severe combined immunodeficiency due to DNA-PKcs deficiency

Summary

severe combined immunodeficiency due to DNA-PKcs deficiency (MONDO:0014423) is a disease caused by PRKDC (GenCC Strong), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: PRKDC (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 2,725

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	severe combined immunodeficiency due to DNA-PKcs deficiency
Mondo ID	MONDO:0014423
OMIM	615966
Orphanet	317425
DOID	DOID:0111961
SNOMED CT	716871006
UMLS	C4014833
MedGen	863270
GARD	0017441
Is cancer (heuristic)	no

Also known as: IMD26 · immunodeficiency 26 with or without neurologic abnormalities · SCID due to DNA-PKcs deficiency

Data availability: 2,725 ClinVar variants · 4 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 › severe combined immunodeficiency › T-B- severe combined immunodeficiency › severe combined immunodeficiency due to DNA-PKcs deficiency

Related subtypes (15): severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency, short-limb skeletal dysplasia with severe combined immunodeficiency, combined immunodeficiency with skin granulomas, reticular dysgenesis, severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive, severe combined immunodeficiency due to DCLRE1C deficiency, Omenn syndrome, DNA ligase IV deficiency, neutrophil immunodeficiency syndrome, combined immunodeficiency due to partial RAG1 deficiency, Cernunnos-XLF deficiency, severe combined immunodeficiency due to LCK deficiency, immunodeficiency 73b with defective neutrophil chemotaxis and lymphopenia, immunodeficiency 73c with defective neutrophil chemotaxis and hypogammaglobulinemia, reticular dysgenesis-like severe combined immunodeficiency

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:

395 uncertain significance, 177 likely benign, 13 conflicting classifications of pathogenicity, 12 benign, 3 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1014210	NM_006904.7(PRKDC):c.1054G>A (p.Val352Met)	PRKDC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1031107	NM_006904.7(PRKDC):c.4773A>G (p.Lys1591=)	PRKDC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1033163	NM_006904.7(PRKDC):c.7080T>C (p.Phe2360=)	PRKDC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1033164	NM_006904.7(PRKDC):c.7371C>T (p.Pro2457=)	PRKDC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1044152	NM_006904.7(PRKDC):c.2620A>G (p.Thr874Ala)	PRKDC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1109219	NM_006904.7(PRKDC):c.509-4T>G	PRKDC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1148224	NM_006904.7(PRKDC):c.12183-5del	PRKDC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1375163	NM_006904.7(PRKDC):c.3481G>A (p.Ala1161Thr)	PRKDC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1375654	NM_006904.7(PRKDC):c.7787G>A (p.Arg2596His)	PRKDC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1434941	NM_006904.7(PRKDC):c.3631G>A (p.Val1211Ile)	PRKDC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1485349	NM_006904.7(PRKDC):c.631G>A (p.Ala211Thr)	PRKDC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1509276	NM_006904.7(PRKDC):c.301G>A (p.Ala101Thr)	PRKDC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1510530	NM_006904.7(PRKDC):c.312T>A (p.Ser104=)	PRKDC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1448870	NC_000008.10:g.(?48686734)(49833824_?)dup	CLXN	Uncertain significance	criteria provided, single submitter
1002035	NM_006904.7(PRKDC):c.8662G>A (p.Val2888Met)	LOC121740717	Uncertain significance	criteria provided, single submitter
1016007	NM_006904.7(PRKDC):c.8744G>A (p.Arg2915His)	LOC121740717	Uncertain significance	criteria provided, single submitter
1045434	NM_006904.7(PRKDC):c.8732G>A (p.Arg2911His)	LOC121740717	Uncertain significance	criteria provided, single submitter
1353242	NM_006904.7(PRKDC):c.8644G>A (p.Ala2882Thr)	LOC121740717	Uncertain significance	criteria provided, single submitter
1393672	NM_006904.7(PRKDC):c.8620G>C (p.Ala2874Pro)	LOC121740717	Uncertain significance	criteria provided, single submitter
1397303	NM_006904.7(PRKDC):c.8696G>A (p.Arg2899His)	LOC121740717	Uncertain significance	criteria provided, single submitter
1438884	NM_006904.7(PRKDC):c.8614G>C (p.Asp2872His)	LOC121740717	Uncertain significance	criteria provided, single submitter
1488654	NM_006904.7(PRKDC):c.8770G>A (p.Val2924Met)	LOC121740717	Uncertain significance	criteria provided, single submitter
1405464	NM_006904.7(PRKDC):c.16G>A (p.Ala6Thr)	LOC129929030	Uncertain significance	criteria provided, single submitter
1511615	NM_006904.7(PRKDC):c.20G>C (p.Gly7Ala)	LOC129929030	Uncertain significance	criteria provided, multiple submitters, no conflicts
1014616	NM_006904.7(PRKDC):c.152T>C (p.Leu51Pro)	LOC130000337	Uncertain significance	criteria provided, single submitter
1450229	NC_000008.10:g.(?48769697)(48889338_?)dup	MCM4	Uncertain significance	criteria provided, single submitter
1450733	NC_000008.10:g.(?48845560)(48889338_?)dup	MCM4	Uncertain significance	criteria provided, single submitter
1000377	NM_006904.7(PRKDC):c.2230G>A (p.Asp744Asn)	PRKDC	Uncertain significance	criteria provided, single submitter
1000710	NM_006904.7(PRKDC):c.12142A>G (p.Lys4048Glu)	PRKDC	Uncertain significance	criteria provided, single submitter
1001391	NM_006904.7(PRKDC):c.9788A>G (p.His3263Arg)	PRKDC	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
PRKDC	Strong	Autosomal recessive	severe combined immunodeficiency due to DNA-PKcs deficiency	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PRKDC	Orphanet:317425	Severe combined immunodeficiency due to DNA-PKcs deficiency
CLXN	Orphanet:244	Primary ciliary dyskinesia
MCM4	Orphanet:75391	Primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PRKDC	HGNC:9413	ENSG00000253729	P78527	DNA-dependent protein kinase catalytic subunit	gencc,clinvar
CLXN	HGNC:25678	ENSG00000034239	Q9HAE3	Calaxin	clinvar
MCM4	HGNC:6947	ENSG00000104738	P33991	DNA replication licensing factor MCM4	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PRKDC	DNA-dependent protein kinase catalytic subunit	Serine/threonine-protein kinase that acts as a molecular sensor for DNA damage.
CLXN	Calaxin	Component of the outer dynein arm-docking complex (ODA-DC) that mediates outer dynein arms (ODA) binding onto the doublet microtubule.
MCM4	DNA replication licensing factor MCM4	Acts as a component of the MCM2-7 complex (MCM complex) which is the replicative helicase essential for ‘once per cell cycle’ DNA replication initiation and elongation in eukaryotic cells.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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	9.2×	0.209
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PRKDC	Kinase	yes	2.7.11.1	PI3/4_kinase_cat_dom, PIK-rel_kinase_FAT, FATC_dom
CLXN	Other/Unknown	no		EF_hand_dom, EF-hand-dom_pair, EF_Hand_1_Ca_BS
MCM4	Other/Unknown	no		MCM_dom, MCM_4, NA-bd_OB-fold

