Is NPR2 p.Ala511= (c.1533A>G) pathogenic?

NPR2 p.Ala511= (c.1533A>G) is classified Uncertain significance in NPR2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-05-21). Very rare (popmax 0.0011%, nfe); Associated with acromesomelic dysplasia 1, Maroteaux type.

What condition is associated with NPR2 p.Ala511= (c.1533A>G)?

NPR2 p.Ala511= (c.1533A>G) is associated with acromesomelic dysplasia 1, Maroteaux type, tall stature-scoliosis-macrodactyly of the great toes syndrome, short stature with nonspecific skeletal abnormalities (ClinVar).

How common is NPR2 p.Ala511= (c.1533A>G) in the general population?

NPR2 p.Ala511= (c.1533A>G) is very rare (popmax 0.0011%, nfe) (gnomAD).

NPR2 p.Ala511=

c.1533A>G · rs1459552048 · VCV1948463

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.0011%, nfe)

Conditions

acromesomelic dysplasia 1, Maroteaux type

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.52	gain · loss 0.08 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 0.57	GERP 0.87, phastCons 0.85
Overall
CADD	18.17	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% European (non-Finnish) · 13/1,180,042 alleles

Filtering AF 0.000615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.000805% 13/1,614,094 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: NPR2
Protein: p.Ala511=
Coding: c.1533A>G
MANE Select: NM_003995
dbSNP: rs1459552048
Type: single nucleotide variant
Location: chr9:35801739 (GRCh38)
Gene constraint: LOEUF 0.517 · pLI 0.45 (gnomAD)
Structure: AlphaFold pLDDT 84.00

Full NPR2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

acromesomelic dysplasia 1, Maroteaux type — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: tall stature-scoliosis-macrodactyly of the great toes syndrome short stature with nonspecific skeletal abnormalities

Similar variants

NPR2 p.Ala511Val Uncertain significance ★ ⚠ same residue
NPR2 c.1887+2T>A Pathogenic/Likely pathogenic ★★ same condition
NPR2 p.Arg299Ter Pathogenic ★★ same condition
NPR2 p.Arg363Ter Pathogenic ★★ same condition
NPR2 p.Arg388Gln Pathogenic ★★ same condition
NPR2 p.Arg479Ter Pathogenic/Likely pathogenic ★★ same condition
NPR2 p.Arg741Ter Pathogenic/Likely pathogenic ★★ same condition
NPR2 p.Arg749Trp Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/npr2-p-ala511 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown