Pulmonary hypertension, primary, 4

Summary

Pulmonary hypertension, primary, 4 (MONDO:0014136) is a disease caused by KCNK3 (GenCC Strong), with 1 cohort gene and 3 clinical trials. Top therapeutic interventions include spironolactone.

At a glance

• Causal gene: KCNK3 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 229
• Clinical trials: 3

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	pulmonary hypertension, primary, 4
Mondo ID	MONDO:0014136
OMIM	615344
UMLS	C3809198
MedGen	815528
GARD	0024974
Is cancer (heuristic)	no

Also known as: KCNK3 primary pulmonary hypertension · PPH4 · primary pulmonary hypertension caused by mutation in KCNK3 · pulmonary hypertension, primary, 4 · pulmonary hypertension, primary, type 4

Data availability: 229 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › heritable pulmonary arterial hypertension › pulmonary hypertension, primary, 4

Related subtypes (6): pulmonary hypertension, primary, 5, pulmonary hypertension, primary, 2, pulmonary hypertension, primary, 3, pulmonary hypertension, primary, 1, pulmonary hypertension, primary, 6, pulmonary hypertension, primary, 7

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

229 retrieved; paginated sample, class counts are floors:

123 uncertain significance, 89 likely benign, 5 pathogenic, 5 conflicting classifications of pathogenicity, 4 benign, 2 likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
2446440	NM_002246.3(KCNK3):c.607G>C (p.Gly203Arg)	KCNK3	Pathogenic	no assertion criteria provided
426049	NM_002246.3(KCNK3):c.23C>A (p.Thr8Lys)	KCNK3	Pathogenic	no assertion criteria provided
60479	NM_002246.3(KCNK3):c.608G>A (p.Gly203Asp)	KCNK3	Pathogenic	criteria provided, single submitter
60481	NM_002246.3(KCNK3):c.661G>C (p.Val221Leu)	KCNK3	Pathogenic	no assertion criteria provided
60483	NM_002246.3(KCNK3):c.575A>G (p.Tyr192Cys)	KCNK3	Pathogenic	no assertion criteria provided
548009	NM_002246.3(KCNK3):c.365T>C (p.Leu122Pro)	KCNK3	Likely pathogenic	criteria provided, single submitter
60482	NM_002246.3(KCNK3):c.544G>A (p.Glu182Lys)	KCNK3	Likely pathogenic	criteria provided, single submitter
3586258	NM_002246.3(KCNK3):c.690G>A (p.Thr230=)	KCNK3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
569441	NM_002246.3(KCNK3):c.953G>A (p.Arg318His)	KCNK3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
60480	NM_002246.3(KCNK3):c.289G>A (p.Gly97Arg)	KCNK3	Conflicting classifications of pathogenicity	no assertion criteria provided
648112	NM_002246.3(KCNK3):c.618G>A (p.Val206=)	KCNK3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
811685	NM_002246.3(KCNK3):c.1097C>T (p.Ala366Val)	KCNK3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1002871	NM_002246.3(KCNK3):c.946A>G (p.Lys316Glu)	KCNK3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1006500	NM_002246.3(KCNK3):c.1094G>A (p.Gly365Glu)	KCNK3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1013806	NM_002246.3(KCNK3):c.991C>T (p.Arg331Trp)	KCNK3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1018829	NM_002246.3(KCNK3):c.28G>A (p.Ala10Thr)	KCNK3	Uncertain significance	criteria provided, single submitter
1023521	NM_002246.3(KCNK3):c.1162A>G (p.Met388Val)	KCNK3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1348771	NM_002246.3(KCNK3):c.1067C>G (p.Thr356Arg)	KCNK3	Uncertain significance	criteria provided, single submitter
1349028	NM_002246.3(KCNK3):c.925A>G (p.Met309Val)	KCNK3	Uncertain significance	criteria provided, single submitter
1354423	NM_002246.3(KCNK3):c.826G>A (p.Gly276Ser)	KCNK3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1376424	NM_002246.3(KCNK3):c.973A>G (p.Ile325Val)	KCNK3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1390001	NM_002246.3(KCNK3):c.1147A>G (p.Thr383Ala)	KCNK3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1393826	NM_002246.3(KCNK3):c.1093G>A (p.Gly365Arg)	KCNK3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1397431	NM_002246.3(KCNK3):c.167A>T (p.Gln56Leu)	KCNK3	Uncertain significance	criteria provided, single submitter
1404432	NM_002246.3(KCNK3):c.894C>A (p.Asn298Lys)	KCNK3	Uncertain significance	criteria provided, single submitter
1414198	NM_002246.3(KCNK3):c.802G>C (p.Gly268Arg)	KCNK3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1427737	NM_002246.3(KCNK3):c.488G>A (p.Gly163Asp)	KCNK3	Uncertain significance	criteria provided, single submitter
1442653	NM_002246.3(KCNK3):c.824G>A (p.Gly275Glu)	KCNK3	Uncertain significance	criteria provided, single submitter
1473962	NM_002246.3(KCNK3):c.877G>A (p.Gly293Ser)	KCNK3	Uncertain significance	criteria provided, single submitter
1475267	NM_002246.3(KCNK3):c.425G>A (p.Arg142His)	KCNK3	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
KCNK3	Definitive	Autosomal dominant	pulmonary arterial hypertension	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KCNK3	Orphanet:275777	Heritable pulmonary arterial hypertension

