Atrial fibrillation, familial, 6

Summary

Atrial fibrillation, familial, 6 (MONDO:0012816) is a disease with 3 cohort genes.

At a glance

• Cohort genes: 3
• ClinVar variants: 163

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	atrial fibrillation, familial, 6
Mondo ID	MONDO:0012816
MeSH	C567400
OMIM	612201
UMLS	C2677294
MedGen	394252
GARD	0015544
Is cancer (heuristic)	no

Also known as: ATFB6 · atrial fibrillation, familial, 6 · atrial fibrillation, familial, type 6 · familial atrial fibrillation caused by mutation in NPPA · NPPA familial atrial fibrillation

Data availability: 163 ClinVar variants · 3 GenCC gene-disease records.

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, 6

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, 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

163 retrieved; paginated sample, class counts are floors:

95 uncertain significance, 55 likely benign, 5 benign, 4 benign/likely benign, 3 conflicting classifications of pathogenicity, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
17788	NM_006172.4(NPPA):c.456_*1del (p.Ter152TrpextTer?)	NPPA	Pathogenic	no assertion criteria provided
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
2425520	NC_000001.10:g.(?10698999)(11907741_?)dup	AGTRAP	Uncertain significance	criteria provided, single submitter
830841	NC_000001.11:g.(?11012634)(11934865_?)del	AGTRAP	Uncertain significance	criteria provided, single submitter
1011647	NM_006172.4(NPPA):c.19A>G (p.Thr7Ala)	LOC114827827	Uncertain significance	criteria provided, single submitter
1025429	NM_006172.4(NPPA):c.154C>T (p.Pro52Ser)	LOC114827827	Uncertain significance	criteria provided, multiple submitters, no conflicts
1035991	NM_006172.4(NPPA):c.59T>C (p.Leu20Pro)	LOC114827827	Uncertain significance	criteria provided, single submitter
1061540	NM_006172.4(NPPA):c.338G>C (p.Ser113Thr)	LOC114827827	Uncertain significance	criteria provided, multiple submitters, no conflicts
1062490	NM_006172.4(NPPA):c.149A>T (p.Lys50Met)	LOC114827827	Uncertain significance	criteria provided, single submitter
1297505	NM_006172.4(NPPA):c.448C>T (p.Arg150Trp)	LOC114827827	Uncertain significance	criteria provided, single submitter
1346660	NM_006172.4(NPPA):c.242C>G (p.Pro81Arg)	LOC114827827	Uncertain significance	criteria provided, multiple submitters, no conflicts
1356904	NM_006172.4(NPPA):c.413T>C (p.Ile138Thr)	LOC114827827	Uncertain significance	criteria provided, single submitter
1362864	NM_006172.4(NPPA):c.134A>G (p.Asp45Gly)	LOC114827827	Uncertain significance	criteria provided, single submitter
1366790	NM_006172.4(NPPA):c.13_15del (p.Ser5del)	LOC114827827	Uncertain significance	criteria provided, single submitter
1376244	NM_006172.4(NPPA):c.209C>G (p.Ala70Gly)	LOC114827827	Uncertain significance	criteria provided, single submitter
1399897	NM_006172.4(NPPA):c.113T>G (p.Met38Arg)	LOC114827827	Uncertain significance	criteria provided, single submitter
1406460	NM_006172.4(NPPA):c.61G>A (p.Gly21Ser)	LOC114827827	Uncertain significance	criteria provided, single submitter
1408346	NM_006172.4(NPPA):c.209C>T (p.Ala70Val)	LOC114827827	Uncertain significance	criteria provided, single submitter
1426372	NM_006172.4(NPPA):c.376C>T (p.Arg126Trp)	LOC114827827	Uncertain significance	criteria provided, single submitter
1426806	NM_006172.4(NPPA):c.225C>A (p.Ser75Arg)	LOC114827827	Uncertain significance	criteria provided, single submitter
1428068	NM_006172.4(NPPA):c.123G>C (p.Lys41Asn)	LOC114827827	Uncertain significance	criteria provided, single submitter
1437686	NM_006172.4(NPPA):c.49T>C (p.Phe17Leu)	LOC114827827	Uncertain significance	criteria provided, single submitter
1441707	NM_006172.4(NPPA):c.393C>A (p.Phe131Leu)	LOC114827827	Uncertain significance	criteria provided, single submitter
1446927	NM_006172.4(NPPA):c.372C>A (p.Ser124Arg)	LOC114827827	Uncertain significance	criteria provided, single submitter
1463836	NM_006172.4(NPPA):c.187C>A (p.Leu63Ile)	LOC114827827	Uncertain significance	criteria provided, single submitter
1500523	NM_006172.4(NPPA):c.224G>A (p.Ser75Asn)	LOC114827827	Uncertain significance	criteria provided, single submitter
1517080	NM_006172.4(NPPA):c.358A>G (p.Thr120Ala)	LOC114827827	Uncertain significance	criteria provided, single submitter
1518425	NM_006172.4(NPPA):c.13T>C (p.Ser5Pro)	LOC114827827	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 2 · 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

