Immunodeficiency 47

Summary

Immunodeficiency 47 (MONDO:0010504) is a disease caused by ATP6AP1 (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ATP6AP1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 33

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		17	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	immunodeficiency 47
Mondo ID	MONDO:0010504
OMIM	300972
Orphanet	692790
DOID	DOID:0112002
UMLS	C4310819
MedGen	934786
GARD	0024733
Is cancer (heuristic)	no

Also known as: ATP6AP1 primary immunodeficiency disease · IMD47 · immunodeficiency 47 · immunodeficiency 47, X-linked recessive · immunodeficiency 47; IMD47 · immunodeficiency type 47 · primary immunodeficiency disease caused by mutation in ATP6AP1

Data availability: 33 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › immune system disorder › inborn error of immunity › immunodeficiency 47

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, 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, autosomal recessive primary immunodeficiency with defective spontaneous natural killer cell cytotoxicity, 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

33 retrieved; paginated sample, class counts are floors:

11 uncertain significance, 7 conflicting classifications of pathogenicity, 7 pathogenic, 4 likely pathogenic, 2 benign/likely benign, 1 pathogenic/likely pathogenic, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1684654	Single allele	ATP6AP1	Pathogenic	criteria provided, single submitter
236239	NM_001183.6(ATP6AP1):c.1284G>A (p.Met428Ile)	ATP6AP1	Pathogenic	no assertion criteria provided
236240	NM_001183.6(ATP6AP1):c.431T>C (p.Leu144Pro)	ATP6AP1	Pathogenic	no assertion criteria provided
236241	NM_001183.6(ATP6AP1):c.1036G>A (p.Glu346Lys)	ATP6AP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
236242	NM_001183.6(ATP6AP1):c.938A>G (p.Tyr313Cys)	ATP6AP1	Pathogenic	criteria provided, single submitter
2687781	NM_001183.6(ATP6AP1):c.289-289G>A	ATP6AP1	Pathogenic	criteria provided, single submitter
915879	NM_001183.6(ATP6AP1):c.221T>C (p.Leu74Pro)	ATP6AP1	Pathogenic	no assertion criteria provided
973847	NM_001183.6(ATP6AP1):c.649T>A (p.Tyr217Asn)	ATP6AP1	Pathogenic	no assertion criteria provided
1686802	NM_001183.6(ATP6AP1):c.230_232del (p.Tyr77del)	ATP6AP1	Likely pathogenic	criteria provided, single submitter
2442381	NM_001183.6(ATP6AP1):c.530T>C (p.Leu177Pro)	ATP6AP1	Likely pathogenic	criteria provided, single submitter
2687780	NM_001183.6(ATP6AP1):c.289-233C>T	ATP6AP1	Likely pathogenic	criteria provided, single submitter
4819731	NM_001183.6(ATP6AP1):c.401C>T (p.Pro134Leu)	ATP6AP1	Likely pathogenic	criteria provided, single submitter
1058652	NM_001183.6(ATP6AP1):c.294C>A (p.Ser98Arg)	ATP6AP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1914019	NM_001183.6(ATP6AP1):c.216G>A (p.Leu72=)	ATP6AP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2016125	NM_001183.6(ATP6AP1):c.971+10G>A	ATP6AP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2571385	NM_001183.6(ATP6AP1):c.220C>G (p.Leu74Val)	ATP6AP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2688649	NM_001183.6(ATP6AP1):c.319G>A (p.Gly107Ser)	ATP6AP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
437913	NM_001183.6(ATP6AP1):c.542T>G (p.Leu181Arg)	ATP6AP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
435315	NM_001493.3(GDI1):c.193T>A (p.Ser65Thr)	GDI1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1339117	NM_001183.6(ATP6AP1):c.1031G>A (p.Arg344His)	ATP6AP1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2439382	NM_001183.6(ATP6AP1):c.301G>A (p.Asp101Asn)	ATP6AP1	Uncertain significance	criteria provided, single submitter
2439383	NM_001183.6(ATP6AP1):c.515G>C (p.Ser172Thr)	ATP6AP1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2444113	NM_001183.6(ATP6AP1):c.385T>C (p.Ser129Pro)	ATP6AP1	Uncertain significance	criteria provided, single submitter
2580152	NM_001183.6(ATP6AP1):c.560C>T (p.Ser187Phe)	ATP6AP1	Uncertain significance	criteria provided, single submitter
2584995	NM_001183.6(ATP6AP1):c.473A>T (p.His158Leu)	ATP6AP1	Uncertain significance	criteria provided, single submitter
3067894	NM_001183.6(ATP6AP1):c.725G>A (p.Arg242His)	ATP6AP1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3731382	NM_001183.6(ATP6AP1):c.289-6T>C	ATP6AP1	Uncertain significance	criteria provided, single submitter
4293209	NM_001183.6(ATP6AP1):c.1306A>T (p.Met436Leu)	ATP6AP1	Uncertain significance	criteria provided, single submitter
804234	NM_001183.6(ATP6AP1):c.932T>A (p.Leu311Gln)	ATP6AP1	Uncertain significance	criteria provided, single submitter
930248	NM_001183.6(ATP6AP1):c.674G>A (p.Arg225His)	ATP6AP1	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 2 · 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
ATP6AP1	Strong	X-linked	immunodeficiency 47	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ATP6AP1	Orphanet:692790	ATP6AP1-CDG
GDI1	Orphanet:777	X-linked non-syndromic intellectual disability

