA):c.2614del (p.Ser872fs)	LRBA	Pathogenic	criteria provided, single submitter
1452672	NM_001364905.1(LRBA):c.6319del (p.Ile2107fs)	LRBA	Pathogenic	criteria provided, single submitter
1453544	NM_001364905.1(LRBA):c.7928del (p.Asn2643fs)	LRBA	Pathogenic	criteria provided, single submitter
1455821	NM_001364905.1(LRBA):c.1736G>A (p.Trp579Ter)	LRBA	Pathogenic	criteria provided, single submitter
1457482	NM_001364905.1(LRBA):c.6551+1del	LRBA	Pathogenic	criteria provided, single submitter
1458653	NC_000004.11:g.(?151504182)(151656538_?)del	LRBA	Pathogenic	criteria provided, single submitter
1458881	NM_001364905.1(LRBA):c.2836_2839del (p.Glu945_Glu946insTer)	LRBA	Pathogenic	criteria provided, multiple submitters, no conflicts
1495928	NM_001364905.1(LRBA):c.5646-2A>T	LRBA	Pathogenic	criteria provided, multiple submitters, no conflicts
1012318	NM_001364905.1(LRBA):c.4239del (p.Val1414fs)	LRBA	Likely pathogenic	criteria provided, single submitter
1066609	NM_001364905.1(LRBA):c.2166-1G>C	LRBA	Likely pathogenic	criteria provided, single submitter
1324677	NM_001364905.1(LRBA):c.6331-2A>G	LRBA	Likely pathogenic	criteria provided, single submitter
1333952	NM_001364905.1(LRBA):c.863del (p.His288fs)	LRBA	Likely pathogenic	criteria provided, single submitter
1008889	NM_001364905.1(LRBA):c.3805C>G (p.Pro1269Ala)	LRBA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1012506	NM_001364905.1(LRBA):c.240G>A (p.Leu80=)	LRBA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
LRBA	Strong	Autosomal recessive	combined immunodeficiency due to LRBA deficiency	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
LRBA	Orphanet:445018	Syndromic autoimmune enteropathy due to LRBA deficiency
MAB21L2	Orphanet:424099	Colobomatous microphthalmia-rhizomelic dysplasia syndrome

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
LRBA	HGNC:1742	ENSG00000198589	P50851	Lipopolysaccharide-responsive and beige-like anchor protein	gencc,clinvar
MAB21L2	HGNC:6758	ENSG00000181541	Q9Y586	Protein mab-21-like 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
LRBA	Lipopolysaccharide-responsive and beige-like anchor protein	Involved in coupling signal transduction and vesicle trafficking to enable polarized secretion and/or membrane deposition of immune effector molecules.
MAB21L2	Protein mab-21-like 2	Required for several aspects of embryonic development including normal development of the eye.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Scaffold/PPI	1	8.6×	0.225
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
LRBA	Scaffold/PPI	no		BEACH_dom, WD40_rpt, NBEA-like_DUF1088
MAB21L2	Other/Unknown	no		MAB21L/cGLR, Mab-21-like_nuc_Trfase, Mab-21_HhH/H2TH-like

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
bronchial epithelial cell	1
epithelium of bronchus	1
upper leg skin	1
muscle layer of sigmoid colon	1
pigmented layer of retina	1
pons	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
LRBA	274	ubiquitous	marker	upper leg skin, bronchial epithelial cell, epithelium of bronchus
MAB21L2	144	broad	marker	muscle layer of sigmoid colon, pons, pigmented layer of retina

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LRBA	1,331
MAB21L2	1,149

Structural data

PDB: 1 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
LRBA	P50851	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MAB21L2	Q9Y586	95.11

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 2 evidence-associated genes (0 with Reactome annotation).

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
embryonic body morphogenesis	1	1053.2×	0.009	MAB21L2
protein localization to phagophore assembly site	1	495.6×	0.009	LRBA
camera-type eye development	1	179.3×	0.011	MAB21L2
eye development	1	175.5×	0.011	MAB21L2
mitophagy	1	159.0×	0.011	LRBA
intracellular protein localization	1	52.3×	0.025	LRBA
cell population proliferation	1	51.4×	0.025	MAB21L2
nervous system development	1	23.0×	0.048	MAB21L2
positive regulation of cell population proliferation	1	16.8×	0.059	MAB21L2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
LRBA	0	0
MAB21L2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
LRBA	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	LRBA, MAB21L2

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
LRBA	1	—
MAB21L2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.