Agammaglobulinemia 8b, autosomal recessive

Summary

Agammaglobulinemia 8b, autosomal recessive (MONDO:0859234) is a disease with 2 cohort genes.

At a glance

• Cohort genes: 2
• ClinVar variants: 31

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	agammaglobulinemia 8b, autosomal recessive
Mondo ID	MONDO:0859234
OMIM	619824
DOID	DOID:0081143
UMLS	C5676958
MedGen	1808468
GARD	0026674
Is cancer (heuristic)	no

Data availability: 31 ClinVar variants · 1 GenCC gene-disease record.

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 8b, autosomal recessive

Related subtypes (9): congenital agammaglobulinemia, immunodeficiency 61, 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

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

31 retrieved; paginated sample, class counts are floors:

15 uncertain significance, 8 conflicting classifications of pathogenicity, 3 benign/likely benign, 2 pathogenic, 2 likely pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1676601	NM_003200.5(TCF3):c.808C>T (p.Gln270Ter)	TCF3	Pathogenic	no assertion criteria provided
1676602	TCF3, EX5-11 DEL	TCF3	Pathogenic	no assertion criteria provided
3255617	NM_001136139.4(TCF3):c.1643_1649dup (p.Asn551fs)	TCF3	Likely pathogenic	criteria provided, single submitter
4292914	NM_003200.5(TCF3):c.1619dup (p.Glu541fs)	TCF3	Likely pathogenic	criteria provided, single submitter
1406326	NM_003200.5(TCF3):c.1555A>G (p.Lys519Glu)	TCF3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1434706	NM_003200.5(TCF3):c.635C>T (p.Ala212Val)	TCF3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1515210	NM_003200.5(TCF3):c.1636C>T (p.Arg546Trp)	TCF3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2807485	NM_001136139.4(TCF3):c.1732A>G (p.Lys578Glu)	TCF3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3007223	NM_003200.5(TCF3):c.760G>A (p.Gly254Ser)	TCF3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
636717	NM_003200.5(TCF3):c.607G>A (p.Ala203Thr)	TCF3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
709097	NM_003200.5(TCF3):c.1948C>A (p.Pro650Thr)	TCF3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
730318	NM_003200.5(TCF3):c.307G>A (p.Gly103Ser)	TCF3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1050473	NM_003200.5(TCF3):c.1541C>T (p.Ser514Leu)	TCF3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1051931	NM_003200.5(TCF3):c.1327-3C>A	TCF3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1364813	NM_003200.5(TCF3):c.1232C>T (p.Thr411Ile)	TCF3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1401732	NM_003200.5(TCF3):c.1496G>A (p.Arg499Gln)	TCF3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1432193	NM_003200.5(TCF3):c.1430G>A (p.Arg477Gln)	TCF3	Uncertain significance	criteria provided, multiple submitters, no conflicts
2500098	NM_003200.5(TCF3):c.320C>T (p.Ala107Val)	TCF3	Uncertain significance	criteria provided, single submitter
2994798	NM_003200.5(TCF3):c.955+3A>G	TCF3	Uncertain significance	criteria provided, multiple submitters, no conflicts
3376353	NM_003200.5(TCF3):c.231G>C (p.Glu77Asp)	TCF3	Uncertain significance	criteria provided, single submitter
3608714	NM_003200.5(TCF3):c.853G>A (p.Gly285Ser)	TCF3	Uncertain significance	criteria provided, multiple submitters, no conflicts
3780696	NM_003200.5(TCF3):c.555C>A (p.Tyr185Ter)	TCF3	Uncertain significance	criteria provided, single submitter
3892614	NM_003200.5(TCF3):c.217C>T (p.Arg73Trp)	TCF3	Uncertain significance	criteria provided, single submitter
3892616	NM_003200.5(TCF3):c.730T>C (p.Ser244Pro)	TCF3	Uncertain significance	criteria provided, single submitter
626027	NM_003200.5(TCF3):c.229G>A (p.Glu77Lys)	TCF3	Uncertain significance	criteria provided, multiple submitters, no conflicts
626182	NM_001136139.4(TCF3):c.1755G>A (p.Lys585=)	TCF3	Uncertain significance	criteria provided, single submitter
811326	NM_003200.5(TCF3):c.23C>T (p.Ala8Val)	TCF3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1607823	NM_003200.5(TCF3):c.823-13C>T	TCF3	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
717103	NM_003200.5(TCF3):c.1713G>A (p.Glu571=)	TCF3	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
719522	NM_003200.5(TCF3):c.315G>A (p.Arg105=)	TCF3	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 3 · 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
TCF3	Strong	Autosomal dominant	agammaglobulinemia 8, autosomal dominant	5
TCF7L1	Strong	Autosomal dominant	agammaglobulinemia 8, autosomal dominant	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TCF3	Orphanet:33110	Autosomal non-syndromic agammaglobulinemia
TCF3	Orphanet:585956	B-lymphoblastic leukemia/lymphoma with t(1;19)(q23;p13.3)
TCF3	Orphanet:641375	B-lymphoblastic leukemia/lymphoma with t(17;19)

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
TCF3	HGNC:11633	ENSG00000071564	P15923	Transcription factor E2-alpha	gencc,clinvar
TCF7L1	HGNC:11640	ENSG00000152284	Q9HCS4	Transcription factor 7-like 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TCF3	Transcription factor E2-alpha	Transcriptional regulator involved in the initiation of neuronal differentiation and mesenchymal to epithelial transition.
TCF7L1	Transcription factor 7-like 1	Participates in the Wnt signaling pathway.

