combined immunodeficiency due to ORAI1 deficiency

Summary

combined immunodeficiency due to ORAI1 deficiency (MONDO:0013007) is a disease caused by ORAI1 (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ORAI1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 433

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		6	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	combined immunodeficiency due to ORAI1 deficiency
Mondo ID	MONDO:0013007
MeSH	C557826
OMIM	612782
Orphanet	317428
DOID	DOID:0111976
ICD-11	677672007
UMLS	C2748568
MedGen	440578
GARD	0010524
Is cancer (heuristic)	no

Also known as: CID due to ORAI1 deficiency · IMD9 · immunodeficiency 9 · immunodeficiency type 9

Data availability: 433 ClinVar variants · 3 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 › combined immunodeficiency due to CRAC channel dysfunction › combined immunodeficiency due to ORAI1 deficiency

Related subtypes (1): combined immunodeficiency due to STIM1 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

433 retrieved; paginated sample, class counts are floors:

249 uncertain significance, 141 likely benign, 11 pathogenic, 11 conflicting classifications of pathogenicity, 9 benign, 9 likely pathogenic, 3 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
3244335	NC_000012.11:g.(?122064648)(122287716_?)del	HPD	Pathogenic	criteria provided, single submitter
1283	NM_032790.4(ORAI1):c.271C>T (p.Arg91Trp)	LOC130008987	Pathogenic	no assertion criteria provided
192286	NM_032790.4(ORAI1):c.261dup (p.Ala88Serfs)	LOC130008987	Pathogenic	no assertion criteria provided
2930250	NM_032790.4(ORAI1):c.208_209del (p.Ser70fs)	LOC130008987	Pathogenic	criteria provided, single submitter
470188	NM_032790.4(ORAI1):c.141_142insCCGCCGCCGCAGCGGGGACGGGGAGCCCCCGGGGGCC (p.Ser48Profs)	LOC130008987	Pathogenic	criteria provided, single submitter
4792097	NC_000012.12:g.121626961C>T	LOC130008987	Pathogenic	criteria provided, single submitter
1069742	NC_000012.12:g.121641056G>A	ORAI1	Pathogenic	criteria provided, single submitter
1428101	NC_000012.11:g.(?122064648)(122064976_?)del	ORAI1	Pathogenic	criteria provided, single submitter
192287	NM_032790.4(ORAI1):c.308C>A (p.Ala103Glu)	ORAI1	Pathogenic	no assertion criteria provided
3383981	NM_032790.1(ORAI1):c.493dup	ORAI1	Pathogenic	criteria provided, single submitter
3754970	NC_000012.12:g.121641254G>T	ORAI1	Pathogenic	criteria provided, single submitter
3236451	NM_032790.4(ORAI1):c.129_133del (p.Pro44fs)	LOC130008987	Likely pathogenic	criteria provided, single submitter
1464680	NM_032790.4(ORAI1):c.750dup (p.Ile251Tyrfs)	ORAI1	Likely pathogenic	criteria provided, single submitter
1505011	NC_000012.12:g.121641350C>T	ORAI1	Likely pathogenic	criteria provided, single submitter
192288	NM_032790.4(ORAI1):c.581T>C (p.Leu194Pro)	ORAI1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2171110	NM_032790.4(ORAI1):c.802C>T (p.Arg268Ter)	ORAI1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2944495	NM_032790.4(ORAI1):c.505dup (p.His169fs)	ORAI1	Likely pathogenic	criteria provided, single submitter
3780063	NM_032790.3(ORAI1):c.131_132insGCCGC	ORAI1	Likely pathogenic	criteria provided, single submitter
4791642	NR_186857.1(ORAI1):n.906_909dup	ORAI1	Likely pathogenic	criteria provided, single submitter
639606	NC_000012.12:g.121641283del	ORAI1	Likely pathogenic	criteria provided, single submitter
475180	NM_032790.4(ORAI1):c.137_143CGCCGTC[3] (p.Thr51Argfs)	LOC130008987	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
541941	NM_032790.4(ORAI1):c.100A>C (p.Ser34Arg)	LOC130008987	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
541945	NM_032790.4(ORAI1):c.49C>T (p.Pro17Ser)	LOC130008987	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
650573	NM_032790.4(ORAI1):c.113_121delAGCCCCCGG (p.Glu38_Pro40del)	LOC130008987	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
717948	NM_032790.4(ORAI1):c.12G>T (p.Glu4Asp)	LOC130008987	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
784675	NM_032790.4(ORAI1):c.121G>A (p.Gly41Arg)	LOC130008987	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
854069	NM_032790.4(ORAI1):c.14C>T (p.Pro5Leu)	LOC130008987	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
189257	NM_032790.4(ORAI1):c.412C>T (p.Leu138Phe)	ORAI1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
193469	NC_000012.12:g.121626879_121626884delACCGCC	ORAI1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2637958	NM_032790.4(ORAI1):c.391G>A (p.Val131Met)	ORAI1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 5 · 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
ORAI1	Strong	Autosomal recessive	combined immunodeficiency due to ORAI1 deficiency	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ORAI1	Orphanet:2593	Tubular aggregate myopathy
ORAI1	Orphanet:317428	Combined immunodeficiency due to ORAI1 deficiency
ORAI1	Orphanet:3204	Stormorken-Sjaastad-Langslet syndrome
HPD	Orphanet:2118	Hawkinsinuria
HPD	Orphanet:69723	Tyrosinemia type 3

