Atrial standstill 2

Summary

Atrial standstill 2 (MONDO:0014329) is a disease with 3 cohort genes.

At a glance

• Cohort genes: 3
• ClinVar variants: 9

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	atrial standstill 2
Mondo ID	MONDO:0014329
OMIM	615745
DOID	DOID:0080663
UMLS	C3810401
MedGen	816731
GARD	0018612
Is cancer (heuristic)	no

Also known as: atrial standstill 2 · atrial standstill caused by mutation in NPPA · atrial standstill type 2 · ATRST2 · NPPA atrial standstill

Data availability: 9 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › muscle tissue disorder › cardiomyopathy › intrinsic cardiomyopathy › restrictive cardiomyopathy › familial restrictive cardiomyopathy › atrial standstill › atrial standstill 2

Related subtypes (1): atrial standstill 1

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

9 retrieved; paginated sample, class counts are floors:

5 conflicting classifications of pathogenicity, 2 uncertain significance, 1 likely benign, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
67763	NM_000335.5(SCN5A):c.2893C>T (p.Arg965Cys)	LOC110121269	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
469605	NM_006172.4(NPPA):c.197C>T (p.Pro66Leu)	LOC114827827	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
126846	NM_006172.4(NPPA):c.449G>A (p.Arg150Gln)	NPPA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
944170	NM_006172.4(NPPA):c.25G>A (p.Val9Met)	NPPA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
201474	NM_000335.5(SCN5A):c.2431C>T (p.Arg811Cys)	SCN5A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
240293	NM_006172.4(NPPA):c.253G>A (p.Gly85Arg)	NPPA-AS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
948535	NM_006172.4(NPPA):c.319C>T (p.Arg107Ter)	NPPA-AS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1080824	NM_006172.4(NPPA):c.375G>A (p.Leu125=)	NPPA	Likely benign	criteria provided, multiple submitters, no conflicts
126847	NM_006172.4(NPPA):c.190A>C (p.Ser64Arg)	NPPA-AS1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 10 · 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
NPPA	Moderate	Autosomal dominant	atrial fibrillation, familial, 6	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NPPA	Orphanet:1344	Isolated atrial standstill
NPPA	Orphanet:334	Hereditary atrial fibrillation
SCN5A	Orphanet:101016	Romano-Ward syndrome
SCN5A	Orphanet:130	Brugada syndrome
SCN5A	Orphanet:1344	Isolated atrial standstill
SCN5A	Orphanet:154	Familial isolated dilated cardiomyopathy
SCN5A	Orphanet:166282	Hereditary sick sinus syndrome
SCN5A	Orphanet:228140	Idiopathic ventricular fibrillation
SCN5A	Orphanet:334	Hereditary atrial fibrillation
SCN5A	Orphanet:871	Hereditary progressive cardiac conduction defect

Cohort genes → proteins

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NPPA	HGNC:7939	ENSG00000175206	P01160	Natriuretic peptides A	gencc,clinvar
SCN5A	HGNC:10593	ENSG00000183873	Q14524	Sodium channel protein type 5 subunit alpha	clinvar
NPPA-AS1	HGNC:37635	ENSG00000242349		NPPA antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NPPA	Natriuretic peptides A	Hormone that plays a key role in mediating cardio-renal homeostasis, and is involved in vascular remodeling and regulating energy metabolism.
SCN5A	Sodium channel protein type 5 subunit alpha	Pore-forming subunit of Nav1.5, a voltage-gated sodium (Nav) channel that directly mediates the depolarizing phase of action potentials in excitable membranes.

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
Ion channel	1	37.2×	0.053
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NPPA	Other/Unknown	no		Natr_peptide, Natriuretic_peptide_atrial, Natr_peptide_CS
SCN5A	Ion channel	yes		Na_channel_asu, Ion_trans_dom, Na_channel_a5su
NPPA-AS1	Other/Unknown	no

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	1

Top tissues across cohort

Tissue	Cohort genes
cardiac atrium	1
cardiac muscle of right atrium	1
right atrium auricular region	1
apex of heart	1
cardiac ventricle	1
heart left ventricle	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NPPA	218	tissue_specific	marker	cardiac muscle of right atrium, cardiac atrium, right atrium auricular region
SCN5A	161	broad	yes	apex of heart, heart left ventricle, cardiac ventricle
NPPA-AS1		tissue_specific

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NPPA	2,701
SCN5A	2,090
NPPA-AS1	0

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SCN5A	Q14524	16
NPPA	P01160	13

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 15. 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
Cardiac conduction	2	108.8×	0.001	NPPA, SCN5A
Muscle contraction	2	77.2×	0.001	NPPA, SCN5A
YAP1- and WWTR1 (TAZ)-stimulated gene expression	1	380.7×	0.011	NPPA
Physiological factors	1	335.9×	0.011	NPPA
Interaction between L1 and Ankyrins	1	184.2×	0.014	SCN5A
Phase 0 - rapid depolarisation	1	173.0×	0.014	SCN5A
L1CAM interactions	1	60.1×	0.036	SCN5A
Amyloid fiber formation	1	51.4×	0.036	NPPA
Axon guidance	1	22.6×	0.069	SCN5A
Nervous system development	1	21.5×	0.069	SCN5A
RNA Polymerase II Transcription	1	11.3×	0.118	NPPA
Gene expression (Transcription)	1	8.9×	0.136	NPPA
Generic Transcription Pathway	1	7.5×	0.143	NPPA
Developmental Biology	1	7.2×	0.143	SCN5A
Metabolism of proteins	1	6.2×	0.155	NPPA

