Ectodermal dysplasia and immunodeficiency 2

Summary

Ectodermal dysplasia and immunodeficiency 2 (MONDO:0012806) is a disease caused by NFKBIA (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: NFKBIA (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 351

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	ectodermal dysplasia and immunodeficiency 2
Mondo ID	MONDO:0012806
MeSH	C567411
OMIM	612132
DOID	DOID:0081079
NCIT	C176826
UMLS	C2677481
MedGen	394295
GARD	0015542
Is cancer (heuristic)	no

Also known as: ectodermal dysplasia, anhidrotic, with T-cell immunodeficiency, autosomal dominant · EPAID2

Data availability: 351 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › immune system disorder › inborn error of immunity › ectodermal dysplasia and immune deficiency › ectodermal dysplasia and immunodeficiency 2

Related subtypes (1): ectodermal dysplasia and immunodeficiency 1

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

351 retrieved; paginated sample, class counts are floors:

142 uncertain significance, 141 likely benign, 35 benign, 17 conflicting classifications of pathogenicity, 9 pathogenic, 6 benign/likely benign, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2577914	NM_020529.3(NFKBIA):c.28G>T (p.Glu10Ter)	LOC130055497	Pathogenic	criteria provided, single submitter
14003	NM_020529.3(NFKBIA):c.95G>T (p.Ser32Ile)	NFKBIA	Pathogenic	no assertion criteria provided
14005	NM_020529.3(NFKBIA):c.40G>T (p.Glu14Ter)	NFKBIA	Pathogenic	no assertion criteria provided
2581077	NM_020529.3(NFKBIA):c.101T>C (p.Leu34Pro)	NFKBIA	Pathogenic	no assertion criteria provided
280143	NM_020529.3(NFKBIA):c.25C>T (p.Gln9Ter)	NFKBIA	Pathogenic	criteria provided, multiple submitters, no conflicts
590308	NM_020529.3(NFKBIA):c.107C>A (p.Ser36Tyr)	NFKBIA	Pathogenic	no assertion criteria provided
590309	NM_020529.3(NFKBIA):c.94A>G (p.Ser32Gly)	NFKBIA	Pathogenic	no assertion criteria provided
590310	NM_020529.3(NFKBIA):c.96C>G (p.Ser32Arg)	NFKBIA	Pathogenic	no assertion criteria provided
590311	NM_020529.3(NFKBIA):c.95G>A (p.Ser32Asn)	NFKBIA	Pathogenic	criteria provided, multiple submitters, no conflicts
3764637	NM_020529.3(NFKBIA):c.106T>G (p.Ser36Ala)	NFKBIA	Likely pathogenic	criteria provided, single submitter
1033535	NM_020529.3(NFKBIA):c.337-20G>A	LOC130055494	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1559668	NM_020529.3(NFKBIA):c.403T>G (p.Cys135Gly)	LOC130055494	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
648247	NM_020529.3(NFKBIA):c.368A>G (p.Gln123Arg)	LOC130055494	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
452693	NM_020529.3(NFKBIA):c.33G>A (p.Trp11Ter)	LOC130055497	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
14004	NM_020529.3(NFKBIA):c.32G>A (p.Trp11Ter)	NFKBIA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1599595	NM_020529.3(NFKBIA):c.866A>G (p.Tyr289Cys)	NFKBIA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1646820	NM_020529.3(NFKBIA):c.885_896del (p.Phe295_Thr299delinsLeu)	NFKBIA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1906172	NM_020529.3(NFKBIA):c.532G>A (p.Ala178Thr)	NFKBIA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2083832	NM_020529.3(NFKBIA):c.506C>T (p.Thr169Ile)	NFKBIA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2143995	NM_020529.3(NFKBIA):c.509C>T (p.Pro170Leu)	NFKBIA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
313113	NM_020529.3(NFKBIA):c.547+10C>T	NFKBIA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
570970	NM_020529.3(NFKBIA):c.409C>T (p.Pro137Ser)	NFKBIA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
576934	NM_020529.3(NFKBIA):c.337-3T>C	NFKBIA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
636651	NM_020529.3(NFKBIA):c.228-15C>T	NFKBIA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
841041	NM_020529.3(NFKBIA):c.179C>T (p.Pro60Leu)	NFKBIA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
853953	NM_020529.3(NFKBIA):c.299A>G (p.Asp100Gly)	NFKBIA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
945894	NM_020529.3(NFKBIA):c.940C>T (p.Arg314Cys)	NFKBIA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1404682	NM_020529.3(NFKBIA):c.340C>G (p.Pro114Ala)	LOC130055494	Uncertain significance	criteria provided, single submitter
1946653	NM_020529.3(NFKBIA):c.416T>C (p.Leu139Pro)	LOC130055494	Uncertain significance	criteria provided, single submitter
2003281	NM_020529.3(NFKBIA):c.416T>G (p.Leu139Arg)	LOC130055494	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 6 · 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
NFKBIA	Definitive	Autosomal dominant	ectodermal dysplasia and immunodeficiency 2	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NFKBIA	Orphanet:150	Nasopharyngeal carcinoma
NFKBIA	Orphanet:251576	Gliosarcoma
NFKBIA	Orphanet:251579	Giant cell glioblastoma
NFKBIA	Orphanet:98813	Hypohidrotic ectodermal dysplasia with immunodeficiency
PPP2R3C	Orphanet:171709	Male infertility due to globozoospermia
PPP2R3C	Orphanet:1770	XY type gonadal dysgenesis-associated anomalies 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
NFKBIA	HGNC:7797	ENSG00000100906	P25963	NF-kappa-B inhibitor alpha	gencc,clinvar
PPP2R3C	HGNC:17485	ENSG00000092020	Q969Q6	Serine/threonine-protein phosphatase 2A regulatory subunit B’’ subunit gamma	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NFKBIA	NF-kappa-B inhibitor alpha	Inhibits the activity of dimeric NF-kappa-B/REL complexes by trapping REL (RELA/p65 and NFKB1/p50) dimers in the cytoplasm by masking their nuclear localization signals.
PPP2R3C	Serine/threonine-protein phosphatase 2A regulatory subunit B’’ subunit gamma	May regulate MCM3AP phosphorylation through phosphatase recruitment.

