Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency

Summary

Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency (MONDO:0013956) is a disease caused by STAT1 (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: STAT1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 658

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		17	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency
Mondo ID	MONDO:0013956
OMIM	614892
Orphanet	319595
DOID	DOID:0111945
UMLS	C4013950
MedGen	862387
GARD	0017462
Is cancer (heuristic)	no

Also known as: autosomal dominant mendelian susceptibility to mycobacterial diseases due to a partial deficiency caused by mutation in STAT1 · IMD31A · immunodeficiency 31A · immunodeficiency type 31A · Mendelian susceptibility to mycobacterial diseases due to partial signal transducer and activator of transcription 1 deficiency · MSMD due to partial signal transducer and activator of transcription 1 deficiency · MSMD due to partial STAT1 deficiency · STAT1 autosomal dominant mendelian susceptibility to mycobacterial diseases due to a partial deficiency

Data availability: 658 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease susceptibility › inherited disease susceptibility › inherited susceptibility to mycobacterial diseases › Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency

Related subtypes (13): immunodeficiency 27A, Mendelian susceptibility to mycobacterial diseases due to complete IL12B deficiency, Mendelian susceptibility to mycobacterial diseases due to complete IL12RB1 deficiency, Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency, autosomal dominant mendelian susceptibility to mycobacterial diseases due to partial IFNgammaR1 deficiency, Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency, autosomal recessive mendelian susceptibility to mycobacterial diseases due to complete RORgamma receptor deficiency, autosomal recessive Mendelian susceptibility to mycobacterial diseases due to complete IFNgammaR2 deficiency, autosomal dominant mendelian susceptibility to mycobacterial diseases due to partial IFNgammaR2 deficiency, X-linked Mendelian susceptibility to mycobacterial diseases, Mendelian susceptibility to mycobacterial diseases due to complete IFNgammaR1 deficiency, Mendelian susceptibility to mycobacterial diseases due to a complete deficiency, Mendelian susceptibility to mycobacterial diseases due to a partial 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

600 retrieved; paginated sample, class counts are floors:

296 likely benign, 201 uncertain significance, 34 pathogenic, 27 benign, 14 conflicting classifications of pathogenicity, 14 benign/likely benign, 13 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1074337	NM_007315.4(STAT1):c.1398C>A (p.Ser466Arg)	STAT1	Pathogenic	criteria provided, single submitter
1354984	NM_007315.4(STAT1):c.1999_2000del (p.Leu667fs)	STAT1	Pathogenic	criteria provided, single submitter
1403340	NM_007315.4(STAT1):c.1231_1232del (p.Glu411fs)	STAT1	Pathogenic	criteria provided, single submitter
1420518	NM_007315.4(STAT1):c.802G>T (p.Glu268Ter)	STAT1	Pathogenic	criteria provided, single submitter
144006	NM_007315.4(STAT1):c.1154C>T (p.Thr385Met)	STAT1	Pathogenic	criteria provided, multiple submitters, no conflicts
1457465	NM_007315.4(STAT1):c.71_74dup (p.Ser25fs)	STAT1	Pathogenic	criteria provided, single submitter
1524110	NM_007315.4(STAT1):c.2102A>G (p.Tyr701Cys)	STAT1	Pathogenic	criteria provided, single submitter
155907	NM_007315.4(STAT1):c.2018A>G (p.Lys673Arg)	STAT1	Pathogenic	no assertion criteria provided
155908	NM_007315.4(STAT1):c.1909A>G (p.Lys637Glu)	STAT1	Pathogenic	no assertion criteria provided
160354	NM_007315.4(STAT1):c.820C>G (p.Arg274Gly)	STAT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1710090	NM_007315.4(STAT1):c.373-2A>C	STAT1	Pathogenic	criteria provided, single submitter
2097602	NM_007315.4(STAT1):c.200A>C (p.Gln67Pro)	STAT1	Pathogenic	criteria provided, single submitter
2203238	NM_007315.4(STAT1):c.1162A>G (p.Lys388Glu)	STAT1	Pathogenic	criteria provided, single submitter
2203239	NM_007315.4(STAT1):c.1159A>G (p.Thr387Ala)	STAT1	Pathogenic	criteria provided, single submitter
2424633	NC_000002.11:g.(?191835429)(192012929_?)del	STAT1	Pathogenic	criteria provided, single submitter
2500092	NM_007315.4(STAT1):c.25C>T (p.Gln9Ter)	STAT1	Pathogenic	criteria provided, single submitter
2925337	NM_007315.4(STAT1):c.961A>G (p.Arg321Gly)	STAT1	Pathogenic	criteria provided, single submitter
2936500	NM_007315.4(STAT1):c.1688A>T (p.Glu563Val)	STAT1	Pathogenic	criteria provided, single submitter
2942064	NM_007315.4(STAT1):c.861C>G (p.Tyr287Ter)	STAT1	Pathogenic	criteria provided, single submitter
2948670	NM_007315.4(STAT1):c.1127+1G>A	STAT1	Pathogenic	criteria provided, single submitter
2952404	NM_007315.4(STAT1):c.1286_1287del (p.Glu429fs)	STAT1	Pathogenic	criteria provided, single submitter
30083	NM_007315.4(STAT1):c.820C>T (p.Arg274Trp)	STAT1	Pathogenic	criteria provided, multiple submitters, no conflicts
30084	NM_007315.4(STAT1):c.800C>T (p.Ala267Val)	STAT1	Pathogenic	criteria provided, multiple submitters, no conflicts
30085	NM_007315.4(STAT1):c.821G>A (p.Arg274Gln)	STAT1	Pathogenic	criteria provided, multiple submitters, no conflicts
30087	NM_007315.4(STAT1):c.604A>G (p.Met202Val)	STAT1	Pathogenic	criteria provided, single submitter
30090	NM_007315.4(STAT1):c.862A>G (p.Thr288Ala)	STAT1	Pathogenic	criteria provided, single submitter
3750632	NM_007315.4(STAT1):c.679dup (p.Thr227fs)	STAT1	Pathogenic	criteria provided, single submitter
3757694	NM_007315.4(STAT1):c.770del (p.Asp257fs)	STAT1	Pathogenic	criteria provided, single submitter
4783914	NM_007315.4(STAT1):c.1833del (p.Ile612fs)	STAT1	Pathogenic	criteria provided, single submitter
4785010	NM_007315.4(STAT1):c.1239_1240insT (p.Asn414Ter)	STAT1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 14 · 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
STAT1	Strong	Autosomal dominant	Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency	14