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
KCNK3	HGNC:6278	ENSG00000171303	O14649	Potassium channel subfamily K member 3	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KCNK3	Potassium channel subfamily K member 3	K(+) channel that conducts voltage-dependent outward rectifying currents upon membrane depolarization.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Ion channel	1	111.5×	0.009

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KCNK3	Ion channel	yes		2pore_dom_K_chnl_TASK, 2pore_dom_K_chnl, KCNK3

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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adrenal cortex	1
left adrenal gland	1
left adrenal gland cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KCNK3	203	broad	marker	left adrenal gland, adrenal cortex, left adrenal gland cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KCNK3	934

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KCNK3	O14649	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 1 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
TWIK-releated acid-sensitive K+ channel (TASK)	1	5710.0×	0.001	KCNK3
Tandem pore domain potassium channels	1	951.7×	0.004	KCNK3
Phase 4 - resting membrane potential	1	601.0×	0.004	KCNK3
Potassium Channels	1	134.3×	0.013	KCNK3
Cardiac conduction	1	108.8×	0.013	KCNK3
Muscle contraction	1	77.2×	0.015	KCNK3
Neuronal System	1	44.3×	0.023	KCNK3

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
detection of hypoxic conditions in blood by carotid body chemoreceptor signaling	1	8426.0×	0.001	KCNK3
regulation of action potential firing rate	1	5617.3×	0.001	KCNK3
negative regulation of cytosolic calcium ion concentration	1	1296.3×	0.003	KCNK3
regulation of resting membrane potential	1	1296.3×	0.003	KCNK3
cellular response to acidic pH	1	732.7×	0.003	KCNK3
cellular response to zinc ion	1	674.1×	0.003	KCNK3
cochlea development	1	468.1×	0.004	KCNK3
monoatomic ion transmembrane transport	1	208.1×	0.008	KCNK3
potassium ion transport	1	191.5×	0.008	KCNK3
potassium ion transmembrane transport	1	135.9×	0.010	KCNK3
cellular response to hypoxia	1	121.2×	0.010	KCNK3
chemical synaptic transmission	1	77.3×	0.014	KCNK3
response to xenobiotic stimulus	1	69.1×	0.014	KCNK3

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 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
KCNK3	ROPIVACAINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KCNK3	6	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ROPIVACAINE	4	KCNK3
BUPIVACAINE	4	KCNK3
ETIDOCAINE	4	KCNK3
MEXILETINE	4	KCNK3
PROPAFENONE	4	KCNK3
BAFREKALANT	2	KCNK3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
KCNK3	39	Binding:38, Functional:1

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

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)
ROPIVACAINE	4	KCNK3
BUPIVACAINE	4	KCNK3
ETIDOCAINE	4	KCNK3
MEXILETINE	4	KCNK3
PROPAFENONE	4	KCNK3
BAFREKALANT	2	KCNK3

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	KCNK3
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: 3.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2
PHASE4	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03344159	PHASE4	COMPLETED	Spironolactone Therapy in Chronic Stable Right HF Trial
NCT04808596	Not specified	RECRUITING	Pulmonary Hypertension Biorepository and Registry
NCT04472533	Not specified	COMPLETED	Serum Bio-markers in Pulmonary Hypertension

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
SPIRONOLACTONE	4	1
CHEMBL1562223	0	1
CHEMBL30458	0	1