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
ganglionic eminence	2
ventricular zone	2
stromal cell of endometrium	1
bronchial epithelial cell	1
epithelium of bronchus	1
right uterine tube	1
embryo	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PRKDC	296	ubiquitous	marker	ventricular zone, stromal cell of endometrium, ganglionic eminence
CLXN	176	broad	marker	right uterine tube, bronchial epithelial cell, epithelium of bronchus
MCM4	283	ubiquitous	marker	ventricular zone, ganglionic eminence, embryo

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PRKDC	6,595
MCM4	4,047
CLXN	1,652

Intra-cohort edges

A	B	Sources
MCM4	PRKDC	string_interaction

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PRKDC	P78527	47
MCM4	P33991	28
CLXN	Q9HAE3	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 21. Enrichment computed across 3 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
DNA strand elongation	1	571.0×	0.016	MCM4
Unwinding of DNA	1	439.2×	0.016	MCM4
IRF3-mediated induction of type I IFN	1	407.9×	0.016	PRKDC
Activation of the pre-replicative complex	1	163.1×	0.016	MCM4
DNA Replication Pre-Initiation	1	158.6×	0.016	MCM4
Activation of ATR in response to replication stress	1	150.3×	0.016	MCM4
Switching of origins to a post-replicative state	1	150.3×	0.016	MCM4
Synthesis of DNA	1	150.3×	0.016	MCM4
Cytosolic sensors of pathogen-associated DNA	1	142.8×	0.016	PRKDC
DNA Replication	1	119.0×	0.016	MCM4
G1/S Transition	1	116.5×	0.016	MCM4
E3 ubiquitin ligases ubiquitinate target proteins	1	96.8×	0.016	PRKDC
Mitotic G1 phase and G1/S transition	1	92.1×	0.016	MCM4
S Phase	1	90.6×	0.016	MCM4
Orc1 removal from chromatin	1	89.2×	0.016	MCM4
Nonhomologous End-Joining (NHEJ)	1	84.0×	0.016	PRKDC
Assembly of the pre-replicative complex	1	69.6×	0.017	MCM4
G2/M Checkpoints	1	67.2×	0.017	MCM4
Cell Cycle Checkpoints	1	44.3×	0.025	MCM4
Cell Cycle, Mitotic	1	24.1×	0.043	MCM4
Cell Cycle	1	18.0×	0.055	MCM4