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
STAT1	Orphanet:319595	Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency
STAT1	Orphanet:391311	Susceptibility to viral and mycobacterial infections due to STAT1 deficiency
STAT1	Orphanet:391487	STAT1-related autoimmune enteropathy and endocrinopathy-susceptibility to chronic infections 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
STAT1	HGNC:11362	ENSG00000115415	P42224	Signal transducer and activator of transcription 1-alpha/beta	gencc,clinvar
ANKAR	HGNC:26350	ENSG00000151687	Q7Z5J8	Ankyrin and armadillo repeat-containing protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
STAT1	Signal transducer and activator of transcription 1-alpha/beta	Signal transducer and transcription activator that mediates cellular responses to interferons (IFNs), cytokine KITLG/SCF and other cytokines and other growth factors.

Protein-family classification

Druggable: 0 · Difficult: 2 · Unknown: 0 · 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
Transcription factor	1	4.1×	0.228

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
STAT1	Transcription factor	no		SH2, STAT, p53-like_TF_DNA-bd_sf
ANKAR	Scaffold/PPI	no		Armadillo, Ankyrin_rpt, ARM-like

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
epithelium of nasopharynx	1
mononuclear cell	1
vermiform appendix	1
calcaneal tendon	1
left ovary	1
male germ line stem cell (sensu Vertebrata) in testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
STAT1	294	ubiquitous	marker	epithelium of nasopharynx, vermiform appendix, mononuclear cell
ANKAR	163	ubiquitous	yes	calcaneal tendon, male germ line stem cell (sensu Vertebrata) in testis, left ovary

