Agammaglobulinemia 10, autosomal dominant

Summary

Agammaglobulinemia 10, autosomal dominant (MONDO:0030529) is a disease caused by SPI1 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: SPI1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 10

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	agammaglobulinemia 10, autosomal dominant
Mondo ID	MONDO:0030529
OMIM	619707
DOID	DOID:0081142
UMLS	C5676900
MedGen	1806624
GARD	0025595
Is cancer (heuristic)	no

Also known as: AGM10

Data availability: 10 ClinVar variants · 2 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 › agammaglobulinemia 10, autosomal dominant

Related subtypes (9): congenital agammaglobulinemia, immunodeficiency 61, Good syndrome, isolated agammaglobulinemia, syndromic agammaglobulinemia, activated PI3K-delta syndrome, agammaglobulinemia 9, autosomal recessive, 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

10 retrieved; paginated sample, class counts are floors:

5 pathogenic, 3 likely pathogenic, 1 conflicting classifications of pathogenicity, 1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
1335903	NM_003120.3(SPI1):c.363C>A (p.Tyr121Ter)	SPI1	Pathogenic	criteria provided, single submitter
4526589	NM_003120.3(SPI1):c.130G>T (p.Glu44Ter)	SPI1	Pathogenic	criteria provided, single submitter
585156	NM_001080547.2(SPI1):c.325_327delinsAG (p.Gly109fs)	SPI1	Pathogenic	no assertion criteria provided
989449	NM_003120.3(SPI1):c.693_694del (p.Leu232fs)	SPI1	Pathogenic	no assertion criteria provided
989450	NM_003120.3(SPI1):c.328C>T (p.Gln110Ter)	SPI1	Pathogenic	criteria provided, single submitter
3075679	NM_003120.3(SPI1):c.573G>A (p.Trp191Ter)	SPI1	Likely pathogenic	criteria provided, single submitter
801321	NM_003120.3(SPI1):c.722T>G (p.Val241Gly)	SPI1	Likely pathogenic	criteria provided, single submitter
801322	NM_003120.3(SPI1):c.632A>C (p.His211Pro)	SPI1	Likely pathogenic	criteria provided, single submitter
2672188	NM_003120.3(SPI1):c.689G>C (p.Arg230Pro)	SPI1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
4076209	NM_003120.3(SPI1):c.425del (p.Pro142fs)	SPI1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · 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
SPI1	Strong	Autosomal dominant	agammaglobulinemia 10, autosomal dominant	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SPI1	Orphanet:33110	Autosomal non-syndromic agammaglobulinemia

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SPI1	HGNC:11241	ENSG00000066336	P17947	Transcription factor PU.1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SPI1	Transcription factor PU.1	Pioneer transcription factor, which controls hematopoietic cell fate by decompacting stem cell heterochromatin and allowing other transcription factors to enter otherwise inaccessible genomic sites.

Protein-family classification

Druggable: 0 · Difficult: 0 · 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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SPI1	Other/Unknown	no		Ets_dom, WH-like_DNA-bd_sf, WH_DNA-bd_sf

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
granulocyte	1
leukocyte	1
monocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SPI1	170	broad	marker	granulocyte, monocyte, leukocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SPI1	3,823

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SPI1	P17947	35

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 1 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
Transcriptional regulation by RUNX1	1	146.4×	0.025	SPI1
Transcriptional regulation of granulopoiesis	1	125.5×	0.025	SPI1
RUNX1 regulates transcription of genes involved in differentiation of HSCs	1	95.2×	0.025	SPI1
RNA Polymerase II Transcription	1	22.5×	0.069	SPI1
Gene expression (Transcription)	1	17.8×	0.069	SPI1
Generic Transcription Pathway	1	15.1×	0.069	SPI1
Developmental Biology	1	14.5×	0.069	SPI1

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
pro-T cell differentiation	1	8426.0×	0.001	SPI1
negative regulation of neutrophil degranulation	1	8426.0×	0.001	SPI1
regulation of myeloid progenitor cell differentiation	1	8426.0×	0.001	SPI1
positive regulation of myeloid dendritic cell chemotaxis	1	8426.0×	0.001	SPI1
myeloid leukocyte differentiation	1	5617.3×	0.001	SPI1
endothelial to hematopoietic transition	1	5617.3×	0.001	SPI1
positive regulation of antifungal innate immune response	1	5617.3×	0.001	SPI1
follicular B cell differentiation	1	4213.0×	0.001	SPI1
positive regulation of microglial cell mediated cytotoxicity	1	4213.0×	0.001	SPI1
negative regulation of MHC class II biosynthetic process	1	3370.4×	0.001	SPI1
anatomical structure regression	1	3370.4×	0.001	SPI1
pericyte cell differentiation	1	3370.4×	0.001	SPI1
regulation of erythrocyte differentiation	1	2808.7×	0.001	SPI1
apoptotic process involved in blood vessel morphogenesis	1	2808.7×	0.001	SPI1
immature B cell differentiation	1	2407.4×	0.001	SPI1
oncogene-induced cell senescence	1	2407.4×	0.001	SPI1
negative regulation of adipose tissue development	1	2407.4×	0.001	SPI1
TRAIL-activated apoptotic signaling pathway	1	1872.4×	0.001	SPI1
germinal center B cell differentiation	1	1685.2×	0.001	SPI1
negative regulation of protein localization to chromatin	1	1532.0×	0.001	SPI1
defense response to tumor cell	1	1296.3×	0.002	SPI1
granulocyte differentiation	1	1203.7×	0.002	SPI1
positive regulation of B cell differentiation	1	1123.5×	0.002	SPI1
interleukin-6-mediated signaling pathway	1	1123.5×	0.002	SPI1
cellular response to ethanol	1	1053.2×	0.002	SPI1
myeloid dendritic cell differentiation	1	936.2×	0.002	SPI1
positive regulation of p38MAPK cascade	1	624.1×	0.003	SPI1
lipopolysaccharide-mediated signaling pathway	1	526.6×	0.003	SPI1
negative regulation of non-canonical NF-kappaB signal transduction	1	510.7×	0.003	SPI1
macrophage differentiation	1	468.1×	0.003	SPI1

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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
SPI1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	1	SPI1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SPI1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.