Is NPR2 p.Cys227= (c.681C>T) pathogenic?

NPR2 p.Cys227= (c.681C>T) is classified Likely benign in NPR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-18). Ultra-rare (popmax 0.0164%, mid); Associated with acromesomelic dysplasia 1, Maroteaux type.

What condition is associated with NPR2 p.Cys227= (c.681C>T)?

NPR2 p.Cys227= (c.681C>T) is associated with acromesomelic dysplasia 1, Maroteaux type, tall stature-scoliosis-macrodactyly of the great toes syndrome (ClinVar).

How common is NPR2 p.Cys227= (c.681C>T) in the general population?

NPR2 p.Cys227= (c.681C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

NPR2 p.Cys227=

c.681C>T · rs780884094 · VCV2197798

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

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
Constraint at this position
Conservation	phyloP -4.3	GERP -3.5
Overall
CADD	6.317	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00919% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00735%

Overall 0.00527% 85/1,614,038 alleles · ultra-rare exomes 76/1,461,868 · genomes 9/152,170 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
South Asian	0.0154%	6,506
East Asian	0.00891%	11,225
Remaining individualsnot grpmax-eligible	0.008%	12,497
European (non-Finnish)	0.005%	20,000
African / African-American	0.00267%	37,456

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.Cys227=
Coding: c.681C>T
MANE Select: NM_003995
dbSNP: rs780884094
Type: single nucleotide variant
Location: chr9:35793911 (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

Similar variants

NPR2 p.Cys227Trp 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-cys227 (accessed [today's date]).

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