GATA2 deficiency with susceptibility to MDS/AML

Summary

GATA2 deficiency with susceptibility to MDS/AML (MONDO:0042982) is a disease caused by GATA2 (GenCC Strong), with 5 cohort genes and 2 clinical trials.

At a glance

• Causal gene: GATA2 (GenCC Strong)
• Cohort genes: 5
• ClinVar variants: 189
• Clinical trials: 2

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	GATA2 deficiency with susceptibility to MDS/AML
Mondo ID	MONDO:0042982
NCIT	C126349
GARD	0027059
Is cancer (heuristic)	no

Also known as: GATA2 deficiency · GATA2 deficiency with susceptibility to MDS/AML · GATA2 deficiency/MonoMac syndrome

Data availability: 189 ClinVar variants · 1 GenCC gene-disease record.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › immunodeficiency disease › GATA2 deficiency with susceptibility to MDS/AML

Related subtypes (94): B cell deficiency, T-cell immunodeficiency, complement deficiency, myalgic encephalomeyelitis/chronic fatigue syndrome, hypoproteinemia, hypercatabolic, X-linked lymphoproliferative syndrome, Wiskott-Aldrich syndrome, autosomal dominant form, immunodeficiency due to CD25 deficiency, immunodeficiency 67, primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency, immunodeficiency 35, pyogenic bacterial infections due to MyD88 deficiency, lymphoproliferative syndrome 1, FADD-related immunodeficiency, immunodeficiency 31B, Wiskott-Aldrich syndrome 2, cryptosporidiosis-chronic cholangitis-liver disease syndrome, idiopathic CD4 lymphocytopenia, immunodeficiency 23, DOCK2 deficiency, immunodeficiency 45, TFRC-related combined immunodeficiency, combined immunodeficiency, autoimmune hemolytic anemia-autoimmune thrombocytopenia-primary immunodeficiency syndrome, immunodeficiency due to selective anti-polysaccharide antibody deficiency, immunodeficiency 57, immunodeficiency 14b, autosomal recessive, immunodeficiency 98 with autoinflammation, X-linked, immunodeficiency 102, immunodeficiency 74, COVID-19-related, X-linked, immunodeficiency 66, immunodeficiency 80 with or without congenital cardiomyopathy, immunodeficiency 81, immunodeficiency 82 with systemic inflammation, immunodeficiency 84, immunodeficiency 85 and autoimmunity, immunodeficiency 86, immunodeficiency 87 and autoimmunity, immunodeficiency 88, immunodeficiency 89 and autoimmunity, immunodeficiency 91 and hyperinflammation, immunodeficiency 92, immunodeficiency 93 and hypertrophic cardiomyopathy, immunodeficiency 95, immunodeficiency 96, immunodeficiency 97 with autoinflammation, immunodeficiency 99 with hypogammaglobulinemia and autoimmune cytopenias, immunodeficiency 101 (varicella zoster virus-specific), immunodeficiency 75, immunodeficiency 76, immunodeficiency 106, susceptibility to viral infections, immunodeficiency 78 with autoimmunity and developmental delay, immunodeficiency 77, immunodeficiency 107, susceptibility to invasive staphylococcus aureus infection, immunodeficiency 15a, immunodeficiency 60, immunodeficiency 62, immunodeficiency 63 with lymphoproliferation and autoimmunity, immunodeficiency 64, immunodeficiency 65, susceptibility to viral infections, immunodeficiency 69, immunodeficiency 70, immunodeficiency 72 with autoinflammation, Shwachman-Diamond syndrome 1, immunodeficiency 53, immunodeficiency 11b with atopic dermatitis, IKBKG-related immunodeficiency with or without ectodermal dysplasia, FNIP1-associated syndrome, FASLG-related immunodeficiency, TNFRSF9-related immunodeficiency, DNAJC21-related Shwachman Diamond syndrome, IRF4-related immune disorder, PTEN harmartoma tumor syndrome with immune disorder, primary immunodeficiency due to calcium channel deficiency, chronic mucocutaneous candidiasis and connective tissue disease due to JNK1 haploinsufficiency, immune deficiency due to impaired neutrophil phagocytosis and migration, hatipoglu immunodeficiency syndrome, immunodeficiency 112, immunodeficiency 113 with autoimmunity and autoinflammation, immunodeficiency 114, folate-responsive, immunodeficiency 115 with autoinflammation, immunodeficiency 117, immunodeficiency 118, immunodeficiency 119, immunodeficiency 121 with autoinflammation, immunodeficiency 122, immunodeficiency 123 with HPV-related verrucosis, immunodeficiency 125, immunodeficiency 126, susceptibility to, immunodeficiency 127, immunodeficiency 128, immunodeficiency 132b, immunodeficiency 133 with ectodermal dysplasia with or without peripheral neuropathy, immunodeficiency 134 (Epstein-Barr virus-specific)

