Is NPR2 p.Phe129Val (c.385T>G) pathogenic?

NPR2 p.Phe129Val (c.385T>G) is classified Uncertain significance in NPR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-17). AlphaMissense: likely pathogenic (0.9695); Absent from gnomAD v4.1; Associated with acromesomelic dysplasia 1, Maroteaux type.

What condition is associated with NPR2 p.Phe129Val (c.385T>G)?

NPR2 p.Phe129Val (c.385T>G) is associated with acromesomelic dysplasia 1, Maroteaux type, tall stature-scoliosis-macrodactyly of the great toes syndrome (ClinVar).

How common is NPR2 p.Phe129Val (c.385T>G) in the general population?

NPR2 p.Phe129Val (c.385T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NPR2 p.Phe129Val (c.385T>G)?

AlphaMissense predicts likely pathogenic (score 0.9695) — an in-silico prediction, not a clinical call.

NPR2 p.Phe129Val

c.385T>G · rs2491028981 · VCV2949695

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9695 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

acromesomelic dysplasia 1, Maroteaux type

Computational evidence

Protein change
AlphaMissense	0.9695	likely pathogenic
REVEL	0.728	pathogenic-leaning
SaProt	LLR -14.24	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
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	24.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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.Phe129Val
Coding: c.385T>G
MANE Select: NM_003995
dbSNP: rs2491028981
Type: single nucleotide variant
Location: chr9:35792793 (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-phe129val (accessed [today's date]).

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