Immunodeficiency 72 with autoinflammation

Summary

Immunodeficiency 72 with autoinflammation (MONDO:0033551) is a disease caused by NCKAP1L (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: NCKAP1L (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 19

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	immunodeficiency 72 with autoinflammation
Mondo ID	MONDO:0033551
OMIM	618982
DOID	DOID:0112015
UMLS	C5436540
MedGen	1749856
Is cancer (heuristic)	no

Also known as: IMD72

Data availability: 19 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › immunodeficiency disease › immunodeficiency 72 with autoinflammation

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, GATA2 deficiency with susceptibility to MDS/AML, 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)

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

19 retrieved; paginated sample, class counts are floors:

7 likely pathogenic, 6 uncertain significance, 3 pathogenic, 2 pathogenic/likely pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1185045	NM_005337.5(NCKAP1L):c.385C>T (p.Arg129Trp)	NCKAP1L	Pathogenic	no assertion criteria provided
2444019	NM_005337.5(NCKAP1L):c.421G>T (p.Val141Phe)	NCKAP1L	Pathogenic	no assertion criteria provided
2444020	NM_005337.5(NCKAP1L):c.2862+1G>A	NCKAP1L	Pathogenic	no assertion criteria provided
976846	NM_005337.5(NCKAP1L):c.1076C>T (p.Pro359Leu)	NCKAP1L	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
976848	NM_005337.5(NCKAP1L):c.1111A>G (p.Met371Val)	NCKAP1L	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3064095	NM_013436.5(NCKAP1):c.3280G>T (p.Glu1094Ter)	NCKAP1	Likely pathogenic	criteria provided, single submitter
2585458	NM_005337.5(NCKAP1L):c.2T>C (p.Met1Thr)	NCKAP1L	Likely pathogenic	criteria provided, single submitter
3383987	NM_005337.5(NCKAP1L):c.1111A>C (p.Met371Leu)	NCKAP1L	Likely pathogenic	criteria provided, single submitter
4279070	NM_005337.5(NCKAP1L):c.1492G>A (p.Val498Met)	NCKAP1L	Likely pathogenic	no assertion criteria provided
4279071	NM_005337.5(NCKAP1L):c.3346G>A (p.Ala1116Thr)	NCKAP1L	Likely pathogenic	no assertion criteria provided
976847	NM_005337.5(NCKAP1L):c.1555G>C (p.Val519Leu)	NCKAP1L	Likely pathogenic	criteria provided, single submitter
976849	NM_005337.5(NCKAP1L):c.773G>T (p.Arg258Leu)	NCKAP1L	Likely pathogenic	criteria provided, single submitter
2043680	NM_005337.5(NCKAP1L):c.736A>C (p.Met246Leu)	NCKAP1L	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2434077	NM_005337.5(NCKAP1L):c.2691G>C (p.Gln897His)	NCKAP1L	Uncertain significance	criteria provided, single submitter
2434078	NM_005337.5(NCKAP1L):c.2156+1G>C	NCKAP1L	Uncertain significance	criteria provided, single submitter
2434079	NM_005337.5(NCKAP1L):c.-797_-794del	NCKAP1L	Uncertain significance	criteria provided, single submitter
2559095	NM_005337.5(NCKAP1L):c.2243T>A (p.Ile748Asn)	NCKAP1L	Uncertain significance	criteria provided, multiple submitters, no conflicts
2968889	NM_005337.5(NCKAP1L):c.2718G>C (p.Lys906Asn)	NCKAP1L	Uncertain significance	criteria provided, multiple submitters, no conflicts
4293799	NM_005337.5(NCKAP1L):c.103-6C>G	NCKAP1L	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
NCKAP1L	Strong	Autosomal recessive	immunodeficiency 72 with autoinflammation	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NCKAP1L	Orphanet:619953	Familial hyperinflammatory lymphoproliferative immunodeficiency

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
NCKAP1L	HGNC:4862	ENSG00000123338	P55160	Nck-associated protein 1-like	gencc,clinvar
NCKAP1	HGNC:7666	ENSG00000061676	Q9Y2A7	Nck-associated protein 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NCKAP1L	Nck-associated protein 1-like	Essential hematopoietic-specific regulator of the actin cytoskeleton.
NCKAP1	Nck-associated protein 1	Part of the WAVE complex that regulates lamellipodia formation.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NCKAP1L	Other/Unknown	no		Nck-associated_protein-1
NCKAP1	Other/Unknown	no		Nck-associated_protein-1

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
leukocyte	1
monocyte	1
mononuclear cell	1
frontal pole	1
seminal vesicle	1
upper arm skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NCKAP1L	242	broad	marker	monocyte, leukocyte, mononuclear cell
NCKAP1	294	ubiquitous	marker	seminal vesicle, frontal pole, upper arm skin

