Is NPR2 p.Ser76Pro (c.226T>C) pathogenic?

NPR2 p.Ser76Pro (c.226T>C) is classified Pathogenic in NPR2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2013-10-01). AlphaMissense: likely pathogenic (0.9778); Absent from gnomAD v4.1; Associated with short stature with nonspecific skeletal abnormalities.

What condition is associated with NPR2 p.Ser76Pro (c.226T>C)?

NPR2 p.Ser76Pro (c.226T>C) is associated with short stature with nonspecific skeletal abnormalities (ClinVar).

How common is NPR2 p.Ser76Pro (c.226T>C) in the general population?

NPR2 p.Ser76Pro (c.226T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NPR2 p.Ser76Pro (c.226T>C)?

AlphaMissense predicts likely pathogenic (score 0.9778) — an in-silico prediction, not a clinical call.

NPR2 p.Ser76Pro

c.226T>C · rs796065355 · VCV208357

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9778 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

short stature with nonspecific skeletal abnormalities

Computational evidence

Protein change
AlphaMissense	0.9778	likely pathogenic ✓ concordant with ClinVar
REVEL	0.567	indeterminate
SaProt	LLR -11.82	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.7, phastCons 1
Overall
CADD	28.3	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.Ser76Pro
Coding: c.226T>C
MANE Select: NM_003995
dbSNP: rs796065355
Type: single nucleotide variant
Location: chr9:35792634 (GRCh38)
Gene constraint: LOEUF 0.517 · pLI 0.45 (gnomAD)
Structure: AlphaFold pLDDT 84.00
Residue 76: a UniProt-annotated variant site (in snsk1; loss of c-type natriuretic peptide-induced signaling; dominant negative effect; loss of localization to the plasma membrane)

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

Disease context

short stature with nonspecific skeletal abnormalities — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NPR2 p.Arg479Ter Pathogenic/Likely pathogenic ★★ same condition
NPR2 p.Arg767Ter Pathogenic ★★ same condition
NPR2 p.Gln201Ter Pathogenic ★★ same condition
NPR2 p.Ala511= Uncertain significance ★★ same condition
NPR2 p.Arg165His Uncertain significance ★★ ⚠ same condition
NPR2 p.Arg358Trp Uncertain significance ★★ ⚠ same condition
NPR2 p.Arg495His Uncertain significance ★★ ⚠ same condition
NPR2 p.Arg557His Uncertain significance ★★ ⚠ 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-ser76pro (accessed [today's date]).

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