Normal pressure hydrocephalus

Summary

Normal pressure hydrocephalus (MONDO:0009366) is a disease with 2 cohort genes (8 GWAS associations across 1 studies) and 52 clinical trials. Top therapeutic interventions include acetazolamide and flutemetamol.

At a glance

• Cohort genes: 2
• GWAS associations: 8
• ClinVar variants: 11
• Clinical trials: 52

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	normal pressure hydrocephalus
Mondo ID	MONDO:0009366
EFO	EFO:1001065
MeSH	D006850
OMIM	236690
Orphanet	314928
DOID	DOID:1572
SNOMED CT	30753002
UMLS	C0020258
MedGen	42526
MedDRA	10029773
Is cancer (heuristic)	no

Also known as: chronic adult hydrocephalus · hydrocephalus, normal pressure, 1 · NPH

Data availability: 11 ClinVar variants · 8 GWAS associations (1 study) · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › brain disorder › hydrocephalus › communicating hydrocephalus › normal pressure hydrocephalus

Genetics & variants

GWAS landscape

8 GWAS associations across 1 studies. Top hits map to 9 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs7962263	9e-14	SLCO1A2	T	0.31
rs798495	4e-13	GNA12, AMZ1	C	0.25
rs561699566	9e-13	CDCA2	TG	0.27
rs10828247	6e-12	MLLT10	G	0.26
rs56023709	3e-11	C16orf95	C	0.23
rs62434144	2e-10	PLEKHG1	T	0.22
rs11217863	6e-08	ARHGEF12	A	0.27
rs576021376	7e-08	TPTEP2-CSNK1E	C	0.42

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90565137	Rasanen J	2024	1,522	451,091	Risk Variants Associated With Normal Pressure Hydrocephalus: Genome-Wide Association Study in the FinnGen Cohort.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	0
Tier 2: splice/UTR	0
Tier 3: regulatory	1
Tier 4: intronic/intergenic	7

MAF distribution

Bucket	Variants
common (>=0.05)	7
low_freq (0.01-0.05)	1
rare (<0.01)	0
unknown	0

Functional consequences

Consequence	Count
intron_variant	6
TF_binding_site_variant	1
intergenic_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs7962263	12	21313183	C>T	0.25	intron_variant	SLCO1A2	9e-14	Tier 4: intronic/intergenic
rs798495	7	2757633	T>A,C	0.365	intron_variant	GNA12, AMZ1	4e-13	Tier 4: intronic/intergenic
rs561699566	8	25492135		0.319	intron_variant	CDCA2	9e-13	Tier 4: intronic/intergenic
rs10828247	10	21533927	A>C,G	0.325	TF_binding_site_variant	MLLT10	6e-12	Tier 3: regulatory
rs56023709	16	87195738	A>C,G	0.457	intergenic_variant	C16orf95	3e-11	Tier 4: intronic/intergenic
rs62434144	6	150702668	C>T	0.433	intron_variant	PLEKHG1	2e-10	Tier 4: intronic/intergenic
rs11217863	11	120422429	G>A	0.124	intron_variant	ARHGEF12	6e-08	Tier 4: intronic/intergenic
rs576021376	22	38354701	T>C	0.042	intron_variant	TPTEP2-CSNK1E	7e-08	Tier 4: intronic/intergenic

ClinVar germline variants

11 retrieved; paginated sample, class counts are floors:

4 pathogenic, 3 likely pathogenic, 3 uncertain significance, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1344887	NM_025145.7(CFAP43):c.2658G>A (p.Trp886Ter)	CFAP43	Pathogenic	criteria provided, single submitter
805993	NM_025145.7(CFAP43):c.4506G>A (p.Trp1502Ter)	CFAP43	Pathogenic	no assertion criteria provided
221552	NM_015160.3(PMPCA):c.1129G>A (p.Ala377Thr)	PMPCA	Pathogenic	no assertion criteria provided
221553	NM_015160.3(PMPCA):c.1066G>A (p.Gly356Ser)	PMPCA	Pathogenic	no assertion criteria provided
2585282	NM_025145.7(CFAP43):c.3937C>T (p.Arg1313Ter)	CFAP43	Likely pathogenic	criteria provided, single submitter
3893050	NM_025145.7(CFAP43):c.3749del (p.Thr1250fs)	CFAP43	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3893051	NM_025145.7(CFAP43):c.4579dup (p.Ser1527fs)	CFAP43	Likely pathogenic	criteria provided, single submitter
2388140	NM_025145.7(CFAP43):c.1999G>A (p.Val667Ile)	CFAP43	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2588866	NM_025145.7(CFAP43):c.3224C>A (p.Thr1075Lys)	CFAP43	Uncertain significance	criteria provided, multiple submitters, no conflicts
3731538	NM_025145.7(CFAP43):c.131G>C (p.Cys44Ser)	CFAP43	Uncertain significance	criteria provided, single submitter
3779057	NM_025145.7(CFAP43):c.2714T>C (p.Val905Ala)	CFAP43	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · 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
CFAP43	Limited	Autosomal dominant	normal pressure hydrocephalus	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CFAP43	Orphanet:276234	Non-syndromic male infertility due to sperm motility disorder
PMPCA	Orphanet:1170	Autosomal recessive cerebelloparenchymal disorder 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
CFAP43	HGNC:26684	ENSG00000197748	Q8NDM7	Cilia- and flagella-associated protein 43	gencc,clinvar
PMPCA	HGNC:18667	ENSG00000165688	Q10713	Mitochondrial-processing peptidase subunit alpha	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CFAP43	Cilia- and flagella-associated protein 43	Flagellar protein involved in sperm flagellum axoneme organization and function.
PMPCA	Mitochondrial-processing peptidase subunit alpha	Substrate recognition and binding subunit of the essential mitochondrial processing protease (MPP), which cleaves the mitochondrial sequence off newly imported precursors proteins.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · 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
Protease	1	18.3×	0.108
Scaffold/PPI	1	8.6×	0.112

