Is NPR2 p.Ser130Pro (c.388T>C) pathogenic?

NPR2 p.Ser130Pro (c.388T>C) is classified Uncertain significance in NPR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-17). AlphaMissense: ambiguous (0.3673); Absent from gnomAD v4.1; Associated with tall stature-scoliosis-macrodactyly of the great toes syndrome.

How common is NPR2 p.Ser130Pro (c.388T>C) in the general population?

NPR2 p.Ser130Pro (c.388T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NPR2 p.Ser130Pro (c.388T>C)?

AlphaMissense predicts ambiguous (score 0.3673) — an in-silico prediction, not a clinical call.

NPR2 p.Ser130Pro

Q: What condition is associated with NPR2 p.Ser130Pro (c.388T>C)?

NPR2 p.Ser130Pro (c.388T>C) 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.388T>C · VCV4783100

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3673 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

tall stature-scoliosis-macrodactyly of the great toes syndrome

Computational evidence

Protein change
AlphaMissense	0.3673	ambiguous
REVEL	0.259	benign-leaning
SaProt	LLR -14.07	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 2.4	GERP -3.5, phastCons 1
Overall
CADD	19.24	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: NPR2
Protein: p.Ser130Pro
Coding: c.388T>C
MANE Select: NM_003995
Type: single nucleotide variant
Location: chr9:35792796 (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

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 p.Ser130Ala Uncertain significance ★ ⚠ same residue
NPR2 p.Ser130= Likely benign ★ 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

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-ser130pro (accessed [today's date]).

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