Sick sinus syndrome 2, autosomal dominant

Summary

Sick sinus syndrome 2, autosomal dominant (MONDO:0008102) is a disease caused by HCN4 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: HCN4 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 183

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	sick sinus syndrome 2, autosomal dominant
Mondo ID	MONDO:0008102
MeSH	C563513
OMIM	163800
UMLS	C1834144
MedGen	320273
GARD	0018284
Is cancer (heuristic)	no

Also known as: HCN4 sick sinus syndrome · sick sinus syndrome 2, autosomal dominant · sick sinus syndrome caused by mutation in HCN4 · SSS2

Data availability: 183 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › cardiovascular disorder › heart disorder › heart conduction disease › sinoatrial node disorder › sick sinus syndrome › familial sick sinus syndrome › sick sinus syndrome 2, autosomal dominant

Related subtypes (3): sinus node disease and myopia, sick sinus syndrome 1, sick sinus syndrome 4

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

183 retrieved; paginated sample, class counts are floors:

113 uncertain significance, 25 benign, 21 conflicting classifications of pathogenicity, 11 benign/likely benign, 6 pathogenic, 5 likely benign, 1 pathogenic/likely pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
374858	NM_005477.3(HCN4):c.1920_1932dup (p.Lys645fs)	HCN4	Pathogenic	no assertion criteria provided
374859	NM_005477.3(HCN4):c.1444G>C (p.Gly482Arg)	HCN4	Pathogenic	criteria provided, single submitter
374860	NM_005477.3(HCN4):c.1441T>C (p.Tyr481His)	HCN4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
374861	NM_005477.3(HCN4):c.1241C>G (p.Ala414Gly)	HCN4	Pathogenic	no assertion criteria provided
5173	NM_005477.3(HCN4):c.2016C>A (p.Ser672Arg)	HCN4	Pathogenic	no assertion criteria provided
5174	NM_005477.3(HCN4):c.1631del (p.Pro544fs)	HCN4	Pathogenic	no assertion criteria provided
5176	NM_005477.3(HCN4):c.1438G>C (p.Gly480Arg)	HCN4	Pathogenic	no assertion criteria provided
4755562	NM_005477.3(HCN4):c.1591-1861_2867del	HCN4	Likely pathogenic	criteria provided, single submitter
167170	NM_005477.3(HCN4):c.2739G>A (p.Ala913=)	HCN4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
180370	NM_005477.3(HCN4):c.458A>G (p.Glu153Gly)	HCN4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
190772	NM_005477.3(HCN4):c.2275G>A (p.Val759Ile)	HCN4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
190779	NM_005477.3(HCN4):c.1132C>T (p.Arg378Cys)	HCN4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
190786	NM_005477.3(HCN4):c.418G>A (p.Gly140Ser)	HCN4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
190788	NM_005477.3(HCN4):c.584C>T (p.Ala195Val)	HCN4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
222648	NM_005477.3(HCN4):c.2197G>A (p.Val733Ile)	HCN4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
240167	NM_005477.3(HCN4):c.2938G>A (p.Gly980Arg)	HCN4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
286612	NM_005477.3(HCN4):c.1356C>T (p.Ser452=)	HCN4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
404120	NM_005477.3(HCN4):c.2701G>A (p.Ala901Thr)	HCN4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
404125	NM_005477.3(HCN4):c.302C>T (p.Ala101Val)	HCN4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
412788	NM_005477.3(HCN4):c.1243G>A (p.Val415Met)	HCN4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
470667	NM_005477.3(HCN4):c.3379G>A (p.Gly1127Arg)	HCN4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
499412	NM_005477.3(HCN4):c.2025C>T (p.Ala675=)	HCN4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
511427	NM_005477.3(HCN4):c.249C>T (p.Gly83=)	HCN4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
580858	NM_005477.3(HCN4):c.3130C>T (p.Arg1044Trp)	HCN4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
701735	NM_005477.3(HCN4):c.2845C>T (p.Arg949Trp)	HCN4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
885696	NM_005477.3(HCN4):c.522G>A (p.Pro174=)	HCN4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
885697	NM_005477.3(HCN4):c.375C>T (p.Ser125=)	HCN4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
886650	NM_005477.3(HCN4):c.3081C>T (p.Pro1027=)	HCN4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
887844	NM_005477.3(HCN4):c.*1085A>C	HCN4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1007466	NM_005477.3(HCN4):c.1987C>A (p.Leu663Met)	HCN4	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 8 · 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
HCN4	Strong	Autosomal dominant	sick sinus syndrome 2, autosomal dominant	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HCN4	Orphanet:130	Brugada syndrome
HCN4	Orphanet:166282	Hereditary sick sinus syndrome
SDHA	Orphanet:139411	Carney triad
SDHA	Orphanet:154	Familial isolated dilated cardiomyopathy
SDHA	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
SDHA	Orphanet:3208	Isolated succinate-CoQ reductase deficiency
SDHA	Orphanet:44890	Gastrointestinal stromal tumor
SDHA	Orphanet:97286	Carney-Stratakis syndrome