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CFAP43	Scaffold/PPI	no		WD40/YVTN_repeat-like_dom_sf, WD40_repeat_dom_sf
PMPCA	Protease	yes	3.4.24.64	Pept_M16_Zn_BS, Peptidase_M16_C, Metalloenz_LuxS/M16

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
bronchial epithelial cell	1
mucosa of paranasal sinus	1
right uterine tube	1
adrenal tissue	1
apex of heart	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CFAP43	190	broad	marker	right uterine tube, bronchial epithelial cell, mucosa of paranasal sinus
PMPCA	276	ubiquitous	marker	right lobe of liver, adrenal tissue, apex of heart

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PMPCA	3,679
CFAP43	731

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CFAP43	Q8NDM7	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PMPCA	Q10713	88.46

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. 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
Processing of SMDT1	1	634.4×	0.006	PMPCA
Mitochondrial calcium ion transport	1	543.8×	0.006	PMPCA
Protein localization	1	190.3×	0.010	PMPCA
Mitochondrial protein import	1	167.9×	0.010	PMPCA
Mitochondrial protein degradation	1	114.2×	0.012	PMPCA
Transport of small molecules	1	25.1×	0.046	PMPCA
Metabolism of proteins	1	12.4×	0.081	PMPCA

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
regulation of cilium beat frequency	1	1053.2×	0.005	CFAP43
obsolete protein processing involved in protein targeting to mitochondrion	1	1053.2×	0.005	PMPCA
mucociliary clearance	1	648.1×	0.006	CFAP43
cerebrospinal fluid circulation	1	443.5×	0.006	CFAP43
nucleus organization	1	280.9×	0.008	CFAP43
sperm axoneme assembly	1	234.1×	0.008	CFAP43
protein processing	1	85.1×	0.015	PMPCA
establishment of localization in cell	1	80.2×	0.015	CFAP43
cell morphogenesis	1	78.8×	0.015	CFAP43
brain development	1	39.8×	0.027	CFAP43
cilium assembly	1	36.8×	0.027	CFAP43

Therapeutics

Drugs indicated for this disease

0 approved, 1 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Acetazolamide	Phase 3 (in late-stage trials)

Drug target analysis

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

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
CFAP43	0	0
PMPCA	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
PMPCA	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PMPCA	3.4.24.64	mitochondrial processing peptidase

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	1	PMPCA
E	Difficult family or no structure, no drug	1	CFAP43

