NIK deficiency

Summary

NIK deficiency (MONDO:0018642) is a disease caused by MAP3K14 (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: MAP3K14 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 503

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		2	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	NIK deficiency
Mondo ID	MONDO:0018642
Orphanet	447731
UMLS	C5680065
MedGen	1808868
GARD	0021864
Is cancer (heuristic)	no

Also known as: MAP3K14 non-severe combined immunodeficiency · non-severe combined immunodeficiency caused by mutation in MAP3K14 · primary immunodeficiency with multifaceted aberrant lymphoid immunity

Data availability: 503 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › immunodeficiency disease › combined immunodeficiency › non-SCID combined immunodeficiency › NIK deficiency

Related subtypes (6): TCR-alpha-beta-positive T-cell deficiency, non-severe combined immunodeficiency due to COPG1 deficiency, HELIOS deficiency, ITPKB deficiency, MAN2B2 deficiency, non-severe combined immunodeficiency due to polymerase delta 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

503 retrieved; paginated sample, class counts are floors:

279 likely benign, 201 uncertain significance, 13 benign, 5 benign/likely benign, 4 conflicting classifications of pathogenicity, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1489957	NM_003954.5(MAP3K14):c.916del (p.Cys306fs)	MAP3K14	Likely pathogenic	criteria provided, single submitter
1580497	NM_003954.5(MAP3K14):c.2433+8G>A	LOC126862575	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2194213	NM_003954.5(MAP3K14):c.89C>T (p.Pro30Leu)	MAP3K14	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
478059	NM_003954.5(MAP3K14):c.2290A>G (p.Thr764Ala)	MAP3K14	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
626135	NM_003954.5(MAP3K14):c.1830C>T (p.Ser610=)	MAP3K14	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1014117	NM_003954.5(MAP3K14):c.2039C>T (p.Ala680Val)	LOC126862575	Uncertain significance	criteria provided, single submitter
1020346	NM_003954.5(MAP3K14):c.2176A>C (p.Lys726Gln)	LOC126862575	Uncertain significance	criteria provided, single submitter
1055934	NM_003954.5(MAP3K14):c.2293G>A (p.Val765Ile)	LOC126862575	Uncertain significance	criteria provided, single submitter
1382233	NM_003954.5(MAP3K14):c.2180C>T (p.Ser727Phe)	LOC126862575	Uncertain significance	criteria provided, single submitter
1396564	NM_003954.5(MAP3K14):c.2249C>G (p.Pro750Arg)	LOC126862575	Uncertain significance	criteria provided, single submitter
1418729	NM_003954.5(MAP3K14):c.2470C>G (p.Leu824Val)	LOC126862575	Uncertain significance	criteria provided, single submitter
1419904	NM_003954.5(MAP3K14):c.2446G>T (p.Ala816Ser)	LOC126862575	Uncertain significance	criteria provided, single submitter
1428781	NM_003954.5(MAP3K14):c.2042A>G (p.Asn681Ser)	LOC126862575	Uncertain significance	criteria provided, single submitter
1437912	NM_003954.5(MAP3K14):c.2144C>G (p.Pro715Arg)	LOC126862575	Uncertain significance	criteria provided, single submitter
1447736	NM_003954.5(MAP3K14):c.2167G>A (p.Glu723Lys)	LOC126862575	Uncertain significance	criteria provided, single submitter
1480463	NM_003954.5(MAP3K14):c.2158G>T (p.Glu720Ter)	LOC126862575	Uncertain significance	criteria provided, single submitter
1495143	NM_003954.5(MAP3K14):c.2206G>C (p.Glu736Gln)	LOC126862575	Uncertain significance	criteria provided, single submitter
1499094	NM_003954.5(MAP3K14):c.2326+5G>A	LOC126862575	Uncertain significance	criteria provided, single submitter
1508174	NM_003954.5(MAP3K14):c.2155C>T (p.Pro719Ser)	LOC126862575	Uncertain significance	criteria provided, single submitter
1523257	NM_003954.5(MAP3K14):c.2116A>G (p.Thr706Ala)	LOC126862575	Uncertain significance	criteria provided, single submitter
1901851	NM_003954.5(MAP3K14):c.2131C>T (p.Pro711Ser)	LOC126862575	Uncertain significance	criteria provided, single submitter
1990081	NM_003954.5(MAP3K14):c.2081C>T (p.Ser694Leu)	LOC126862575	Uncertain significance	criteria provided, single submitter
2088572	NM_003954.5(MAP3K14):c.2033A>G (p.Asn678Ser)	LOC126862575	Uncertain significance	criteria provided, single submitter
2092486	NM_003954.5(MAP3K14):c.2183C>T (p.Pro728Leu)	LOC126862575	Uncertain significance	criteria provided, single submitter
2171574	NM_003954.5(MAP3K14):c.2437C>A (p.Pro813Thr)	LOC126862575	Uncertain significance	criteria provided, single submitter
3723649	NM_003954.5(MAP3K14):c.1997G>A (p.Arg666Lys)	LOC126862575	Uncertain significance	criteria provided, single submitter
544324	NM_003954.5(MAP3K14):c.2312A>C (p.Gln771Pro)	LOC126862575	Uncertain significance	criteria provided, single submitter
574281	NM_003954.5(MAP3K14):c.2433+3G>A	LOC126862575	Uncertain significance	criteria provided, single submitter
664708	NM_003954.5(MAP3K14):c.2405G>C (p.Ser802Thr)	LOC126862575	Uncertain significance	criteria provided, single submitter
837870	NM_003954.5(MAP3K14):c.2127_2128dup (p.Ala710fs)	LOC126862575	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
MAP3K14	Strong	Autosomal recessive	NIK deficiency	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MAP3K14	Orphanet:447731	NIK deficiency

