Is NPR2 p.Phe543= (c.1629C>T) pathogenic?

NPR2 p.Phe543= (c.1629C>T) is classified Likely benign in NPR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-03). Ultra-rare (popmax 0.0521%, afr); Associated with acromesomelic dysplasia 1, Maroteaux type.

What condition is associated with NPR2 p.Phe543= (c.1629C>T)?

NPR2 p.Phe543= (c.1629C>T) is associated with acromesomelic dysplasia 1, Maroteaux type, tall stature-scoliosis-macrodactyly of the great toes syndrome (ClinVar).

How common is NPR2 p.Phe543= (c.1629C>T) in the general population?

NPR2 p.Phe543= (c.1629C>T) is ultra-rare (popmax 0.0521%, afr) (gnomAD).

NPR2 p.Phe543=

c.1629C>T · rs375740003 · VCV774095

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0521%, afr)

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 7.7	GERP 1.6, phastCons 1
Overall
CADD	15.7	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0521% African / African-American · 39/74,910 alleles

Filtering AF 0.0391% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0346%

Overall 0.00248% 40/1,613,622 alleles · ultra-rare exomes 18/1,461,418 · genomes 22/152,204 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0521%	1,921
European (non-Finnish)	8.48e-05%	1,179,617

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.Phe543=
Coding: c.1629C>T
MANE Select: NM_003995
dbSNP: rs375740003
Type: single nucleotide variant
Location: chr9:35801997 (GRCh38)
Gene constraint: LOEUF 0.517 · pLI 0.45 (gnomAD)
Structure: AlphaFold pLDDT 84.00
Residue 543: the protein kinase domain

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 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
NPR2 p.Arg767Ter 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-phe543 (accessed [today's date]).

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