NPPA

Chr 1ADAR

natriuretic peptide A

Also known as: ANF, ANP, ATFB6, ATRST2, CDD, CDD-ANF, CDP, PND

NCBI Gene: 4878 ENSG00000175206 UniProt: P01160 OMIM: 108780

The protein encoded by this gene is a natriuretic peptide hormone that regulates blood pressure, fluid-electrolyte balance, and cardiac function by binding to receptors that produce cGMP and activate downstream signaling pathways. Mutations cause familial atrial fibrillation type 6 and atrial standstill 2, both cardiac arrhythmia disorders affecting the atria. Inheritance can be either autosomal dominant or autosomal recessive.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene belongs to the natriuretic peptide family. Natriuretic peptides are implicated in the control of extracellular fluid volume and electrolyte homeostasis. This protein is synthesized as a large precursor (containing a signal peptide), which is processed to release a peptide from the N-terminus with similarity to vasoactive peptide, cardiodilatin, and another peptide from the C-terminus with natriuretic-diuretic activity. Mutations in this gene have been associated with atrial fibrillation familial type 6. This gene is located adjacent to another member of the natriuretic family of peptides on chromosome 1. [provided by RefSeq, Oct 2015]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Atrial fibrillation, familial, 6MIM #612201

Atrial standstill 2MIM #615745

Clinical highlights

Gene–disease validity (ClinGen)

Refuted · dilated cardiomyopathy · AR · ClinGen 2024

evidence has disproved this relationship

Active trials

110

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.74

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.74LOEUF

pLI 0.001

Z-score 0.19

OE 0.91 (0.47–1.74)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.27Z-score

OE missense 1.08 (0.92–1.27)

100 obs / 92.8 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.91 (0.47–1.74)

0≤0.351.4

Missense OE?1.08 (0.92–1.27)

0≤0.61.4

Synonymous OE?1.13

0≤1.21.6

LoF obs/exp: 5 / 5.5Missense obs/exp: 100 / 92.8Syn Z: -0.63

Background carrier burden — how many people carry a rare variant somewhere in NPPA?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 210

217 rare PASS variants

Rare truncating (LoF)

1 in 3,600

30 rare PASS variants

Rare synonymous (reference)

1 in 520

91 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for NPPA. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 270	1 in 4,200
South Asian	~43k	1 in 330	≈ 1 in 11,000
Remaining (unassigned)	~30k	1 in 140	1 in 2,300
European (Finnish)	~27k	1 in 300	≈ 1 in 27,000
Admixed American	~22k	1 in 120	1 in 2,200
African / African American	~21k	1 in 150	1 in 2,000
East Asian	~20k	1 in 330	≈ 1 in 20,000
Ashkenazi Jewish	~13k	1 in 1,000	none seen
Middle Eastern	~2,884	1 in 360	≈ 1 in 2,900

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 3 coding exons well covered in gnomAD exomes and genomes.? see exons ↓