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MAP3K14	HGNC:6853	ENSG00000006062	Q99558	Mitogen-activated protein kinase kinase kinase 14	gencc,clinvar
MAP3K14-AS1	HGNC:44359	ENSG00000267278		MAP3K14 antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MAP3K14	Mitogen-activated protein kinase kinase kinase 14	Lymphotoxin beta-activated kinase which seems to be exclusively involved in the activation of NF-kappa-B and its transcriptional activity.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Kinase	1	13.9×	0.142
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MAP3K14	Kinase	yes		Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
MAP3K14-AS1	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

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
gastrocnemius	1
granulocyte	1
muscle layer of sigmoid colon	1
left testis	1
right testis	1
testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MAP3K14	187	ubiquitous	yes	granulocyte, gastrocnemius, muscle layer of sigmoid colon
MAP3K14-AS1	160	broad	yes	right testis, left testis, testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MAP3K14	3,094
MAP3K14-AS1	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MAP3K14	Q99558	8

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. 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
TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathway	1	671.8×	0.009	MAP3K14
Regulation of T cell activation by CD28 family	1	423.0×	0.009	MAP3K14
CD28 dependent PI3K/Akt signaling	1	393.8×	0.009	MAP3K14
Co-stimulation by CD28	1	380.7×	0.009	MAP3K14
C-type lectin receptors (CLRs)	1	237.9×	0.009	MAP3K14
NIK–>noncanonical NF-kB signaling	1	228.4×	0.009	MAP3K14
Dectin-1 mediated noncanonical NF-kB signaling	1	215.5×	0.009	MAP3K14
TNFR2 non-canonical NF-kB pathway	1	181.3×	0.009	MAP3K14
CLEC7A (Dectin-1) signaling	1	142.8×	0.010	MAP3K14
Cytokine Signaling in Immune system	1	40.8×	0.032	MAP3K14
Adaptive Immune System	1	29.8×	0.040	MAP3K14
Innate Immune System	1	25.5×	0.042	MAP3K14
Immune System	1	13.0×	0.077	MAP3K14

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
non-canonical NF-kappaB signal transduction	1	842.6×	0.006	MAP3K14
cellular response to mechanical stimulus	1	216.1×	0.011	MAP3K14
MAPK cascade	1	153.2×	0.011	MAP3K14
defense response to virus	1	69.3×	0.018	MAP3K14
immune response	1	47.1×	0.021	MAP3K14

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · 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).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MAP3K14	1	2
MAP3K14-AS1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CROZBACICLIB	2	MAP3K14

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
MAP3K14	143	Binding:143

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
MAP3K14	143

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

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)
CROZBACICLIB	2	MAP3K14

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	MAP3K14
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	MAP3K14-AS1

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)
MAP3K14-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.