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 atrial cardiac muscle cell membrane repolarization	2	2407.4×	1e-05	NPPA, SCN5A
cardiac conduction system development	2	1053.2×	3e-05	NPPA, SCN5A
negative regulation of collecting lymphatic vessel constriction	1	8426.0×	0.002	NPPA
bundle of His cell action potential	1	4213.0×	0.002	SCN5A
AV node cell to bundle of His cell communication	1	4213.0×	0.002	SCN5A
response to 3-methylcholanthrene	1	4213.0×	0.002	NPPA
membrane depolarization during Purkinje myocyte cell action potential	1	2808.7×	0.002	SCN5A
membrane depolarization during bundle of His cell action potential	1	2808.7×	0.002	SCN5A
membrane depolarization during atrial cardiac muscle cell action potential	1	2808.7×	0.002	SCN5A
positive regulation of potassium ion export across plasma membrane	1	2808.7×	0.002	NPPA
AV node cell action potential	1	2106.5×	0.003	SCN5A
membrane depolarization during AV node cell action potential	1	1685.2×	0.003	SCN5A
membrane depolarization during SA node cell action potential	1	1685.2×	0.003	SCN5A
regulation of ventricular cardiac muscle cell membrane depolarization	1	1404.3×	0.003	SCN5A
SA node cell action potential	1	1404.3×	0.003	SCN5A
cardiac ventricle development	1	1203.7×	0.003	SCN5A
obsolete positive regulation of cGMP-mediated signaling	1	1203.7×	0.003	NPPA
response to denervation involved in regulation of muscle adaptation	1	1203.7×	0.003	SCN5A
negative regulation of JUN kinase activity	1	1203.7×	0.003	NPPA
cell growth involved in cardiac muscle cell development	1	1203.7×	0.003	NPPA
brainstem development	1	1053.2×	0.003	SCN5A
positive regulation of action potential	1	1053.2×	0.003	SCN5A
positive regulation of cardiac muscle contraction	1	1053.2×	0.003	NPPA
regulation of atrial cardiac muscle cell membrane depolarization	1	936.2×	0.003	SCN5A
membrane depolarization during action potential	1	842.6×	0.003	SCN5A
atrial cardiac muscle cell action potential	1	842.6×	0.003	SCN5A
regulation of calcium ion transmembrane transport via high voltage-gated calcium channel	1	842.6×	0.003	NPPA
synaptic signaling via neuropeptide	1	766.0×	0.003	NPPA
cGMP biosynthetic process	1	702.2×	0.003	NPPA
membrane depolarization during cardiac muscle cell action potential	1	702.2×	0.003	SCN5A

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · 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
SCN5A	BEPRIDIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SCN5A	108	4
NPPA	1	2
NPPA-AS1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BEPRIDIL	4	SCN5A
CANDESARTAN CILEXETIL	4	SCN5A
TELMISARTAN	4	SCN5A
CARBAMAZEPINE	4	SCN5A
DIBUCAINE	4	SCN5A
IMIPRAMINE	4	SCN5A
DROPERIDOL	4	SCN5A
PONATINIB	4	SCN5A
DULOXETINE	4	SCN5A
PALONOSETRON	4	SCN5A
VILANTEROL	4	SCN5A
MEXILETINE HYDROCHLORIDE	4	SCN5A
UNOPROSTONE ISOPROPYL	4	SCN5A
LURASIDONE	4	SCN5A
LETERMOVIR	4	SCN5A
SERTINDOLE	4	SCN5A
FEDRATINIB	4	SCN5A
QUINIDINE	4	SCN5A
DARUNAVIR	4	SCN5A
DARIFENACIN	4	SCN5A
BENZONATATE	4	SCN5A
TOLTERODINE	4	SCN5A
RANOLAZINE	4	SCN5A
PIMOZIDE	4	SCN5A
NIMODIPINE	4	SCN5A
FELODIPINE	4	SCN5A
NICARDIPINE	4	SCN5A
AMLODIPINE	4	SCN5A
PHENYTOIN	4	SCN5A
PALIPERIDONE	4	SCN5A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SCN5A	594	Binding:380, Functional:98, ADMET:72, Toxicity:43, Unclassified:1
NPPA	5	Binding:5

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
SCN5A	594

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

30 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)
BEPRIDIL	4	SCN5A
CANDESARTAN CILEXETIL	4	SCN5A
TELMISARTAN	4	SCN5A
CARBAMAZEPINE	4	SCN5A
DIBUCAINE	4	SCN5A
IMIPRAMINE	4	SCN5A
DROPERIDOL	4	SCN5A
PONATINIB	4	SCN5A
DULOXETINE	4	SCN5A
PALONOSETRON	4	SCN5A
VILANTEROL	4	SCN5A
MEXILETINE HYDROCHLORIDE	4	SCN5A
UNOPROSTONE ISOPROPYL	4	SCN5A
LURASIDONE	4	SCN5A
LETERMOVIR	4	SCN5A
SERTINDOLE	4	SCN5A
FEDRATINIB	4	SCN5A
QUINIDINE	4	SCN5A
DARUNAVIR	4	SCN5A
DARIFENACIN	4	SCN5A
BENZONATATE	4	SCN5A
TOLTERODINE	4	SCN5A
RANOLAZINE	4	SCN5A
PIMOZIDE	4	SCN5A
NIMODIPINE	4	SCN5A
FELODIPINE	4	SCN5A
NICARDIPINE	4	SCN5A
AMLODIPINE	4	SCN5A
PHENYTOIN	4	SCN5A
PALIPERIDONE	4	SCN5A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	SCN5A
B	Phased (≥1) drug, not yet approved	1	NPPA
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	NPPA-AS1

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)
NPPA-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.