Atrial fibrillation, familial, 18

Summary

Atrial fibrillation, familial, 18 (MONDO:0015001) is a disease caused by MYL4 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: MYL4 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 268

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	atrial fibrillation, familial, 18
Mondo ID	MONDO:0015001
OMIM	617280
UMLS	C4310636
MedGen	934603
GARD	0016219
Is cancer (heuristic)	no

Also known as: ATFB18 · atrial fibrillation, familial, 18 · atrial fibrillation, familial, 18; ATFB18 · atrial fibrillation, familial, type 18 · familial atrial fibrillation caused by mutation in MYL4 · MYL4 familial atrial fibrillation

Data availability: 268 ClinVar variants · 1 GenCC gene-disease record.

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, 18

Related subtypes (17): atrial fibrillation, familial, 3, atrial fibrillation, familial, 1, atrial fibrillation, familial, 2, atrial fibrillation, familial, 4, 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, 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

268 retrieved; paginated sample, class counts are floors:

146 uncertain significance, 96 likely benign, 10 likely pathogenic, 6 benign, 6 pathogenic, 2 conflicting classifications of pathogenicity, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
2053340	NM_002476.2(MYL4):c.532C>T (p.Gln178Ter)	MYL4	Pathogenic	criteria provided, single submitter
2165639	NM_002476.2(MYL4):c.361C>T (p.Gln121Ter)	MYL4	Pathogenic	criteria provided, single submitter
224067	NM_002476.2(MYL4):c.31G>A (p.Glu11Lys)	MYL4	Pathogenic	criteria provided, single submitter
3243111	NC_000017.10:g.(?45291145)(45291212_?)del	MYL4	Pathogenic	criteria provided, single submitter
3656250	NM_002476.2(MYL4):c.187_190del (p.Phe63fs)	MYL4	Pathogenic	criteria provided, single submitter
3725515	NM_002476.2(MYL4):c.455del (p.Gly152fs)	MYL4	Pathogenic	criteria provided, single submitter
1474944	NM_002476.2(MYL4):c.487+1G>A	MYL4	Likely pathogenic	criteria provided, single submitter
2052621	NM_002476.2(MYL4):c.314-1G>C	MYL4	Likely pathogenic	criteria provided, single submitter
2090713	NM_002476.2(MYL4):c.313+1G>T	MYL4	Likely pathogenic	criteria provided, single submitter
2147045	NM_002476.2(MYL4):c.135+1G>A	MYL4	Likely pathogenic	criteria provided, single submitter
3020997	NM_002476.2(MYL4):c.164-1G>C	MYL4	Likely pathogenic	criteria provided, single submitter
3366361	NM_002476.2(MYL4):c.234C>A (p.Cys78Ter)	MYL4	Likely pathogenic	criteria provided, single submitter
3630172	NM_002476.2(MYL4):c.163+1G>A	MYL4	Likely pathogenic	criteria provided, single submitter
4728001	NM_002476.2(MYL4):c.136-2A>C	MYL4	Likely pathogenic	criteria provided, single submitter
476205	NM_002476.2(MYL4):c.487+1G>C	MYL4	Likely pathogenic	criteria provided, single submitter
648701	NM_002476.2(MYL4):c.488-1G>A	MYL4	Likely pathogenic	criteria provided, single submitter
1430788	NM_002476.2(MYL4):c.234del (p.Cys78fs)	MYL4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
476199	NM_002476.2(MYL4):c.167T>C (p.Phe56Ser)	MYL4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1010457	NM_002476.2(MYL4):c.344C>T (p.Thr115Met)	MYL4	Uncertain significance	criteria provided, single submitter
1011955	NM_002476.2(MYL4):c.557A>G (p.Asn186Ser)	MYL4	Uncertain significance	criteria provided, single submitter
1016119	NM_002476.2(MYL4):c.248G>T (p.Arg83Leu)	MYL4	Uncertain significance	criteria provided, single submitter
1017440	NM_002476.2(MYL4):c.153C>G (p.Asp51Glu)	MYL4	Uncertain significance	criteria provided, single submitter
1021850	NM_002476.2(MYL4):c.353C>G (p.Pro118Arg)	MYL4	Uncertain significance	criteria provided, multiple submitters, no conflicts
1025818	NM_002476.2(MYL4):c.136A>G (p.Ile46Val)	MYL4	Uncertain significance	criteria provided, multiple submitters, no conflicts
1037096	NM_002476.2(MYL4):c.374G>A (p.Arg125His)	MYL4	Uncertain significance	criteria provided, single submitter
1039908	NC_000017.10:g.(?45297260)(45300418_?)del	MYL4	Uncertain significance	criteria provided, single submitter
1043151	NM_002476.2(MYL4):c.68C>T (p.Pro23Leu)	MYL4	Uncertain significance	criteria provided, single submitter
1045962	NM_002476.2(MYL4):c.304A>G (p.Lys102Glu)	MYL4	Uncertain significance	criteria provided, single submitter
1046399	NM_002476.2(MYL4):c.318G>A (p.Met106Ile)	MYL4	Uncertain significance	criteria provided, single submitter
1050366	NM_002476.2(MYL4):c.137T>G (p.Ile46Arg)	MYL4	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · 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
MYL4	Strong	Autosomal dominant	atrial fibrillation, familial, 18	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MYL4	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
MYL4	HGNC:7585	ENSG00000198336	P12829	Myosin light chain 4	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MYL4	Myosin light chain 4	Regulatory light chain of myosin.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MYL4	Other/Unknown	no		EF_hand_dom, EF-hand-dom_pair, CALM/Myosin/TropC-like

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
cardiac atrium	1
cardiac muscle of right atrium	1
right atrium auricular region	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MYL4	186	broad	marker	right atrium auricular region, cardiac atrium, cardiac muscle of right atrium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MYL4	46

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MYL4	P12829	90.85

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. 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
Striated Muscle Contraction	1	308.6×	0.006	MYL4
Muscle contraction	1	77.2×	0.013	MYL4

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
regulation of the force of heart contraction	1	991.3×	0.003	MYL4
cardiac muscle contraction	1	401.2×	0.004	MYL4
muscle contraction	1	208.1×	0.005	MYL4

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MYL4	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
MYL4	1	Binding: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

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	MYL4

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)
MYL4	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.