Subtypes (2): deafness-lymphedema-leukemia syndrome, monocytopenia with susceptibility to infections

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

189 retrieved; paginated sample, class counts are floors:

111 pathogenic, 27 likely pathogenic, 21 conflicting classifications of pathogenicity, 16 pathogenic/likely pathogenic, 14 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
1183990	Single allele	ATP2C1	Pathogenic	criteria provided, single submitter
1183991	Single allele	COPG1	Pathogenic	criteria provided, single submitter
1183989	Single allele	CSTA	Pathogenic	criteria provided, single submitter
1183986	Single allele	DNAJB8	Pathogenic	criteria provided, single submitter
1183987	Single allele	DNAJB8	Pathogenic	criteria provided, single submitter
1183992	Single allele	DNAJB8	Pathogenic	criteria provided, single submitter
1013219	NM_032638.5(GATA2):c.177C>G (p.Tyr59Ter)	GATA2	Pathogenic	criteria provided, multiple submitters, no conflicts
1183993	Single allele	GATA2	Pathogenic	criteria provided, single submitter
1184007	NM_032638.5(GATA2):c.83del (p.Gly28fs)	GATA2	Pathogenic	criteria provided, single submitter
1184008	NM_032638.5(GATA2):c.1073C>A (p.Thr358Asn)	GATA2	Pathogenic	criteria provided, single submitter
1184012	NM_032638.5(GATA2):c.1172_1175del (p.Glu391fs)	GATA2	Pathogenic	criteria provided, single submitter
1184014	NM_032638.5(GATA2):c.1200_1216dup (p.Lys406fs)	GATA2	Pathogenic	criteria provided, single submitter
1184015	NM_032638.5(GATA2):c.1281dup (p.Phe428fs)	GATA2	Pathogenic	criteria provided, single submitter
1184018	NC_000003.11:g.(?128199862)(128205874_?)del	GATA2	Pathogenic	criteria provided, single submitter
1184019	NC_000003.11:g.(?128199862)(128200787_?)del	GATA2	Pathogenic	criteria provided, single submitter
1184142	NM_032638.5(GATA2):c.17_18del (p.Glu6fs)	GATA2	Pathogenic	criteria provided, single submitter
1184143	NM_032638.5(GATA2):c.58C>T (p.Gln20Ter)	GATA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1184144	NM_032638.5(GATA2):c.941_951del (p.Tyr314fs)	GATA2	Pathogenic	criteria provided, single submitter
1184146	NM_032638.5(GATA2):c.941_951dup (p.Ala318fs)	GATA2	Pathogenic	criteria provided, single submitter
1184147	NM_032638.5(GATA2):c.952G>A (p.Ala318Thr)	GATA2	Pathogenic	criteria provided, single submitter
1184148	NM_032638.5(GATA2):c.956_962del (p.Cys319fs)	GATA2	Pathogenic	criteria provided, single submitter
1184149	NM_032638.5(GATA2):c.968dup (p.His323fs)	GATA2	Pathogenic	criteria provided, single submitter
1184150	NM_032638.5(GATA2):c.982C>T (p.Gln328Ter)	GATA2	Pathogenic	criteria provided, single submitter
1184151	NM_032638.5(GATA2):c.989_992dup (p.Leu332fs)	GATA2	Pathogenic	criteria provided, single submitter
1184152	NM_032638.5(GATA2):c.970_994dup (p.Leu332fs)	GATA2	Pathogenic	criteria provided, single submitter
1184153	NM_032638.5(GATA2):c.1017+1del	GATA2	Pathogenic	criteria provided, single submitter
1184154	NM_032638.5(GATA2):c.1017+2T>G	GATA2	Pathogenic	criteria provided, single submitter
1184155	NM_032638.5(GATA2):c.1017+2T>C	GATA2	Pathogenic	criteria provided, single submitter
1184158	NM_032638.5(GATA2):c.1099del (p.Asp367fs)	GATA2	Pathogenic	criteria provided, single submitter
1184159	NM_032638.5(GATA2):c.1099dup (p.Asp367fs)	GATA2	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 5 · 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
GATA2	Strong	Autosomal dominant	GATA2 deficiency with susceptibility to MDS/AML	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GATA2	Orphanet:228423	GATA2 deficiency spectrum
ATP2C1	Orphanet:2841	Hailey-Hailey disease
COPG1	Orphanet:718017	Combined immunodeficiency due to COPG1 deficiency
CSTA	Orphanet:263534	Acral peeling skin syndrome
CSTA	Orphanet:289586	Exfoliative ichthyosis

