Immunodeficiency 61

Summary

Immunodeficiency 61 (MONDO:0010296) is a disease with 3 cohort genes.

At a glance

• Cohort genes: 3
• ClinVar variants: 4

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	immunodeficiency 61
Mondo ID	MONDO:0010296
MeSH	C538057
OMIM	300310
Orphanet	696945
DOID	DOID:0111999
UMLS	C1845903
MedGen	337462
GARD	0010007
Is cancer (heuristic)	no

Also known as: agammaglobulinemia X-linked type 2 · agammaglobulinemia, X-linked, type 2 · AGMX2 · immunodeficiency 61, X-linked recessive · XLA2

Data availability: 4 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › immune system disorder › inborn error of immunity › B cell deficiency › agammaglobulinemia › immunodeficiency 61

Related subtypes (9): congenital agammaglobulinemia, Good syndrome, isolated agammaglobulinemia, syndromic agammaglobulinemia, activated PI3K-delta syndrome, agammaglobulinemia 9, autosomal recessive, agammaglobulinemia 10, autosomal dominant, agammaglobulinemia, autosomal recessive, due to BOB1 deficiency, agammaglobulinemia 8b, autosomal recessive

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

4 retrieved; paginated sample, class counts are floors:

1 benign/likely benign, 1 uncertain significance, 1 likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
626219	NC_000023.10:g.19667630_19886572del	SH3KBP1	Pathogenic	no assertion criteria provided
3767281	NC_000001.11:g.19676448_19875998del	RNF186	Likely pathogenic	no assertion criteria provided
2506552	GRCh37/hg19 Xp22.12(chrX:19564040-19954016)	BCLAF3	Uncertain significance	criteria provided, single submitter
1165691	NM_031892.3(SH3KBP1):c.1266G>A (p.Pro422=)	SH3KBP1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · 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
SH3KBP1	Moderate	X-linked	immunodeficiency 61	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SH3KBP1	Orphanet:696945	X-linked common variable immunodeficiency phenotype due to SH3KBP1 deficiency

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SH3KBP1	HGNC:13867	ENSG00000147010	Q96B97	SH3 domain-containing kinase-binding protein 1	gencc,clinvar
RNF186	HGNC:25978	ENSG00000178828	Q9NXI6	E3 ubiquitin-protein ligase RNF186	clinvar
BCLAF3	HGNC:27413	ENSG00000173681	A2AJT9	BCLAF1 and THRAP3 family member 3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SH3KBP1	SH3 domain-containing kinase-binding protein 1	Adapter protein involved in regulating diverse signal transduction pathways.
RNF186	E3 ubiquitin-protein ligase RNF186	E3 ubiquitin protein ligase that is part of an apoptotic signaling pathway activated by endoplasmic reticulum stress.
BCLAF3	BCLAF1 and THRAP3 family member 3	Component of the spliceosome complex, important for maintaining embryonic stem cell (ESC) fate.

Protein-family classification

Druggable: 0 · Difficult: 2 · 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	5.8×	0.482
Transcription factor	1	2.8×	0.482
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SH3KBP1	Scaffold/PPI	no		SH3_domain, CIN85_SH3_1, CIN85_SH3_2
RNF186	Transcription factor	no	2.3.2.27	Znf_RING, Znf_RING/FYVE/PHD, Znf_RING_CS
BCLAF3	Other/Unknown	no		THRAP3_BCLAF1

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
secondary oocyte	2
ileal mucosa	1
left ventricle myocardium	1
corpus epididymis	1
duodenum	1
jejunal mucosa	1
calcaneal tendon	1
oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SH3KBP1	254	ubiquitous	marker	secondary oocyte, left ventricle myocardium, ileal mucosa
RNF186	76	tissue_specific	marker	jejunal mucosa, duodenum, corpus epididymis
BCLAF3	194		marker	secondary oocyte, oocyte, calcaneal tendon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SH3KBP1	2,825
BCLAF3	471
RNF186	455

Structural data

PDB: 1 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SH3KBP1	Q96B97	7

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
RNF186	Q9NXI6	68.89
BCLAF3	A2AJT9	48.92

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 26. Enrichment computed across 3 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Reelin signalling pathway	1	1903.3×	0.008	SH3KBP1
Listeria monocytogenes entry into host cells	1	1038.2×	0.008	SH3KBP1
InlB-mediated entry of Listeria monocytogenes into host cell	1	761.3×	0.008	SH3KBP1
Negative regulation of MET activity	1	519.1×	0.008	SH3KBP1
Antigen activates B Cell Receptor (BCR) leading to generation of second messengers	1	356.9×	0.008	SH3KBP1
EGFR downregulation	1	346.1×	0.008	SH3KBP1
Signaling by the B Cell Receptor (BCR)	1	346.1×	0.008	SH3KBP1
Bacterial Infection Pathways	1	335.9×	0.008	SH3KBP1
Signaling by EGFR	1	326.3×	0.008	SH3KBP1
Signaling by MET	1	317.2×	0.008	SH3KBP1
Potential therapeutics for SARS	1	114.2×	0.021	SH3KBP1
Cargo recognition for clathrin-mediated endocytosis	1	104.8×	0.021	SH3KBP1
Clathrin-mediated endocytosis	1	85.2×	0.023	SH3KBP1
SARS-CoV Infections	1	55.4×	0.034	SH3KBP1
Signaling by Receptor Tyrosine Kinases	1	51.7×	0.034	SH3KBP1
Axon guidance	1	45.1×	0.036	SH3KBP1
Nervous system development	1	42.9×	0.036	SH3KBP1
Membrane Trafficking	1	37.1×	0.039	SH3KBP1
Vesicle-mediated transport	1	34.8×	0.039	SH3KBP1
Viral Infection Pathways	1	30.8×	0.042	SH3KBP1
Adaptive Immune System	1	29.8×	0.042	SH3KBP1
Infectious disease	1	24.8×	0.048	SH3KBP1
Developmental Biology	1	14.5×	0.078	SH3KBP1
Disease	1	13.1×	0.080	SH3KBP1
Immune System	1	13.0×	0.080	SH3KBP1
Signal Transduction	1	10.2×	0.098	SH3KBP1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of B cell activation	1	702.2×	0.012	SH3KBP1
protein K29-linked ubiquitination	1	510.7×	0.012	RNF186
protein localization to mitochondrion	1	432.1×	0.012	RNF186
intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress	1	160.5×	0.023	RNF186
protein K63-linked ubiquitination	1	89.2×	0.032	RNF186
protein autoubiquitination	1	78.0×	0.032	RNF186
cytoskeleton organization	1	44.2×	0.042	SH3KBP1
regulation of cell shape	1	41.0×	0.042	SH3KBP1
actin filament organization	1	39.6×	0.042	SH3KBP1
endocytosis	1	31.7×	0.047	SH3KBP1
cell-cell signaling	1	23.2×	0.058	SH3KBP1
cell migration	1	20.5×	0.060	SH3KBP1
proteasome-mediated ubiquitin-dependent protein catabolic process	1	17.4×	0.065	RNF186
apoptotic process	1	9.6×	0.108	SH3KBP1
positive regulation of transcription by RNA polymerase II	1	5.0×	0.188	BCLAF3

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 3 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SH3KBP1	0	0
RNF186	0	0
BCLAF3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
RNF186	2.3.2.27	RING-type E3 ubiquitin transferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	3	SH3KBP1, RNF186, BCLAF3

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SH3KBP1	0	—
RNF186	0	—
BCLAF3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.