Sinoatrial node disorder

Summary

Sinoatrial node disorder (MONDO:0000469) is a disease with 3 cohort genes (3 GWAS associations across 5 studies).

At a glance

• Cohort genes: 3
• GWAS associations: 3
• ClinVar variants: 4

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	sinoatrial node disorder
Mondo ID	MONDO:0000469
DOID	DOID:0050824
UMLS	C0428908
MedGen	98448
Anatomy (UBERON)	UBERON:0002351
Is cancer (heuristic)	no

Also known as: disease of sinoatrial node · disease or disorder of sinoatrial node · disorder of sinoatrial node · sinoatrial node disease · sinoatrial node disease or disorder

Data availability: 4 ClinVar variants · 3 GWAS associations (5 studies).

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by body system or component › cardiovascular disorder › heart disorder › heart conduction disease › sinoatrial node disorder

Related subtypes (9): short QT syndrome, atrioventricular block, Wolff-Parkinson-White syndrome, postural orthostatic tachycardia syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, progressive familial heart block, sinoatrial block, NKX2.5-related congenital, conduction and myopathic heart disease

Subtypes (1): sick sinus syndrome

Genetics & variants

GWAS landscape

3 GWAS associations across 5 studies. Top hits map to 1 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs1906618	1e-17	PITX2 - LINC01438	A	0.21
chr4:111669220	5e-17		T	0.19
rs560163526	1e-11	RFX4	G	2.97

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90475980	Verma A	2024	6,431	439,404	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90477950	Verma A	2024	695	120,312	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90480179	Verma A	2024	695	120,312	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90436125	Zhou W	2018	403	380,919	Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies.
GCST90482005	Verma A	2024	380	59,126	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.

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	0
Tier 4: intronic/intergenic	3

MAF distribution

Bucket	Variants
common (>=0.05)	2
low_freq (0.01-0.05)	0
rare (<0.01)	1
unknown	0

Functional consequences

Consequence	Count
intergenic_variant	1
unknown	1
intron_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs1906618	4	110774266	A>G	0.142	intergenic_variant	PITX2 - LINC01438	1e-17	Tier 4: intronic/intergenic
chr4:111669220				0.204			5e-17	Tier 4: intronic/intergenic
rs560163526	12	106622768	G>A,C	0	intron_variant	RFX4	1e-11	Tier 4: intronic/intergenic

ClinVar germline variants

4 retrieved; paginated sample, class counts are floors:

1 likely pathogenic, 1 pathogenic, 1 uncertain significance, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
179829	NM_000335.5(SCN5A):c.1936del (p.Gln646fs)	SCN5A	Pathogenic	criteria provided, multiple submitters, no conflicts
9377	NM_000335.5(SCN5A):c.5347G>A (p.Glu1783Lys)	SCN5A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1679822	NM_007074.4(CORO1A):c.189_190dup (p.Leu64fs)	CORO1A	Likely pathogenic	no assertion criteria provided
191377	NM_005477.3(HCN4):c.3502_3505del (p.Phe1168fs)	HCN4	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 11 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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
HCN4	Orphanet:130	Brugada syndrome
HCN4	Orphanet:166282	Hereditary sick sinus syndrome
CORO1A	Orphanet:228003	Severe combined immunodeficiency due to CORO1A deficiency

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SCN5A	HGNC:10593	ENSG00000183873	Q14524	Sodium channel protein type 5 subunit alpha	clinvar
HCN4	HGNC:16882	ENSG00000138622	Q9Y3Q4	Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4	clinvar
CORO1A	HGNC:2252	ENSG00000102879	P31146	Coronin-1A	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.
HCN4	Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4	Hyperpolarization-activated ion channel that are permeable to Na(+) and K(+) ions with very slow activation and inactivation.
CORO1A	Coronin-1A	May be a crucial component of the cytoskeleton of highly motile cells, functioning both in the invagination of large pieces of plasma membrane, as well as in forming protrusions of the plasma membrane involved in cell locomotion.

