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…

MultiplemechanismAD/ARLOEUF 1.742 OMIM phenotypes

Clinical Summary— NPPA

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Gene-Disease Validity (ClinGen)

dilated cardiomyopathy · ARNo Known Disease Relationship

No known disease relationship

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

2 unique Pathogenic / Likely Pathogenic· 102 VUS of 188 total submissions

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Clinical Trials

3 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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

This gene — mechanism propensity

0.84top 10%

GOF

0.6737th %ile

LOF

0.1993th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). The Badonyi & Marsh model scores dominant-negative highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports gain-of-function. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median · 1 literature citation

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

GOFNPPA Gain-of-Function Mutation Associated with Familial Atrial Fibrillation1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References

1.PMID 19646991 ↗

ClinVar Variant Classifications

188 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

Likely Pathogenic1

VUS102

Likely Benign60

Benign19

Conflicting3

Pathogenic

Likely Pathogenic

102

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	0	0	0	1
Likely Pathogenic	1	0	0	0	1
VUS	5	91	4	2	102
Likely Benign	0	6	18	36	60
Benign	1	1	17	0	19
Conflicting	—				3
Total	8	98	39	38	186

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

39 pathogenic / likely-pathogenic (of 58) ClinVar copy-number / structural variants overlap NPPA — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →