Autosomal recessive primary immunodeficiency with defective spontaneous natural killer cell cytotoxicity

Summary

Autosomal recessive primary immunodeficiency with defective spontaneous natural killer cell cytotoxicity (MONDO:0014313) is a disease with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 1
• ClinVar variants: 7

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		3	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive primary immunodeficiency with defective spontaneous natural killer cell cytotoxicity
Mondo ID	MONDO:0014313
OMIM	615707
Orphanet	437552
DOID	DOID:0111941
UMLS	C3810342
MedGen	816672
GARD	0017732
Is cancer (heuristic)	no

Also known as: autosomal recessive primary immunodeficiency with defective spontaneous NK cell cytotoxicity · CD16 deficiency · IMD20 · immunodeficiency 20 · immunodeficiency type 20

Data availability: 7 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › immune system disorder › inborn error of immunity › autosomal recessive primary immunodeficiency with defective spontaneous natural killer cell cytotoxicity

Related subtypes (40): B cell deficiency, complement deficiency, phagocyte bactericidal dysfunction, trichohepatoenteric syndrome, hepatic veno-occlusive disease-immunodeficiency syndrome, immunodeficiency with defective T-cell response to interleukin 1, Say-Barber-Miller syndrome, familial isolated congenital asplenia, X-linked immunoneurologic disorder, ectodermal dysplasia and immune deficiency, immunodeficiency 33, immunodeficiency 47, combined immunodeficiency due to moesin deficiency, immunodeficiency, X-linked, with deficiency of 115,000 Dalton surface glycoprotein, properdin deficiency, X-linked, combined immunodeficiency with faciooculoskeletal anomalies, recurrent infections associated with rare immunoglobulin isotypes deficiency, immunodeficiency 28, immunodeficiency 37, immunodeficiency 39, BENTA disease, primary immunodeficiency with post-measles-mumps-rubella vaccine viral infection, immunodeficiency 49, chronic mucocutaneous candidiasis, hereditary hemophagocytic lymphohistiocytosis, immunoglobulin heavy chain deficiency, immuno-osseous dysplasia, lymphoproliferative syndrome, IL10-related early-onset inflammatory bowel disease, T-cell immunodeficiency with epidermodysplasia verruciformis, Aicardi-Goutieres syndrome, immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections-lymphopenia syndrome, inflammatory bowel disease-recurrent sinopulmonary infections syndrome, A20 haploinsufficiency, NK cell deficiency, T cell and NK cell immunodeficiency, dendritic cell deficiency, immunodysregulation with variable immunodeficiency and autoimmunity, immune dysregulation with immunodeficiency due to AIOLOS haploinsufficiency, STAT5 haploinsufficiency

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

7 retrieved; paginated sample, class counts are floors:

7 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
1034271	NM_000569.8(FCGR3A):c.145G>A (p.Gly49Arg)	FCGR3A	Uncertain significance	criteria provided, multiple submitters, no conflicts
1034274	NM_001127593.1(FCGR3A):c.-62-192T>C	FCGR3A	Uncertain significance	criteria provided, multiple submitters, no conflicts
14828	NM_000569.8(FCGR3A):c.197T>A (p.Leu66His)	FCGR3A	Uncertain significance	criteria provided, multiple submitters, no conflicts
3599045	NM_000569.8(FCGR3A):c.62-9G>T	FCGR3A	Uncertain significance	criteria provided, single submitter
3891971	NM_001127593.1(FCGR3A):c.-62-57G>A	FCGR3A	Uncertain significance	criteria provided, single submitter
3902015	NM_000569.8(FCGR3A):c.325C>G (p.Leu109Val)	FCGR3A	Uncertain significance	criteria provided, single submitter
626106	NM_000569.8(FCGR3A):c.96T>C (p.Pro32=)	FCGR3A	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
FCGR3A	Moderate	Autosomal recessive	autosomal recessive primary immunodeficiency with defective spontaneous natural killer cell cytotoxicity	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FCGR3A	Orphanet:437552	Autosomal recessive primary immunodeficiency with defective spontaneous natural killer cell cytotoxicity

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
FCGR3A	HGNC:3619	ENSG00000203747	P08637	Low affinity immunoglobulin gamma Fc region receptor III-A	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FCGR3A	Low affinity immunoglobulin gamma Fc region receptor III-A	Receptor for the invariable Fc fragment of immunoglobulin gamma (IgG).

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Antibody/Immunoglobulin	1	29.2×	0.034

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FCGR3A	Antibody/Immunoglobulin	yes		Ig_sub, Ig-like_dom, Ig-like_fold

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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
granulocyte	1
leukocyte	1
monocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FCGR3A	130	broad	marker	granulocyte, leukocyte, monocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FCGR3A	3,492

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FCGR3A	P08637	15

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 1 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
FCGR activation	1	878.5×	0.007	FCGR3A
Role of phospholipids in phagocytosis	1	456.8×	0.007	FCGR3A
FCGR3A-mediated IL10 synthesis	1	292.8×	0.007	FCGR3A
FCGR3A-mediated phagocytosis	1	187.2×	0.007	FCGR3A
Regulation of actin dynamics for phagocytic cup formation	1	184.2×	0.007	FCGR3A
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell	1	87.2×	0.011	FCGR3A

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
antibody-dependent cellular cytotoxicity	1	2808.7×	0.002	FCGR3A
natural killer cell degranulation	1	2407.4×	0.002	FCGR3A
Fc-gamma receptor signaling pathway	1	1872.4×	0.002	FCGR3A
positive regulation of natural killer cell proliferation	1	1404.3×	0.002	FCGR3A
macrophage activation	1	702.2×	0.003	FCGR3A
natural killer cell activation	1	581.1×	0.003	FCGR3A
natural killer cell mediated cytotoxicity	1	432.1×	0.004	FCGR3A
phosphatidylinositol 3-kinase/protein kinase B signal transduction	1	210.7×	0.007	FCGR3A
calcium-mediated signaling	1	183.2×	0.007	FCGR3A
positive regulation of tumor necrosis factor production	1	153.2×	0.008	FCGR3A
cell surface receptor signaling pathway	1	64.1×	0.017	FCGR3A
immune response	1	47.1×	0.021	FCGR3A

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 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
FCGR3A	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	1	FCGR3A
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
FCGR3A	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.