NPR2

Chr 9ARAD

natriuretic peptide receptor 2

Also known as: AMD1, AMDM, ANPRB, ANPb, ECDM, GC-B, GCB, GUC2B

NCBI Gene: 4882ENSG00000159899UniProt: P20594

This gene encodes natriuretic peptide receptor B, one of two integral membrane receptors for natriuretic peptides. Both NPR1 and NPR2 contain five functional domains: an extracellular ligand-binding domain, a single membrane-spanning region, and intracellularly a protein kinase homology domain, a helical hinge region involved in oligomerization, and a carboxyl-terminal guanylyl cyclase catalytic domain. The protein is the primary receptor for C-type natriuretic peptide (CNP), which upon ligand binding exhibits greatly increased guanylyl cyclase activity. Mutations in this gene are the cause of acromesomelic dysplasia Maroteaux type. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Acromesomelic dysplasia 1, Maroteaux typeMIM #602875
AR
Epiphyseal chondrodysplasia, Miura typeMIM #615923
AD
Short stature with nonspecific skeletal abnormalitiesMIM #616255
AD
828
ClinVar variants
58
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— NPR2
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.33) despite low pLI — interpret in context.
📋
ClinVar Variants
58 Pathogenic / Likely Pathogenic· 306 VUS of 828 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.49LOEUF
pLI 0.000
Z-score 4.54
OE 0.33 (0.23–0.49)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
2.96Z-score
OE missense 0.66 (0.61–0.72)
398 obs / 602.3 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.33 (0.23–0.49)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.66 (0.61–0.72)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.96
0≤1.21.6
LoF obs/exp: 18 / 54.0Missense obs/exp: 398 / 602.3Syn Z: 0.46

ClinVar Variant Classifications

828 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic38
Likely Pathogenic20
VUS306
Likely Benign100
Benign13
Conflicting9
38
Pathogenic
20
Likely Pathogenic
306
VUS
100
Likely Benign
13
Benign
9
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
12
2
24
0
38
Likely Pathogenic
11
2
7
0
20
VUS
0
285
17
4
306
Likely Benign
0
1
42
57
100
Benign
0
0
12
1
13
Conflicting
—9
Total2329010262486

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

View in ClinVar →

Protein Context — Lollipop Plot

NPR2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

NPR2-related acromesomelic dysplasia Maroteaux type

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. DisordersSkinSkeletal
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Acromesomelic dysplasia 1, Maroteaux type

MIM #602875

Molecular basis of disorder known

Autosomal recessive

Epiphyseal chondrodysplasia, Miura type

MIM #615923

Molecular basis of disorder known

Autosomal dominant

Short stature with nonspecific skeletal abnormalities

MIM #616255

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Genetics of short stature.
Nicolae R et al.·Curr Opin Pediatr
2025Review
Clinical Characteristics of Short-Stature Patients With Collagen Gene Mutation and the Therapeutic Response to rhGH.
Chen M et al.·Front Endocrinol (Lausanne)
2022Cohort
Sex-stratified genome-wide association and transcriptome-wide Mendelian randomization studies reveal drug targets of heart failure.
Yang Q et al.·Cell Rep Med
2024
Novel pathogenic NPR2 variants in short stature patients and the therapeutic response to rhGH.
Chen H et al.·Orphanet J Rare Dis
2023Cohort
Clinical Characteristics and Response to Growth Hormone Treatment in 27 Children With Heterozygous NPR2 Variants: Real-World Data.
Renes JS et al.·J Clin Endocrinol Metab
2025
Heterozygous NPR2 Variants in Idiopathic Short Stature.
Stavber L et al.·Genes (Basel)
2022
Identification of NPR2 gene mutations affecting chondrocyte differentiation in short stature through JAK2-STAT5.
Wei S et al.·Orphanet J Rare Dis
2025
Clinical Characteristics of Short-Stature Patients With an NPR2 Mutation and the Therapeutic Response to rhGH.
Ke X et al.·J Clin Endocrinol Metab
2021Case report
NPR2 gene variants in familial short stature: a single-center study.
Yuan K et al.·J Pediatr Endocrinol Metab
2021
The Genetic Landscape of Children Born Small for Gestational Age with Persistent Short Stature.
Toni L et al.·Horm Res Paediatr
2024
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools