Is NPR2 p.Arg263Pro (c.788G>C) pathogenic?

NPR2 p.Arg263Pro (c.788G>C) is classified Uncertain significance in NPR2 (ClinVar, Single submitter, 2 submitters; last evaluated 2022-05-16). AlphaMissense: likely benign (0.3382); Very rare (popmax 0.00223%, eas); Associated with acromesomelic dysplasia 1, Maroteaux type.

What condition is associated with NPR2 p.Arg263Pro (c.788G>C)?

NPR2 p.Arg263Pro (c.788G>C) 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.Arg263Pro (c.788G>C) in the general population?

NPR2 p.Arg263Pro (c.788G>C) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about NPR2 p.Arg263Pro (c.788G>C)?

AlphaMissense predicts likely benign (score 0.3382) — an in-silico prediction, not a clinical call.

NPR2 p.Arg263Pro

c.788G>C · rs139036657 · VCV208358

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3382 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

acromesomelic dysplasia 1, Maroteaux type

Computational evidence

Protein change
AlphaMissense	0.3382	likely benign
REVEL	0.384	indeterminate
SaProt	LLR -10.95	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP 1.5, phastCons 1
Overall
CADD	22.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,894 alleles

Overall 0.000657% 1/152,164 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.Arg263Pro
Coding: c.788G>C
MANE Select: NM_003995
dbSNP: rs139036657
Type: single nucleotide variant
Location: chr9:35794018 (GRCh38)
Gene constraint: LOEUF 0.517 · pLI 0.45 (gnomAD)
Structure: AlphaFold pLDDT 84.00
Residue 263: a UniProt-annotated variant site (in snsk1; loss of c-type natriuretic peptide-induced signaling; dominant negative effect; loss of localization to the plasma membrane)

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.Arg263Cys Uncertain significance ★★ ⚠ same residue
NPR2 p.Arg263His 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

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-arg263pro (accessed [today's date]).

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