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
Transcription factor	1	4.1×	0.455
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TCF3	Transcription factor	no		bHLH_dom, HLH_DNA-bd_sf, NeuroDiff_E-box_TFs
TCF7L1	Other/Unknown	no		HMG_box_dom, CTNNB1-bd_N, TCF/LEF

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
embryo	1
ganglionic eminence	1
ventricular zone	1
aorta	1
popliteal artery	1
tibial artery	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TCF3	294	ubiquitous	marker	ganglionic eminence, ventricular zone, embryo
TCF7L1	230	ubiquitous	marker	popliteal artery, tibial artery, aorta

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TCF7L1	1,635
TCF3	457

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TCF3	P15923	5

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TCF7L1	Q9HCS4	52.59

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 30. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Binding of TCF/LEF:CTNNB1 to target gene promoters	1	571.0×	0.014	TCF7L1
RUNX3 regulates WNT signaling	1	571.0×	0.014	TCF7L1
Repression of WNT target genes	1	356.9×	0.014	TCF7L1
Specification of the neural plate border	1	317.2×	0.014	TCF7L1
Regulation of MITF-M-dependent genes involved in cell cycle and proliferation	1	285.5×	0.014	TCF7L1
TGFBR3 expression	1	228.4×	0.014	TCF3
Myogenesis	1	190.3×	0.014	TCF3
Signaling by TGFBR3	1	184.2×	0.014	TCF3
RNA Polymerase II Transcription	2	22.5×	0.014	TCF3, TCF7L1
Gene expression (Transcription)	2	17.8×	0.014	TCF3, TCF7L1
Generic Transcription Pathway	2	15.1×	0.014	TCF3, TCF7L1
Developmental Biology	2	14.5×	0.014	TCF3, TCF7L1
Beta-catenin independent WNT signaling	1	146.4×	0.015	TCF7L1
Transcriptional regulation by RUNX3	1	135.9×	0.015	TCF7L1
Gastrulation	1	129.8×	0.015	TCF7L1
Deactivation of the beta-catenin transactivating complex	1	116.5×	0.016	TCF7L1
Signal Transduction	2	10.2×	0.017	TCF3, TCF7L1
MITF-M-dependent gene expression	1	90.6×	0.017	TCF7L1
Ca2+ pathway	1	89.2×	0.017	TCF7L1
Degradation of beta-catenin by the destruction complex	1	86.5×	0.017	TCF7L1
Transcriptional regulation by RUNX1	1	73.2×	0.019	TCF3
Formation of the beta-catenin:TCF transactivating complex	1	60.1×	0.019	TCF7L1
Negative Regulation of CDH1 Gene Transcription	1	60.1×	0.019	TCF3
TCF dependent signaling in response to WNT	1	58.9×	0.019	TCF7L1
Signaling by TGFB family members	1	57.7×	0.019	TCF3
MITF-M-regulated melanocyte development	1	57.1×	0.019	TCF7L1
Signaling by WNT	1	56.0×	0.019	TCF7L1
Regulation of PD-L1(CD274) transcription	1	54.4×	0.019	TCF7L1
CHD1 and CHD2 subfamily	1	54.4×	0.019	TCF3
RUNX1 regulates transcription of genes involved in differentiation of HSCs	1	47.6×	0.021	TCF3

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
B cell lineage commitment	1	1685.2×	0.006	TCF3
immunoglobulin V(D)J recombination	1	1404.3×	0.006	TCF3
regulation of DNA-templated transcription	2	31.6×	0.006	TCF3, TCF7L1
regulation of Wnt signaling pathway	1	443.5×	0.010	TCF7L1
obsolete positive regulation of DNA-binding transcription factor activity	1	300.9×	0.011	TCF3
positive regulation of cell cycle	1	221.7×	0.013	TCF3
positive regulation of B cell proliferation	1	172.0×	0.014	TCF3
regulation of G1/S transition of mitotic cell cycle	1	153.2×	0.014	TCF3
regulation of transcription by RNA polymerase II	2	11.7×	0.014	TCF3, TCF7L1
B cell differentiation	1	109.4×	0.016	TCF3
positive regulation of neuron differentiation	1	99.1×	0.016	TCF3
canonical Wnt signaling pathway	1	76.6×	0.018	TCF7L1
chromatin organization	1	49.6×	0.026	TCF7L1
nervous system development	1	23.0×	0.052	TCF3
positive regulation of DNA-templated transcription	1	14.0×	0.080	TCF3
negative regulation of transcription by RNA polymerase II	1	8.9×	0.117	TCF3
positive regulation of transcription by RNA polymerase II	1	7.4×	0.130	TCF3

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 2 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
TCF3	0	0
TCF7L1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	TCF3, TCF7L1

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)
TCF3	0	—
TCF7L1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.