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
Scaffold/PPI	1	8.6×	0.225
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NFKBIA	Scaffold/PPI	no		Ankyrin_rpt, Ankyrin_rpt-contain_sf, NF-kappa-B_inhibitor
PPP2R3C	Other/Unknown	no		EF-hand-dom_pair, EF_Hand_1_Ca_BS, PPP2R3C

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
lower lobe of lung	1
pericardium	1
vena cava	1
left testis	1
right testis	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NFKBIA	302	ubiquitous	marker	vena cava, pericardium, lower lobe of lung
PPP2R3C	288	ubiquitous	marker	right testis, left testis, ventricular zone

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NFKBIA	6,991
PPP2R3C	945

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NFKBIA	P25963	5

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PPP2R3C	Q969Q6	90.08

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 15. 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
IkBA variant leads to EDA-ID	1	1631.4×	0.004	NFKBIA
SUMOylation of immune response proteins	1	951.7×	0.004	NFKBIA
NF-kB is activated and signals survival	1	878.5×	0.004	NFKBIA
Dengue virus modulates apoptosis	1	713.8×	0.004	NFKBIA
RIP-mediated NFkB activation via ZBP1	1	671.8×	0.004	NFKBIA
TRAF6 mediated NF-kB activation	1	456.8×	0.005	NFKBIA
Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells	1	356.9×	0.006	NFKBIA
TAK1-dependent IKK and NF-kappa-B activation	1	300.5×	0.006	NFKBIA
SARS-CoV-1 activates/modulates innate immune responses	1	271.9×	0.006	NFKBIA
Activation of NF-kappaB in B cells	1	196.9×	0.008	NFKBIA
FCERI mediated NF-kB activation	1	156.4×	0.009	NFKBIA
CLEC7A (Dectin-1) signaling	1	142.8×	0.009	NFKBIA
Downstream TCR signaling	1	128.3×	0.009	NFKBIA
Interleukin-1 signaling	1	124.1×	0.009	NFKBIA
Ub-specific processing proteases	1	53.1×	0.019	NFKBIA

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
regulation of antimicrobial humoral response	1	4213.0×	0.005	PPP2R3C
negative regulation of cholesterol transport	1	2106.5×	0.005	NFKBIA
nucleotide-binding oligomerization domain containing 1 signaling pathway	1	1685.2×	0.005	NFKBIA
regulation of dephosphorylation	1	1404.3×	0.005	PPP2R3C
regulation of mitochondrial depolarization	1	1404.3×	0.005	PPP2R3C
cortical cytoskeleton organization	1	842.6×	0.006	PPP2R3C
negative regulation of lipid storage	1	766.0×	0.006	NFKBIA
nucleotide-binding oligomerization domain containing 2 signaling pathway	1	766.0×	0.006	NFKBIA
response to muramyl dipeptide	1	702.2×	0.006	NFKBIA
negative regulation of macrophage derived foam cell differentiation	1	648.1×	0.006	NFKBIA
positive regulation of B cell differentiation	1	561.7×	0.006	PPP2R3C
cellular response to cold	1	526.6×	0.006	NFKBIA
negative regulation of protein import into nucleus	1	468.1×	0.006	NFKBIA
negative regulation of myeloid cell differentiation	1	468.1×	0.006	NFKBIA
non-canonical NF-kappaB signal transduction	1	421.3×	0.006	NFKBIA
interleukin-1-mediated signaling pathway	1	401.2×	0.006	NFKBIA
response to muscle stretch	1	383.0×	0.006	NFKBIA
B cell homeostasis	1	280.9×	0.007	PPP2R3C
lipopolysaccharide-mediated signaling pathway	1	263.3×	0.007	NFKBIA
toll-like receptor 4 signaling pathway	1	263.3×	0.007	NFKBIA
response to exogenous dsRNA	1	263.3×	0.007	NFKBIA
T cell homeostasis	1	227.7×	0.007	PPP2R3C
negative regulation of Notch signaling pathway	1	216.1×	0.007	NFKBIA
negative regulation of cytokine production involved in inflammatory response	1	210.7×	0.007	NFKBIA
spleen development	1	200.6×	0.007	PPP2R3C
B cell receptor signaling pathway	1	200.6×	0.007	NFKBIA
canonical NF-kappaB signal transduction	1	183.2×	0.008	NFKBIA
obsolete negative regulation of NF-kappaB transcription factor activity	1	179.3×	0.008	NFKBIA
tumor necrosis factor-mediated signaling pathway	1	165.2×	0.008	NFKBIA
positive regulation of transcription initiation by RNA polymerase II	1	135.9×	0.009	NFKBIA

Therapeutics

Drug target analysis

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

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

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NFKBIA	0	0
PPP2R3C	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
NFKBIA	48	Binding:48

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	NFKBIA, PPP2R3C

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)
NFKBIA	48	—
PPP2R3C	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.