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
AGTRAP	HGNC:13539	ENSG00000177674	Q6RW13	Type-1 angiotensin II receptor-associated protein	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.
AGTRAP	Type-1 angiotensin II receptor-associated protein	Appears to be a negative regulator of type-1 angiotensin II receptor-mediated signaling by regulating receptor internalization as well as mechanism of receptor desensitization such as phosphorylation.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · 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	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NPPA	Other/Unknown	no		Natr_peptide, Natriuretic_peptide_atrial, Natr_peptide_CS
AGTRAP	Other/Unknown	no		AGTRAP
NPPA-AS1	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

2 cohort genes 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
granulocyte	1
leukocyte	1
monocyte	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
AGTRAP	245	ubiquitous	marker	granulocyte, monocyte, leukocyte
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
AGTRAP	1,315
NPPA-AS1	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NPPA	P01160	13

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
AGTRAP	Q6RW13	80.97

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. 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
YAP1- and WWTR1 (TAZ)-stimulated gene expression	1	380.7×	0.019	NPPA
Physiological factors	1	335.9×	0.019	NPPA
Oncogenic MAPK signaling	1	124.1×	0.035	AGTRAP
Signaling by BRAF and RAF1 fusions	1	85.2×	0.038	AGTRAP
Cardiac conduction	1	54.4×	0.042	NPPA
Amyloid fiber formation	1	51.4×	0.042	NPPA
Muscle contraction	1	38.6×	0.048	NPPA
Diseases of signal transduction by growth factor receptors and second messengers	1	28.4×	0.057	AGTRAP
RNA Polymerase II Transcription	1	11.3×	0.125	NPPA
Gene expression (Transcription)	1	8.9×	0.142	NPPA
Generic Transcription Pathway	1	7.5×	0.151	NPPA
Disease	1	6.5×	0.155	AGTRAP
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 blood pressure	2	221.7×	6e-04	NPPA, AGTRAP
negative regulation of collecting lymphatic vessel constriction	1	8426.0×	0.001	NPPA
response to hypoxia	2	95.8×	0.001	NPPA, AGTRAP
response to 3-methylcholanthrene	1	4213.0×	0.002	NPPA
positive regulation of potassium ion export across plasma membrane	1	2808.7×	0.002	NPPA
obsolete positive regulation of cGMP-mediated signaling	1	1203.7×	0.003	NPPA
negative regulation of JUN kinase activity	1	1203.7×	0.003	NPPA
regulation of atrial cardiac muscle cell membrane repolarization	1	1203.7×	0.003	NPPA
cell growth involved in cardiac muscle cell development	1	1203.7×	0.003	NPPA
positive regulation of cardiac muscle contraction	1	1053.2×	0.003	NPPA
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
receptor guanylyl cyclase signaling pathway	1	648.1×	0.003	NPPA
negative regulation of systemic arterial blood pressure	1	526.6×	0.003	NPPA
cardiac conduction system development	1	526.6×	0.003	NPPA
cardiac muscle hypertrophy in response to stress	1	526.6×	0.003	NPPA
sodium ion export across plasma membrane	1	526.6×	0.003	NPPA
cellular response to angiotensin	1	468.1×	0.004	NPPA
obsolete cGMP-mediated signaling	1	401.2×	0.004	NPPA
response to muscle stretch	1	383.0×	0.004	NPPA
positive regulation of heart rate	1	351.1×	0.004	NPPA
aortic valve morphogenesis	1	216.1×	0.006	NPPA
vasodilation	1	183.2×	0.007	NPPA
cellular response to glucose stimulus	1	133.8×	0.010	NPPA
cellular response to hydrogen peroxide	1	117.0×	0.010	NPPA
response to insulin	1	115.4×	0.010	NPPA
cellular response to mechanical stimulus	1	108.0×	0.010	NPPA
female pregnancy	1	105.3×	0.010	NPPA
neuropeptide signaling pathway	1	86.0×	0.012	NPPA

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NPPA	1	2
AGTRAP	0	0
NPPA-AS1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
SAMPATRILAT	2	NPPA

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
NPPA	5	Binding:5

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

1 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)
SAMPATRILAT	2	NPPA

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	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	2	AGTRAP, NPPA-AS1

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
AGTRAP	0	—
NPPA-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.