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.67

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	2	74.3×	5e-04
Scaffold/PPI	1	5.8×	0.164

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SCN5A	Ion channel	yes		Na_channel_asu, Ion_trans_dom, Na_channel_a5su
HCN4	Ion channel	yes		cNMP-bd_dom, K_chnl_volt-dep_EAG/ELK/ERG, Ion_trans_dom
CORO1A	Scaffold/PPI	no		WD40_rpt, DUF1899, Trimer_CC

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	1
cardiac ventricle	1
heart left ventricle	1
cardiac atrium	1
right atrium auricular region	1
tibialis anterior	1
granulocyte	1
leukocyte	1
monocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SCN5A	161	broad	yes	apex of heart, heart left ventricle, cardiac ventricle
HCN4	86	tissue_specific	yes	tibialis anterior, right atrium auricular region, cardiac atrium
CORO1A	252	ubiquitous	marker	granulocyte, monocyte, leukocyte

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CORO1A	3,620
SCN5A	2,090
HCN4	1,279

Intra-cohort edges

A	B	Sources
HCN4	SCN5A	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SCN5A	Q14524	16
HCN4	Q9Y3Q4	8

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CORO1A	P31146	93.25

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
HCN channels	1	951.7×	0.011	HCN4
Prevention of phagosomal-lysosomal fusion	1	423.0×	0.012	CORO1A
Interaction between L1 and Ankyrins	1	122.8×	0.022	SCN5A
Phase 0 - rapid depolarisation	1	115.3×	0.022	SCN5A
L1CAM interactions	1	40.1×	0.046	SCN5A
Cardiac conduction	1	36.2×	0.046	SCN5A
Muscle contraction	1	25.7×	0.055	SCN5A
Axon guidance	1	15.1×	0.076	SCN5A
Nervous system development	1	14.3×	0.076	SCN5A
Developmental Biology	1	4.8×	0.194	SCN5A

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
membrane depolarization during SA node cell action potential	2	2246.9×	1e-05	SCN5A, HCN4
SA node cell action potential	2	1872.4×	1e-05	SCN5A, HCN4
membrane depolarization during cardiac muscle cell action potential	2	936.2×	4e-05	SCN5A, HCN4
regulation of heart rate	2	312.1×	3e-04	SCN5A, HCN4
regulation of heart rate by cardiac conduction	2	249.7×	3e-04	SCN5A, HCN4
sodium ion transmembrane transport	2	135.4×	1e-03	SCN5A, HCN4
negative regulation of vesicle fusion	1	2808.7×	0.003	CORO1A
uropod organization	1	2808.7×	0.003	CORO1A
negative regulation of actin nucleation	1	2808.7×	0.003	CORO1A
bundle of His cell action potential	1	2808.7×	0.003	SCN5A
AV node cell to bundle of His cell communication	1	2808.7×	0.003	SCN5A
thymocyte migration	1	1872.4×	0.003	CORO1A
membrane depolarization during Purkinje myocyte cell action potential	1	1872.4×	0.003	SCN5A
membrane depolarization during bundle of His cell action potential	1	1872.4×	0.003	SCN5A
membrane depolarization during atrial cardiac muscle cell action potential	1	1872.4×	0.003	SCN5A
AV node cell action potential	1	1404.3×	0.004	SCN5A
phagolysosome assembly	1	1123.5×	0.004	CORO1A
obsolete early endosome to recycling endosome transport	1	1123.5×	0.004	CORO1A
membrane depolarization during AV node cell action potential	1	1123.5×	0.004	SCN5A
regulation of ventricular cardiac muscle cell membrane depolarization	1	936.2×	0.004	SCN5A
regulation of SA node cell action potential	1	936.2×	0.004	HCN4
cardiac ventricle development	1	802.5×	0.004	SCN5A
response to denervation involved in regulation of muscle adaptation	1	802.5×	0.004	SCN5A
natural killer cell degranulation	1	802.5×	0.004	CORO1A
regulation of atrial cardiac muscle cell membrane repolarization	1	802.5×	0.004	SCN5A
sinoatrial node development	1	702.2×	0.004	HCN4
brainstem development	1	702.2×	0.004	SCN5A
positive regulation of action potential	1	702.2×	0.004	SCN5A
cellular response to cGMP	1	702.2×	0.004	HCN4
regulation of membrane depolarization	1	624.1×	0.004	HCN4

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 3 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
SCN5A	BEPRIDIL
HCN4	IVABRADINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SCN5A	108	4
HCN4	2	4
CORO1A	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
HCN4	30	Binding:20, ADMET:5, Functional:4, Toxicity:1
CORO1A	12	Binding:12

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)	2	SCN5A, HCN4
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	1	CORO1A

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)
CORO1A	12	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.