Atrial fibrillation, familial, 4

Summary

Atrial fibrillation, familial, 4 (MONDO:0012677) is a disease with 1 cohort gene.

At a glance

• Cohort genes: 1
• ClinVar variants: 31

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	atrial fibrillation, familial, 4
Mondo ID	MONDO:0012677
MeSH	C566244
OMIM	611493
UMLS	C1862394
MedGen	400041
GARD	0015516
Is cancer (heuristic)	no

Also known as: ATFB4 · atrial fibrillation, familial, 4 · atrial fibrillation, familial, type 4 · familial atrial fibrillation caused by mutation in KCNE2 · KCNE2 familial atrial fibrillation

Data availability: 31 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by body system or component › cardiovascular disorder › heart disorder › cardiac rhythm disease › atrial fibrillation › familial atrial fibrillation › atrial fibrillation, familial, 4

Related subtypes (17): atrial fibrillation, familial, 3, atrial fibrillation, familial, 1, atrial fibrillation, familial, 2, atrial fibrillation, familial, 5, atrial fibrillation, familial, 6, atrial fibrillation, familial, 7, atrial fibrillation, familial, 8, atrial fibrillation, familial, 9, atrial fibrillation, familial, 10, atrial fibrillation, familial, 11, atrial fibrillation, familial, 12, atrial fibrillation, familial, 13, atrial fibrillation, familial, 14, atrial fibrillation, familial, 15, atrial fibrillation, familial, 18, atrial fibrillation, familial, 17, atrial fibrillation, familial, 16

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

31 retrieved; paginated sample, class counts are floors:

14 uncertain significance, 13 conflicting classifications of pathogenicity, 3 benign/likely benign, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
190792	NM_172201.2(KCNE2):c.354G>A (p.Gly118=)	KCNE2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
339714	NM_172201.2(KCNE2):c.-85G>A	KCNE2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
538876	NM_172201.2(KCNE2):c.204G>A (p.Leu68=)	KCNE2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
6054	NM_172201.2(KCNE2):c.170T>C (p.Ile57Thr)	KCNE2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
6055	NM_172201.2(KCNE2):c.79C>T (p.Arg27Cys)	KCNE2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
898249	NM_172201.2(KCNE2):c.*11A>C	KCNE2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1390131	NM_172201.2(KCNE2):c.346G>A (p.Ala116Thr)	LOC105372791	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1475863	NM_172201.2(KCNE2):c.144dup (p.Val49fs)	LOC105372791	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
190797	NM_172201.2(KCNE2):c.369_370del (p.Ter124IleextTer?)	LOC105372791	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
339718	NM_172201.2(KCNE2):c.153G>T (p.Leu51=)	LOC105372791	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
339719	NM_172201.2(KCNE2):c.*62G>A	LOC105372791	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
67614	NM_172201.2(KCNE2):c.229C>T (p.Arg77Trp)	LOC105372791	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
67623	NM_172201.2(KCNE2):c.80G>A (p.Arg27His)	LOC105372791	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
190793	NM_172201.2(KCNE2):c.-13+5G>A	KCNE2	Uncertain significance	criteria provided, multiple submitters, no conflicts
339715	NM_172201.2(KCNE2):c.-80C>T	KCNE2	Uncertain significance	criteria provided, single submitter
339720	NM_172201.2(KCNE2):c.*240G>C	KCNE2	Uncertain significance	criteria provided, single submitter
3587668	NM_172201.2(KCNE2):c.58A>G (p.Ile20Val)	KCNE2	Uncertain significance	criteria provided, single submitter
560697	NM_172201.2(KCNE2):c.67A>T (p.Met23Leu)	KCNE2	Uncertain significance	criteria provided, multiple submitters, no conflicts
67612	NM_172201.2(KCNE2):c.193G>C (p.Val65Leu)	KCNE2	Uncertain significance	criteria provided, multiple submitters, no conflicts
895204	NM_172201.2(KCNE2):c.17A>G (p.Asn6Ser)	KCNE2	Uncertain significance	criteria provided, multiple submitters, no conflicts
898248	NM_172201.2(KCNE2):c.178T>A (p.Phe60Ile)	KCNE2	Uncertain significance	criteria provided, single submitter
898250	NM_172201.2(KCNE2):c.*61C>T	KCNE2	Uncertain significance	criteria provided, single submitter
899357	NM_172201.2(KCNE2):c.*234G>A	KCNE2	Uncertain significance	criteria provided, multiple submitters, no conflicts
956020	NM_172201.2(KCNE2):c.242A>G (p.Asn81Ser)	KCNE2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1217300	NM_172201.2(KCNE2):c.13T>C (p.Ser5Pro)	LOC105372791	Uncertain significance	criteria provided, multiple submitters, no conflicts
339713	NM_172201.2(KCNE2):c.-121C>T	LOC105372791	Uncertain significance	criteria provided, single submitter
659161	NM_172201.2(KCNE2):c.2T>C (p.Met1Thr)	LOC105372791	Uncertain significance	criteria provided, multiple submitters, no conflicts
1107314	NM_172201.2(KCNE2):c.228A>G (p.Arg76=)	KCNE2	Likely benign	criteria provided, multiple submitters, no conflicts
339716	NM_172201.2(KCNE2):c.-79G>A	KCNE2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
6052	NM_172201.2(KCNE2):c.25C>G (p.Gln9Glu)	KCNE2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KCNE2	Orphanet:101016	Romano-Ward syndrome
KCNE2	Orphanet:334	Hereditary atrial fibrillation