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
ORAI1	HGNC:25896	ENSG00000276045	Q96D31	Calcium release-activated calcium channel protein 1	gencc,clinvar
HPD	HGNC:5147	ENSG00000158104	P32754	4-hydroxyphenylpyruvate dioxygenase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ORAI1	Calcium release-activated calcium channel protein 1	Pore-forming subunit of two major inward rectifying Ca(2+) channels at the plasma membrane: Ca(2+) release-activated Ca(2+) (CRAC) channels and arachidonate-regulated Ca(2+)-selective (ARC) channels.
HPD	4-hydroxyphenylpyruvate dioxygenase	Catalyzes the conversion of 4-hydroxyphenylpyruvic acid to homogentisic acid, one of the steps in tyrosine catabolism.

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
Enzyme (other)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ORAI1	Other/Unknown	no		CRAC_channel, Orai_sf
HPD	Enzyme (other)	yes	1.13.11.27	Glyas_Fos-R_dOase_dom, 4OHPhenylPyrv_dOase, Glyas_Bleomycin-R_OHBP_Dase

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
granulocyte	1
hindlimb stylopod muscle	1
skin of leg	1
adult mammalian kidney	1
liver	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ORAI1	177	ubiquitous	yes	granulocyte, hindlimb stylopod muscle, skin of leg
HPD	163	broad	marker	right lobe of liver, liver, adult mammalian kidney

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HPD	1,766
ORAI1	1,239

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HPD	P32754	4
ORAI1	Q96D31	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. 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
Tyrosine catabolism	1	1142.0×	0.004	HPD
Elevation of cytosolic Ca2+ levels	1	356.9×	0.006	ORAI1
Antigen activates B Cell Receptor (BCR) leading to generation of second messengers	1	178.4×	0.007	ORAI1
Ion homeostasis	1	102.0×	0.010	ORAI1

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
positive regulation of adenylate cyclase activity	1	1685.2×	0.003	ORAI1
L-tyrosine catabolic process	1	1404.3×	0.003	HPD
L-phenylalanine catabolic process	1	1053.2×	0.003	HPD
mammary gland epithelium development	1	936.2×	0.003	ORAI1
ligand-gated ion channel signaling pathway	1	936.2×	0.003	ORAI1
store-operated calcium entry	1	842.6×	0.003	ORAI1
calcium-ion regulated exocytosis	1	495.6×	0.004	ORAI1
calcineurin-NFAT signaling cascade	1	421.3×	0.004	ORAI1
regulation of calcium ion transport	1	401.2×	0.004	ORAI1
calcium ion import	1	401.2×	0.004	ORAI1
positive regulation of calcium ion transport	1	290.6×	0.005	ORAI1
positive regulation of insulin secretion	1	127.7×	0.010	ORAI1
calcium ion transmembrane transport	1	105.3×	0.011	ORAI1
phospholipase C-activating G protein-coupled receptor signaling pathway	1	65.8×	0.016	ORAI1
adaptive immune response	1	42.1×	0.024	ORAI1

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 evidence-associated genes (100%) 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
ORAI1	MIBEFRADIL
HPD	NITISINONE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ORAI1	5	4
HPD	1	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MIBEFRADIL	4	ORAI1
ECONAZOLE	4	ORAI1
MICONAZOLE	4	ORAI1
TERIFLUNOMIDE	4	ORAI1
NITISINONE	4	HPD
ZEGOCRACTIN	2	ORAI1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
ORAI1	59	Binding:57, Functional:1, ADMET:1
HPD	6	Binding:6

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
HPD	1.13.11.27	4-hydroxyphenylpyruvate dioxygenase

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

6 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)
MIBEFRADIL	4	ORAI1
ECONAZOLE	4	ORAI1
MICONAZOLE	4	ORAI1
TERIFLUNOMIDE	4	ORAI1
NITISINONE	4	HPD
ZEGOCRACTIN	2	ORAI1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	ORAI1, HPD
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	0

Undrugged target profiles

0 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Clinical trials & evidence

Clinical trials

Clinical trials: 0.