Is NPR2 p.Val548= (c.1644C>T) pathogenic?

NPR2 p.Val548= (c.1644C>T) is classified Conflicting classifications of pathogenicity in NPR2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-10-30). Very rare (popmax 0.00536%, afr); Associated with tall stature-scoliosis-macrodactyly of the great toes syndrome.

How common is NPR2 p.Val548= (c.1644C>T) in the general population?

NPR2 p.Val548= (c.1644C>T) is very rare (popmax 0.00536%, afr) (gnomAD).

NPR2 p.Val548=

Q: What condition is associated with NPR2 p.Val548= (c.1644C>T)?

NPR2 p.Val548= (c.1644C>T) is associated with tall stature-scoliosis-macrodactyly of the great toes syndrome, acromesomelic dysplasia 1, Maroteaux type (ClinVar).

Q: How is Tall stature-long halluces-multiple extra-epiphyses syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.1644C>T · rs772510686 · VCV366786

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00536%, afr)

Conditions

tall stature-scoliosis-macrodactyly of the great toes syndrome

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 -5.3	GERP -3.5
Overall
CADD	1.203	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00536% African / African-American · 4/74,678 alleles

Filtering AF 0.00337% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00304%

Overall 0.00368% 59/1,603,238 alleles · very rare exomes 55/1,451,098 · genomes 4/152,140 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00536%	18,669
Admixed American	0.005%	19,994
European (non-Finnish)	0.00436%	22,950
Remaining individualsnot grpmax-eligible	0.00161%	62,170

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.Val548=
Coding: c.1644C>T
MANE Select: NM_003995
dbSNP: rs772510686
Type: single nucleotide variant
Location: chr9:35802217 (GRCh38)
Gene constraint: LOEUF 0.517 · pLI 0.45 (gnomAD)
Structure: AlphaFold pLDDT 84.00
Residue 548: the protein kinase domain

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

Disease context

tall stature-scoliosis-macrodactyly of the great toes syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: acromesomelic dysplasia 1, Maroteaux type

For Tall stature-long halluces-multiple extra-epiphyses syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood

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-val548 (accessed [today's date]).

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