Is NPR2 p.Arg65Pro (c.194G>C) pathogenic?

NPR2 p.Arg65Pro (c.194G>C) is classified Uncertain significance in NPR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-28). AlphaMissense: likely pathogenic (0.7228); Absent from gnomAD v4.1; Associated with tall stature-scoliosis-macrodactyly of the great toes syndrome.

How common is NPR2 p.Arg65Pro (c.194G>C) in the general population?

NPR2 p.Arg65Pro (c.194G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NPR2 p.Arg65Pro (c.194G>C)?

AlphaMissense predicts likely pathogenic (score 0.7228) — an in-silico prediction, not a clinical call.

NPR2 p.Arg65Pro

Q: What condition is associated with NPR2 p.Arg65Pro (c.194G>C)?

NPR2 p.Arg65Pro (c.194G>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.194G>C · VCV4788233

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7228 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

tall stature-scoliosis-macrodactyly of the great toes syndrome

Computational evidence

Protein change
AlphaMissense	0.7228	likely pathogenic
REVEL	0.492	indeterminate
SaProt	LLR -9.23	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 1.4, phastCons 1
Overall
CADD	22.4	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.Arg65Pro
Coding: c.194G>C
MANE Select: NM_003995
Type: single nucleotide variant
Location: chr9:35792602 (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.Arg65Trp Uncertain significance ★★ ⚠ same residue
NPR2 p.Arg65Gln Uncertain significance ★ ⚠ 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-arg65pro (accessed [today's date]).

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