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
KCNE2	HGNC:6242	ENSG00000159197	Q9Y6J6	Potassium voltage-gated channel subfamily E member 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KCNE2	Potassium voltage-gated channel subfamily E member 2	Ancillary protein that functions as a regulatory subunit of the voltage-gated potassium (Kv) channel complex composed of pore-forming and potassium-conducting alpha subunits and of regulatory beta subunits.

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)
KCNE2	Ion channel	yes		K_chnl_KCNE, K_chnl_volt-dep_bsu_KCNE2

Expression context

Cohort genes with no expression data: 0.

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
body of stomach	1
cardia of stomach	1
pylorus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KCNE2	161	tissue_specific	yes	body of stomach, pylorus, cardia of stomach

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KCNE2	749

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KCNE2	Q9Y6J6	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. 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
Phase 3 - rapid repolarisation	1	1142.0×	0.003	KCNE2
Phase 2 - plateau phase	1	761.3×	0.003	KCNE2
Cardiac conduction	1	108.8×	0.012	KCNE2
Muscle contraction	1	77.2×	0.013	KCNE2

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
negative regulation of delayed rectifier potassium channel activity	1	2808.7×	0.002	KCNE2
membrane repolarization during action potential	1	1685.2×	0.002	KCNE2
membrane repolarization during ventricular cardiac muscle cell action potential	1	1685.2×	0.002	KCNE2
regulation of membrane repolarization	1	1296.3×	0.002	KCNE2
membrane repolarization	1	1296.3×	0.002	KCNE2
potassium ion export across plasma membrane	1	1053.2×	0.002	KCNE2
ventricular cardiac muscle cell action potential	1	991.3×	0.002	KCNE2
positive regulation of proteasomal protein catabolic process	1	991.3×	0.002	KCNE2
regulation of ventricular cardiac muscle cell membrane repolarization	1	842.6×	0.002	KCNE2
cardiac muscle cell action potential involved in contraction	1	702.2×	0.002	KCNE2
regulation of potassium ion transmembrane transport	1	624.1×	0.002	KCNE2
regulation of heart rate by cardiac conduction	1	374.5×	0.003	KCNE2
potassium ion import across plasma membrane	1	366.4×	0.003	KCNE2
cellular response to xenobiotic stimulus	1	240.7×	0.004	KCNE2
potassium ion transmembrane transport	1	135.9×	0.007	KCNE2

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KCNE2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

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	1	KCNE2
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
KCNE2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.