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
ATP6AP1	HGNC:868	ENSG00000071553	Q15904	V-type proton ATPase subunit S1	gencc,clinvar
GDI1	HGNC:4226	ENSG00000203879	P31150	Rab GDP dissociation inhibitor alpha	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ATP6AP1	V-type proton ATPase subunit S1	Accessory subunit of the proton-transporting vacuolar (V)-ATPase protein pump, which is required for luminal acidification of secretory vesicles.
GDI1	Rab GDP dissociation inhibitor alpha	Regulates the GDP/GTP exchange reaction of most Rab proteins by inhibiting the dissociation of GDP from them, and the subsequent binding of GTP to them.

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)
ATP6AP1	Other/Unknown	no		Ac45_acc_su, VAS1_LD, VAS1/VOA1_TM
GDI1	Other/Unknown	no		RabGDI, GDP_dissociation_inhibitor, FAD/NAD-bd_sf

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
Brodmann (1909) area 10	1
endometrium epithelium	1
paraflocculus	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ATP6AP1	291	ubiquitous	marker	endometrium epithelium, Brodmann (1909) area 10, paraflocculus
GDI1	294	ubiquitous	marker	right hemisphere of cerebellum, cerebellar cortex, cerebellar hemisphere

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GDI1	2,331
ATP6AP1	1,759

Intra-cohort edges

A	B	Sources
ATP6AP1	GDI1	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ATP6AP1	Q15904	9

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
GDI1	P31150	93.32

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. 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
Insulin receptor recycling	1	190.3×	0.014	ATP6AP1
Transferrin endocytosis and recycling	1	184.2×	0.014	ATP6AP1
RAB GEFs exchange GTP for GDP on RABs	1	62.1×	0.026	GDI1
Ion channel transport	1	48.0×	0.026	ATP6AP1
RHOA GTPase cycle	1	37.3×	0.027	ATP6AP1

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
negative regulation of protein localization	1	2808.7×	0.003	GDI1
positive regulation of toll-like receptor signaling pathway	1	2106.5×	0.003	GDI1
obsolete regulation of cellular pH	1	1685.2×	0.003	ATP6AP1
endosome to plasma membrane protein transport	1	1685.2×	0.003	ATP6AP1
negative regulation of protein targeting to membrane	1	1404.3×	0.003	GDI1
osteoclast development	1	1053.2×	0.003	ATP6AP1
cellular response to increased oxygen levels	1	1053.2×	0.003	ATP6AP1
Golgi lumen acidification	1	842.6×	0.003	ATP6AP1
negative regulation of axonogenesis	1	648.1×	0.003	GDI1
endosomal lumen acidification	1	601.9×	0.003	ATP6AP1
intracellular pH reduction	1	601.9×	0.003	ATP6AP1
Rab protein signal transduction	1	495.6×	0.004	GDI1
synaptic vesicle lumen acidification	1	468.1×	0.004	ATP6AP1
vacuolar acidification	1	366.4×	0.004	ATP6AP1
lysosomal lumen acidification	1	337.0×	0.004	ATP6AP1
positive regulation of axon extension	1	255.3×	0.005	GDI1
response to calcium ion	1	159.0×	0.008	GDI1
proton transmembrane transport	1	156.0×	0.008	ATP6AP1
intracellular iron ion homeostasis	1	122.1×	0.009	ATP6AP1
vesicle-mediated transport	1	48.1×	0.023	GDI1
protein transport	1	21.9×	0.047	GDI1
signal transduction	1	8.0×	0.121	GDI1

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
ATP6AP1	0	0
GDI1	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
ATP6AP1	7	Binding:7
GDI1	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	ATP6AP1, GDI1

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)
ATP6AP1	7	—
GDI1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.