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
HCN4	HGNC:16882	ENSG00000138622	Q9Y3Q4	Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4	gencc,clinvar
SDHA	HGNC:10680	ENSG00000073578	P31040	Succinate dehydrogenase [ubiquinone] flavoprotein subunit, mitochondrial	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.
SDHA	Succinate dehydrogenase [ubiquinone] flavoprotein subunit, mitochondrial	Flavoprotein (FP) subunit of succinate dehydrogenase (SDH) that is involved in complex II of the mitochondrial electron transport chain and is responsible for transferring electrons from succinate to ubiquinone (coenzyme Q).

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · 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
Ion channel	1	55.8×	0.036
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HCN4	Ion channel	yes		cNMP-bd_dom, K_chnl_volt-dep_EAG/ELK/ERG, Ion_trans_dom
SDHA	Other/Unknown	no		FRD_SDH_FAD_BS, FAD-dep_OxRdtase_2_FAD-bd, Succ_DH_flav_su_fwd

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	0

Top tissues across cohort

Tissue	Cohort genes
cardiac atrium	1
right atrium auricular region	1
tibialis anterior	1
apex of heart	1
heart left ventricle	1
mucosa of transverse colon	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HCN4	86	tissue_specific	yes	tibialis anterior, right atrium auricular region, cardiac atrium
SDHA	143	ubiquitous	marker	apex of heart, heart left ventricle, mucosa of transverse colon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SDHA	6,141
HCN4	1,279

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HCN4	Q9Y3Q4	8
SDHA	P31040	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. 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
HCN channels	1	1427.5×	0.004	HCN4
Maturation of TCA enzymes and regulation of TCA cycle	1	285.5×	0.009	SDHA
Citric acid cycle (TCA cycle)	1	211.5×	0.009	SDHA
Respiratory electron transport	1	47.6×	0.027	SDHA
Aerobic respiration and respiratory electron transport	1	44.3×	0.027	SDHA
Metabolism	1	5.8×	0.165	SDHA

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
succinate metabolic process	1	1685.2×	0.003	SDHA
mitochondrial electron transport, succinate to ubiquinone	1	1685.2×	0.003	SDHA
membrane depolarization during SA node cell action potential	1	1685.2×	0.003	HCN4
SA node cell action potential	1	1404.3×	0.003	HCN4
regulation of SA node cell action potential	1	1404.3×	0.003	HCN4
sinoatrial node development	1	1053.2×	0.003	HCN4
cellular response to cGMP	1	1053.2×	0.003	HCN4
regulation of membrane depolarization	1	936.2×	0.003	HCN4
regulation of cardiac muscle cell action potential involved in regulation of contraction	1	936.2×	0.003	HCN4
membrane depolarization during cardiac muscle cell action potential	1	702.2×	0.004	HCN4
regulation of cardiac muscle contraction	1	443.5×	0.005	HCN4
respiratory electron transport chain	1	421.3×	0.005	SDHA
monoatomic cation transport	1	383.0×	0.005	HCN4
sodium ion import across plasma membrane	1	312.1×	0.006	HCN4
tricarboxylic acid cycle	1	255.3×	0.006	SDHA
blood circulation	1	255.3×	0.006	HCN4
regulation of heart rate	1	234.1×	0.007	HCN4
regulation of heart rate by cardiac conduction	1	187.2×	0.007	HCN4
potassium ion import across plasma membrane	1	183.2×	0.007	HCN4
cellular response to cAMP	1	145.3×	0.009	HCN4
proton motive force-driven mitochondrial ATP synthesis	1	131.7×	0.009	SDHA
regulation of membrane potential	1	115.4×	0.010	HCN4
muscle contraction	1	104.0×	0.011	HCN4
sodium ion transmembrane transport	1	101.5×	0.011	HCN4
potassium ion transmembrane transport	1	68.0×	0.015	HCN4
nervous system development	1	23.0×	0.043	SDHA

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 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
HCN4	IVABRADINE
SDHA	LINEZOLID

Top cohort targets by molecule count

Symbol	Molecules	Max phase
HCN4	2	4
SDHA	1	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
IVABRADINE	4	HCN4
LINEZOLID	4	SDHA
ZATEBRADINE	2	HCN4

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
HCN4	30	Binding:20, ADMET:5, Functional:4, Toxicity:1
SDHA	3	Binding:3

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

3 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)
IVABRADINE	4	HCN4
LINEZOLID	4	SDHA
ZATEBRADINE	2	HCN4

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	HCN4, SDHA
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: 0.