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GATA2	HGNC:4171	ENSG00000179348	P23769	Endothelial transcription factor GATA-2	gencc,clinvar
ATP2C1	HGNC:13211	ENSG00000017260	P98194	Calcium-transporting ATPase type 2C member 1	clinvar
COPG1	HGNC:2236	ENSG00000181789	Q9Y678	Coatomer subunit gamma-1	clinvar
DNAJB8	HGNC:23699	ENSG00000179407	Q8NHS0	DnaJ homolog subfamily B member 8	clinvar
CSTA	HGNC:2481	ENSG00000121552	P01040	Cystatin-A	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GATA2	Endothelial transcription factor GATA-2	Transcriptional activator which regulates endothelin-1 gene expression in endothelial cells.
ATP2C1	Calcium-transporting ATPase type 2C member 1	ATP-driven pump that supplies the Golgi apparatus with Ca(2+) and Mn(2+) ions, both essential cofactors for processing and trafficking of newly synthesized proteins in the secretory pathway.
COPG1	Coatomer subunit gamma-1	The coatomer is a cytosolic protein complex that binds to dilysine motifs and reversibly associates with Golgi non-clathrin-coated vesicles, which further mediate biosynthetic protein transport from the ER, via the Golgi up to the trans Go…
DNAJB8	DnaJ homolog subfamily B member 8	Efficient suppressor of aggregation and toxicity of disease-associated polyglutamine proteins.
CSTA	Cystatin-A	This is an intracellular thiol proteinase inhibitor.

Protein-family classification

Druggable: 1 · Difficult: 2 · Unknown: 2 · Druggable fraction: 0.2

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
Antibody/Immunoglobulin	1	5.8×	0.240
Transcription factor	2	3.3×	0.240
Other/Unknown	2	0.7×	0.877

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GATA2	Transcription factor	no		Znf_GATA, Znf_NHR/GATA, TF_GATA-2/3
ATP2C1	Transcription factor	no	7.2.2.10	P_typ_ATPase, ATPase_P-typ_cation-transptr_N, ATPase_P-typ_cation-transptr_C
COPG1	Antibody/Immunoglobulin	yes		Clathrin/coatomer_adapt-like_N, Coatomer/calthrin_app_sub_C, ARM-like
DNAJB8	Other/Unknown	no		DnaJ_domain, DnaJ_domain_CS, J_dom_sf
CSTA	Other/Unknown	no		Cystatin_dom, Prot_inh_stefin, Prot_inh_cystat_CS

Expression context

Cohort genes with no expression data: 0.

5 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)	1
broad (>20)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left uterine tube	1
right lung	1
seminal vesicle	1
cortical plate	1
secondary oocyte	1
ventricular zone	1
adenohypophysis	1
body of pancreas	1
stromal cell of endometrium	1
left testis	1
right testis	1
sperm	1
gingiva	1
oral cavity	1
pharyngeal mucosa	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GATA2	273	ubiquitous	marker	seminal vesicle, right lung, left uterine tube
ATP2C1	289	ubiquitous	marker	cortical plate, secondary oocyte, ventricular zone
COPG1	283	ubiquitous	marker	stromal cell of endometrium, adenohypophysis, body of pancreas
DNAJB8	19	tissue_specific	marker	sperm, left testis, right testis
CSTA	248	ubiquitous	marker	pharyngeal mucosa, oral cavity, gingiva

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GATA2	4,979
ATP2C1	2,410
COPG1	2,216
DNAJB8	2,176
CSTA	2,102