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)
CFAP43	0	—
PMPCA	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 52.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	44
PHASE3	3
PHASE2	3
PHASE4	1
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00793416	PHASE4	WITHDRAWN	ShuntCheck Accuracy in Detecting Shunt Obstruction Normal Pressure Hydrocephalus (NPH) Patients
NCT00196196	PHASE3	COMPLETED	A Precision and Accuracy Study of the Codman Valve Position Verification (VPV) System.
NCT01053312	PHASE3	COMPLETED	PET Imaging of Brain Amyloid in Normal Pressure Hydrocephalus
NCT01092546	PHASE3	TERMINATED	Positron Emission Tomography Imaging of Brain Amyloid in Normal Pressure Hydrocephalus
NCT06563817	PHASE2	RECRUITING	The Safety and Efficacy of Rapamycin on Communicating Hydrocephalus Secondary to Intraventricular Hemorrhage
NCT00221091	PHASE2	COMPLETED	Study to Evaluate Efficacy of Shunt Operation for Idiopathic Normal Pressure Hydrocephalus
NCT03779594	PHASE2	UNKNOWN	Acetazolamide for Treating NPH in Shunt-candidates Patients
NCT01815775	EARLY_PHASE1	COMPLETED	Predictive Value of Flow MRI in Normal Pressure Hydrocephalus Surgery
NCT04471740	Not specified	RECRUITING	Normal Pressure Hydrocephalus and Sleep Apnea
NCT04998175	Not specified	RECRUITING	Multi-omics Research of Idopathic Normal Pressure Hydrocephalus (iNPH)
NCT05397106	Not specified	ACTIVE_NOT_RECRUITING	Post Market Clinical Follow-up of CODMAN CERTAS Programmable Valve
NCT05910944	Not specified	RECRUITING	European Study of Prodromal iNPH
NCT06426004	Not specified	NOT_YET_RECRUITING	Addressing Health Disparities in Normal Pressure Hydrocephalus (NPH) in Maryland
NCT06428734	Not specified	RECRUITING	Clinical Outcome in Patients With INPH
NCT06498960	Not specified	RECRUITING	Evaluation of the Safety and Effectiveness of the CereVasc® eShunt® System in Normal Pressure Hydrocephalus
NCT06528964	Not specified	RECRUITING	Proteinopathies Expression in Skin of Neurodegenerative Disorders
NCT06722768	Not specified	RECRUITING	Identifying Gait Changes From a CSF Tap Test Using a Smart Insole in iNPH
NCT06724029	Not specified	RECRUITING	Neurosurgical Outcome Network
NCT07103681	Not specified	RECRUITING	White Matter Distortion and Dementia Biomarkers in Normal Pressure Hydrocephalus (NPH)
NCT07172841	Not specified	NOT_YET_RECRUITING	Non-invasive Diagnostics of Shunt Obstruction in Adult Hydrocephalus
NCT07427836	Not specified	RECRUITING	Integrated Multimodal Assessment to Optimize Diagnosis and Surgical Selection in Idiopathic Normal Pressure Hydrocephalus
NCT07494812	Not specified	NOT_YET_RECRUITING	Examining the Feasibility of Using Pressure Gradient Regulated Automated Cerebral Spinal Fluid Drainage During External Lumbar Drain Trials
NCT00149721	Not specified	TERMINATED	Anterior Pituitary Function in Patients With Hydrocephalus
NCT00233701	Not specified	COMPLETED	Normal Pressure Hydrocephalus (NPH) Registry
NCT00600795	Not specified	COMPLETED	Prognostic Value of Transforming Growth Factor-Beta 1 in Normal Pressure Hydrocephalus
NCT00613886	Not specified	TERMINATED	Factors Predicting Response to Shunting in Normal Pressure Hydrocephalus
NCT00727142	Not specified	TERMINATED	Conservative Versus Surgical Management of Idiopathic Normal Pressure Hydrocephalus (INPH)
NCT00874198	Not specified	UNKNOWN	European Study on Prediction of Outcome in Patients With Idiopathic Normal Pressure Hydrocephalus
NCT01265251	Not specified	COMPLETED	Computerized Neuropsychology in Idiopathic Normal Pressure Hydrocephalus (INPH)
NCT01319136	Not specified	COMPLETED	Improved Analysis Methods for Infusion Tests
NCT01374048	Not specified	COMPLETED	Intracranial Pressure Waves Via Lumbar Puncture
NCT01570257	Not specified	COMPLETED	A Trial of High and Low Pressure Level Settings on a Programmable Ventriculoperitoneal Shunt Valve for Idiopathic Normal Pressure Hydrocephalus
NCT01618500	Not specified	UNKNOWN	Computerised Testing of Cognitive Response to Cerebrospinal Fluid Shunting in Idiopathic Normal Pressure Hydrocephalus
NCT01798641	Not specified	COMPLETED	A Randomized Cross-over Study for Normal Pressure Hydrocephalus
NCT01909960	Not specified	UNKNOWN	Flow MRI in Normal Pressure Hydrocephalus
NCT02016352	Not specified	COMPLETED	Cerebrospinal Fluid Proteome in Hydrocephalus
NCT02278848	Not specified	COMPLETED	Multimodal Investigation in the Diagnosis and Treatment of Chronic Adult Hydrocephalus
NCT02495610	Not specified	COMPLETED	Novel Parameters for the Prediction of Ventriculoperitoneal Shunting Efficacy in Patients With iNPH
NCT03092804	Not specified	UNKNOWN	The Brain Structure and Neural Network Changing the Before and After Ventriculo-peritoneal Shunting in the Normal Pressure Hydrocephalus Patients
NCT03245138	Not specified	UNKNOWN	Endoscopic Third Ventriculostomy Versus Ventriculo-peritoneal Shunting in Idiopathic Normal Pressure Hydrocephalus

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ACETAZOLAMIDE	4	1
FLUTEMETAMOL	4	1