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of platelet formation	1	2808.7×	0.005	PRKDC
small-subunit processome assembly	1	1872.4×	0.005	PRKDC
positive regulation of lymphocyte differentiation	1	1872.4×	0.005	PRKDC
pro-B cell differentiation	1	1404.3×	0.005	PRKDC
regulation of cilium movement	1	1404.3×	0.005	CLXN
T cell receptor V(D)J recombination	1	1404.3×	0.005	PRKDC
B cell lineage commitment	1	1123.5×	0.005	PRKDC
T cell lineage commitment	1	1123.5×	0.005	PRKDC
regulation of flagellated sperm motility	1	1123.5×	0.005	CLXN
immunoglobulin V(D)J recombination	1	936.2×	0.005	PRKDC
mitotic DNA replication initiation	1	936.2×	0.005	MCM4
immature B cell differentiation	1	802.5×	0.006	PRKDC
DNA strand elongation involved in DNA replication	1	624.1×	0.007	MCM4
double-strand break repair via alternative nonhomologous end joining	1	561.7×	0.007	PRKDC
regulation of hematopoietic stem cell differentiation	1	510.7×	0.007	PRKDC
double-strand break repair via break-induced replication	1	432.1×	0.007	MCM4
telomere capping	1	432.1×	0.007	PRKDC
regulation of smooth muscle cell proliferation	1	432.1×	0.007	PRKDC
maturation of 5.8S rRNA	1	351.1×	0.007	PRKDC
regulation of DNA-templated DNA replication initiation	1	351.1×	0.007	MCM4
mitotic G1 DNA damage checkpoint signaling	1	351.1×	0.007	PRKDC
negative regulation of cGAS/STING signaling pathway	1	351.1×	0.007	PRKDC
positive regulation of double-strand break repair via nonhomologous end joining	1	330.4×	0.007	PRKDC
regulation of epithelial cell proliferation	1	312.1×	0.007	PRKDC
peptidyl-threonine phosphorylation	1	295.6×	0.007	PRKDC
ectopic germ cell programmed cell death	1	280.9×	0.008	PRKDC
outer dynein arm assembly	1	244.2×	0.008	CLXN
negative regulation of protein phosphorylation	1	193.7×	0.010	PRKDC
response to gamma radiation	1	193.7×	0.010	PRKDC
positive regulation of erythrocyte differentiation	1	170.2×	0.011	PRKDC

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) 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
PRKDC	IDELALISIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PRKDC	23	4
MCM4	1	3
CLXN	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
IDELALISIB	4	PRKDC
LENIOLISIB	4	PRKDC
TRIFLUOPERAZINE	4	PRKDC
DACTOLISIB	3	PRKDC
BUPARLISIB	3	PRKDC
SURAMIN	3	PRKDC
CERALASERTIB	3	PRKDC
ALISERTIB	3	MCM4
OMIPALISIB	2	PRKDC
APITOLISIB	2	PRKDC
AZD-6482	2	PRKDC
OSI-027	2	PRKDC
PILARALISIB	2	PRKDC
CC-115	2	PRKDC
FIMEPINOSTAT	2	PRKDC
EGANELISIB	2	PRKDC
BERZOSERTIB	2	PRKDC
BIMIRALISIB	2	PRKDC
PICTILISIB	2	PRKDC
SAR-260301	1	PRKDC
CB-5083	1	PRKDC
NEDISERTIB	1	PRKDC
AZD-7648	1	PRKDC
ELIMUSERTIB	1	PRKDC

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
PRKDC	363	Binding:363
MCM4	7	Binding:7

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PRKDC	2.7.11.1	non-specific serine/threonine protein kinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
PRKDC	363

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

24 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)
IDELALISIB	4	PRKDC
LENIOLISIB	4	PRKDC
TRIFLUOPERAZINE	4	PRKDC
DACTOLISIB	3	PRKDC
BUPARLISIB	3	PRKDC
SURAMIN	3	PRKDC
CERALASERTIB	3	PRKDC
ALISERTIB	3	MCM4
OMIPALISIB	2	PRKDC
APITOLISIB	2	PRKDC
AZD-6482	2	PRKDC
OSI-027	2	PRKDC
PILARALISIB	2	PRKDC
CC-115	2	PRKDC
FIMEPINOSTAT	2	PRKDC
EGANELISIB	2	PRKDC
BERZOSERTIB	2	PRKDC
BIMIRALISIB	2	PRKDC
PICTILISIB	2	PRKDC
SAR-260301	1	PRKDC
CB-5083	1	PRKDC
NEDISERTIB	1	PRKDC
AZD-7648	1	PRKDC
ELIMUSERTIB	1	PRKDC

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PRKDC
B	Phased (≥1) drug, not yet approved	1	MCM4
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	CLXN

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)
CLXN	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.