Structural data

PDB: 5 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CSTA	P01040	14
ATP2C1	P98194	11
GATA2	P23769	2
DNAJB8	Q8NHS0	2
COPG1	Q9Y678	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. Enrichment computed across 5 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Ion transport by P-type ATPases	1	51.9×	0.058	ATP2C1
Transcriptional regulation of granulopoiesis	1	31.4×	0.058	GATA2
COPI-dependent Golgi-to-ER retrograde traffic	1	27.7×	0.058	COPG1
COPI-mediated anterograde transport	1	27.4×	0.058	COPG1
Ion channel transport	1	24.0×	0.058	ATP2C1
RUNX1 regulates transcription of genes involved in differentiation of HSCs	1	23.8×	0.058	GATA2
Formation of the cornified envelope	1	22.0×	0.058	CSTA
Factors involved in megakaryocyte development and platelet production	1	16.6×	0.066	GATA2
Transport of small molecules	1	6.3×	0.150	ATP2C1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
semicircular canal development	1	3370.4×	0.007	GATA2
regulation of forebrain neuron differentiation	1	3370.4×	0.007	GATA2
regulation of primitive erythrocyte differentiation	1	1685.2×	0.007	GATA2
Golgi calcium ion homeostasis	1	1685.2×	0.007	ATP2C1
Golgi calcium ion transport	1	1685.2×	0.007	ATP2C1
eosinophil fate commitment	1	1685.2×	0.007	GATA2
trans-Golgi network membrane organization	1	1685.2×	0.007	ATP2C1
ventral spinal cord interneuron differentiation	1	1123.5×	0.008	GATA2
cell differentiation in hindbrain	1	1123.5×	0.008	GATA2
negative regulation of hematopoietic progenitor cell differentiation	1	842.6×	0.009	GATA2
intracellular manganese ion homeostasis	1	674.1×	0.009	ATP2C1
GABAergic neuron differentiation	1	674.1×	0.009	GATA2
commitment of neuronal cell to specific neuron type in forebrain	1	561.7×	0.009	GATA2
positive regulation of Golgi to plasma membrane protein transport	1	561.7×	0.009	ATP2C1
thyroid-stimulating hormone-secreting cell differentiation	1	561.7×	0.009	GATA2
negative regulation of brown fat cell differentiation	1	561.7×	0.009	GATA2
glandular epithelial cell maturation	1	481.5×	0.009	GATA2
response to lipid	1	481.5×	0.009	GATA2
manganese ion transport	1	421.3×	0.009	ATP2C1
negative regulation of macrophage differentiation	1	421.3×	0.009	GATA2
establishment of Golgi localization	1	374.5×	0.010	COPG1
vascular wound healing	1	374.5×	0.010	GATA2
negative regulation of inclusion body assembly	1	337.0×	0.010	DNAJB8
positive regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis	1	337.0×	0.010	GATA2
positive regulation of mast cell degranulation	1	306.4×	0.010	GATA2
negative regulation of neural precursor cell proliferation	1	306.4×	0.010	GATA2
peptide cross-linking	1	280.9×	0.010	CSTA
positive regulation of megakaryocyte differentiation	1	280.9×	0.010	GATA2
positive regulation of phagocytosis, engulfment	1	259.3×	0.010	GATA2
negative regulation of neuroblast proliferation	1	240.7×	0.011	GATA2

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 5 evidence-associated genes (60%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
COPG1	1	2
GATA2	0	0
ATP2C1	0	0
DNAJB8	0	0
CSTA	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	COPG1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
COPG1	7	Binding:7
GATA2	1	Binding:1
ATP2C1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ATP2C1	7.2.2.10	P-type Ca2+ transporter

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

1 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.

Compound	Max phase	Cohort target (bioactivity)
MOLIBRESIB	2	COPG1

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	1	COPG1
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	4	GATA2, ATP2C1, DNAJB8, CSTA

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
GATA2	1	—
ATP2C1	1	—
DNAJB8	0	—
CSTA	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	1
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04844177	PHASE2	UNKNOWN	Total Lymphoid Irradiation Pre-HSCT in Severe Congenital Neutropenia
NCT01905826	Not specified	RECRUITING	Natural History Study of GATA2 Deficiency and Related Disorders