Is NPR2 p.Arg299Ter (c.895C>T) pathogenic?

NPR2 p.Arg299Ter (c.895C>T) is classified Pathogenic in NPR2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-24). Very rare (popmax 0.00267%, afr); Associated with NPR2-related disorder.

How common is NPR2 p.Arg299Ter (c.895C>T) in the general population?

NPR2 p.Arg299Ter (c.895C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

NPR2 p.Arg299Ter

Q: What condition is associated with NPR2 p.Arg299Ter (c.895C>T)?

NPR2 p.Arg299Ter (c.895C>T) is associated with NPR2-related disorder, acromesomelic dysplasia 1, Maroteaux type, tall stature-scoliosis-macrodactyly of the great toes syndrome (ClinVar).

c.895C>T · rs1255635522 · VCV1224426

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Conditions

NPR2-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 3 of 22
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.23	loss · gain 0.06 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 4.9	GERP 0.52, phastCons 1
Overall
CADD	43.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,874 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000186% 3/1,613,668 alleles · very rare exomes 2/1,461,624 · genomes 1/152,044 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,437
East Asian	0.00223%	44,898

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.Arg299Ter
Coding: c.895C>T
MANE Select: NM_003995
dbSNP: rs1255635522
Type: single nucleotide variant
Location: chr9:35799639 (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

NPR2-related disorder

Also linked: acromesomelic dysplasia 1, Maroteaux type tall stature-scoliosis-macrodactyly of the great toes syndrome

Similar variants

NPR2 p.Arg299Gln Uncertain significance ★ ⚠ same residue
NPR2 p.Arg299= Likely benign ★ same residue
NPR2 c.1436+1G>T Likely pathogenic ★★ same condition
NPR2 c.1887+2T>A Pathogenic/Likely 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-arg299ter (accessed [today's date]).

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