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NCKAP1	2,097
NCKAP1L	1,420

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NCKAP1	Q9Y2A7	5

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
NCKAP1L	P55160	92.83

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 24. 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
Parasite infection	2	346.1×	8e-05	NCKAP1L, NCKAP1
Leishmania phagocytosis	2	346.1×	8e-05	NCKAP1L, NCKAP1
RHO GTPases Activate WASPs and WAVEs	2	317.2×	8e-05	NCKAP1L, NCKAP1
Fcgamma receptor (FCGR) dependent phagocytosis	2	278.5×	8e-05	NCKAP1L, NCKAP1
Signaling by VEGF	2	219.6×	1e-04	NCKAP1L, NCKAP1
FCGR3A-mediated phagocytosis	2	187.2×	1e-04	NCKAP1L, NCKAP1
Regulation of actin dynamics for phagocytic cup formation	2	184.2×	1e-04	NCKAP1L, NCKAP1
Leishmania infection	2	163.1×	1e-04	NCKAP1L, NCKAP1
Parasitic Infection Pathways	2	163.1×	1e-04	NCKAP1L, NCKAP1
VEGFA-VEGFR2 Pathway	2	139.3×	1e-04	NCKAP1L, NCKAP1
RAC2 GTPase cycle	2	126.9×	1e-04	NCKAP1L, NCKAP1
RAC3 GTPase cycle	2	119.0×	1e-04	NCKAP1L, NCKAP1
RHO GTPase Effectors	2	68.0×	4e-04	NCKAP1L, NCKAP1
RAC1 GTPase cycle	2	61.1×	4e-04	NCKAP1L, NCKAP1
RHO GTPase cycle	2	60.1×	4e-04	NCKAP1L, NCKAP1
Signaling by Receptor Tyrosine Kinases	2	51.7×	6e-04	NCKAP1L, NCKAP1
Signaling by Rho GTPases	2	34.2×	0.001	NCKAP1L, NCKAP1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	2	33.5×	0.001	NCKAP1L, NCKAP1
Innate Immune System	2	25.5×	0.002	NCKAP1L, NCKAP1
Infectious disease	2	24.8×	0.002	NCKAP1L, NCKAP1
Disease	2	13.1×	0.006	NCKAP1L, NCKAP1
Immune System	2	13.0×	0.006	NCKAP1L, NCKAP1
Signal Transduction	2	10.2×	0.010	NCKAP1L, NCKAP1
Neutrophil degranulation	1	11.5×	0.085	NCKAP1L

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
cell projection assembly	2	936.2×	6e-05	NCKAP1L, NCKAP1
cortical actin cytoskeleton organization	2	601.9×	8e-05	NCKAP1L, NCKAP1
positive regulation of actin filament polymerization	2	330.4×	2e-04	NCKAP1L, NCKAP1
neuron projection morphogenesis	2	276.3×	2e-04	NCKAP1L, NCKAP1
cell morphogenesis	2	157.5×	5e-04	NCKAP1L, NCKAP1
zygotic determination of anterior/posterior axis, embryo	1	4213.0×	0.002	NCKAP1
basal protein localization	1	4213.0×	0.002	NCKAP1
negative regulation of cytotoxic T cell degranulation	1	2808.7×	0.002	NCKAP1L
positive regulation of lymphocyte differentiation	1	2808.7×	0.002	NCKAP1L
paraxial mesoderm morphogenesis	1	2808.7×	0.002	NCKAP1
cell migration	2	61.5×	0.002	NCKAP1L, NCKAP1
establishment or maintenance of actin cytoskeleton polarity	1	2106.5×	0.002	NCKAP1
mesodermal cell migration	1	1685.2×	0.002	NCKAP1
positive regulation of CD8-positive, alpha-beta T cell differentiation	1	1685.2×	0.002	NCKAP1L
notochord morphogenesis	1	1685.2×	0.002	NCKAP1
positive regulation of CD4-positive, alpha-beta T cell differentiation	1	1404.3×	0.002	NCKAP1L
positive regulation of neutrophil migration	1	1404.3×	0.002	NCKAP1L
maintenance of cell polarity	1	1203.7×	0.002	NCKAP1L
actin polymerization-dependent cell motility	1	1203.7×	0.002	NCKAP1L
myeloid cell homeostasis	1	1053.2×	0.002	NCKAP1L
embryonic body morphogenesis	1	1053.2×	0.002	NCKAP1
positive regulation of TORC2 signaling	1	1053.2×	0.002	NCKAP1L
positive regulation of Arp2/3 complex-mediated actin nucleation	1	1053.2×	0.002	NCKAP1
positive regulation of gamma-delta T cell differentiation	1	936.2×	0.003	NCKAP1L
embryonic foregut morphogenesis	1	842.6×	0.003	NCKAP1
cell migration involved in gastrulation	1	766.0×	0.003	NCKAP1
erythrocyte homeostasis	1	648.1×	0.003	NCKAP1L
positive regulation of phagocytosis, engulfment	1	648.1×	0.003	NCKAP1L
positive regulation of B cell differentiation	1	561.7×	0.004	NCKAP1L
negative regulation of interleukin-17 production	1	526.6×	0.004	NCKAP1L

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NCKAP1L	0	0
NCKAP1	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
NCKAP1L	7	Binding:7
NCKAP1	1	Binding:1

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	NCKAP1L, NCKAP1

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)
NCKAP1L	7	—
NCKAP1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.