Is NPR2 p.Pro432Ser (c.1294C>T) pathogenic?

NPR2 p.Pro432Ser (c.1294C>T) is classified Uncertain significance in NPR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-09). AlphaMissense: ambiguous (0.4634); Very rare (popmax 0.005%, amr); Associated with acromesomelic dysplasia 1, Maroteaux type.

What condition is associated with NPR2 p.Pro432Ser (c.1294C>T)?

NPR2 p.Pro432Ser (c.1294C>T) is associated with acromesomelic dysplasia 1, Maroteaux type, tall stature-scoliosis-macrodactyly of the great toes syndrome (ClinVar).

How common is NPR2 p.Pro432Ser (c.1294C>T) in the general population?

NPR2 p.Pro432Ser (c.1294C>T) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about NPR2 p.Pro432Ser (c.1294C>T)?

AlphaMissense predicts ambiguous (score 0.4634) — an in-silico prediction, not a clinical call.

NPR2 p.Pro432Ser

c.1294C>T · rs1185438999 · VCV2924076

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4634 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

acromesomelic dysplasia 1, Maroteaux type

Computational evidence

Protein change
AlphaMissense	0.4634	ambiguous
REVEL	0.207	benign-leaning
SaProt	LLR -10.28	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.6, phastCons 1
Overall
CADD	24.8	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 0.005% Admixed American · 3/59,988 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000186% 3/1,613,978 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.Pro432Ser
Coding: c.1294C>T
MANE Select: NM_003995
dbSNP: rs1185438999
Type: single nucleotide variant
Location: chr9:35800784 (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 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-pro432ser (accessed [today's date]).

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