Is NPR2 p.Pro438Arg (c.1313C>G) pathogenic?

NPR2 p.Pro438Arg (c.1313C>G) is classified Uncertain significance in NPR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-21). AlphaMissense: likely benign (0.137); Very rare (popmax 0.00223%, eas); Associated with Inborn genetic diseases.

What condition is associated with NPR2 p.Pro438Arg (c.1313C>G)?

NPR2 p.Pro438Arg (c.1313C>G) is associated with Inborn genetic diseases (ClinVar).

How common is NPR2 p.Pro438Arg (c.1313C>G) in the general population?

NPR2 p.Pro438Arg (c.1313C>G) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about NPR2 p.Pro438Arg (c.1313C>G)?

AlphaMissense predicts likely benign (score 0.137) — an in-silico prediction, not a clinical call.

NPR2 p.Pro438Arg

c.1313C>G · rs778410447 · VCV3201760

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.137 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.137	likely benign
REVEL	0.104	moderately benign-leaning
SaProt	LLR -5.62	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 0.48, phastCons 1
Overall
CADD	22.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.00223% East Asian · 1/44,874 alleles

Overall 6.2e-05% 1/1,614,144 alleles · very rare exomes 1/1,461,894 · genomes 0/152,250 · joint denominator

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.Pro438Arg
Coding: c.1313C>G
MANE Select: NM_003995
dbSNP: rs778410447
Type: single nucleotide variant
Location: chr9:35800803 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NPR2 p.Pro438Leu Uncertain significance ★★ ⚠ same residue
NPR2 p.Pro438His Uncertain significance ★ ⚠ same residue
NPR2 p.Ala190Gly Uncertain significance ★★ ⚠ same condition
NPR2 p.Ala22Val Uncertain significance ★★ ⚠ same condition
NPR2 p.Arg268His Uncertain significance ★★ ⚠ same condition
NPR2 p.Arg272Gln Uncertain significance ★★ ⚠ same condition
NPR2 p.Arg363Gln Uncertain significance ★★ ⚠ same condition
NPR2 p.Arg58Pro 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-pro438arg (accessed [today's date]).

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