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
STAT1	6,459
ANKAR	573

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
STAT1	P42224	10

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ANKAR	Q7Z5J8	84.79

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 64. Enrichment computed across 2 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
Signaling by PDGFR in disease	1	1631.4×	0.006	STAT1
Interleukin-6 family signaling	1	1427.5×	0.006	STAT1
Interleukin-9 signaling	1	1268.9×	0.006	STAT1
FGFR1 mutant receptor activation	1	1142.0×	0.006	STAT1
Interleukin-21 signaling	1	1142.0×	0.006	STAT1
Signaling by KIT in disease	1	1142.0×	0.006	STAT1
Interleukin-27 signaling	1	1038.2×	0.006	STAT1
Interleukin-6 signaling	1	951.7×	0.006	STAT1
Interleukin-35 Signalling	1	951.7×	0.006	STAT1
Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants	1	878.5×	0.006	STAT1
Signaling by PDGFRA extracellular domain mutants	1	878.5×	0.006	STAT1
Differentiation of naive CD4+ T cells to T helper 1 cells (Th1 cells)	1	878.5×	0.006	STAT1
Regulation of IFNG signaling	1	815.7×	0.006	STAT1
Signaling by cytosolic FGFR1 fusion mutants	1	634.4×	0.006	STAT1
Interleukin-2 family signaling	1	634.4×	0.006	STAT1
Signaling by CSF3 (G-CSF)	1	571.0×	0.006	STAT1
Signaling by NOTCH3	1	519.1×	0.006	STAT1
Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants	1	519.1×	0.006	STAT1
Interleukin-12 family signaling	1	475.8×	0.006	STAT1
Growth hormone receptor signaling	1	475.8×	0.006	STAT1
NOTCH3 Intracellular Domain Regulates Transcription	1	439.2×	0.006	STAT1
Regulation of IFNA/IFNB signaling	1	439.2×	0.006	STAT1
Inactivation of CSF3 (G-CSF) signaling	1	439.2×	0.006	STAT1
Signaling by FGFR in disease	1	423.0×	0.006	STAT1
Interleukin-20 family signaling	1	423.0×	0.006	STAT1
Downstream signal transduction	1	380.7×	0.006	STAT1
Downregulation of SMAD2/3:SMAD4 transcriptional activity	1	368.4×	0.006	STAT1
Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells	1	356.9×	0.006	STAT1
Signaling by CSF1 (M-CSF) in myeloid cells	1	346.1×	0.006	STAT1
Response of endothelial cells to shear stress	1	300.5×	0.007	STAT1

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
negative regulation of metanephric nephron tubule epithelial cell differentiation	1	16852.0×	0.002	STAT1
negative regulation of mesenchymal to epithelial transition involved in metanephros morphogenesis	1	8426.0×	0.002	STAT1
negative regulation by virus of viral protein levels in host cell	1	8426.0×	0.002	STAT1
metanephric mesenchymal cell proliferation involved in metanephros development	1	5617.3×	0.002	STAT1
renal tubule development	1	4213.0×	0.002	STAT1
metanephric mesenchymal cell differentiation	1	3370.4×	0.002	STAT1
interleukin-27-mediated signaling pathway	1	2407.4×	0.002	STAT1
interleukin-7-mediated signaling pathway	1	2106.5×	0.002	STAT1
interleukin-9-mediated signaling pathway	1	2106.5×	0.002	STAT1
response to interferon-beta	1	1532.0×	0.003	STAT1
type II interferon-mediated signaling pathway	1	1203.7×	0.003	STAT1
positive regulation of interferon-alpha production	1	648.1×	0.004	STAT1
positive regulation of mesenchymal cell proliferation	1	601.9×	0.004	STAT1
cell surface receptor signaling pathway via STAT	1	561.7×	0.004	STAT1
negative regulation of endothelial cell proliferation	1	543.6×	0.004	STAT1
positive regulation of defense response to virus by host	1	526.6×	0.004	STAT1
response to type II interferon	1	526.6×	0.004	STAT1
cellular response to interferon-beta	1	526.6×	0.004	STAT1
blood circulation	1	510.7×	0.004	STAT1
positive regulation of erythrocyte differentiation	1	510.7×	0.004	STAT1
response to cAMP	1	510.7×	0.004	STAT1
response to hydrogen peroxide	1	468.1×	0.004	STAT1
positive regulation of nitric oxide biosynthetic process	1	455.5×	0.004	STAT1
response to peptide hormone	1	391.9×	0.005	STAT1
type I interferon-mediated signaling pathway	1	343.9×	0.005	STAT1
tumor necrosis factor-mediated signaling pathway	1	330.4×	0.005	STAT1
positive regulation of smooth muscle cell proliferation	1	330.4×	0.005	STAT1
response to mechanical stimulus	1	300.9×	0.005	STAT1
response to nutrient	1	295.6×	0.005	STAT1
cell surface receptor signaling pathway via JAK-STAT	1	290.6×	0.005	STAT1

Therapeutics

Drug target analysis

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

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

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
STAT1	FILGOTINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
STAT1	5	4
ANKAR	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FILGOTINIB	4	STAT1
DEUCRAVACITINIB	4	STAT1
EPIGALOCATECHIN GALLATE	3	STAT1
SURAMIN HEXASODIUM	3	STAT1
IPRIFLAVONE	2	STAT1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
STAT1	147	Binding:137, Functional:8, Unclassified:2

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
STAT1	147

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

5 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)
FILGOTINIB	4	STAT1
DEUCRAVACITINIB	4	STAT1
EPIGALOCATECHIN GALLATE	3	STAT1
SURAMIN HEXASODIUM	3	STAT1
IPRIFLAVONE	2	STAT1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	STAT1
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	ANKAR

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)
ANKAR	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.