Is NPR2 p.Ala48Ser (c.142G>T) pathogenic?

NPR2 p.Ala48Ser (c.142G>T) is classified Uncertain significance in NPR2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-16). AlphaMissense: ambiguous (0.4191); Very rare (popmax 8.48e-05%, nfe); Associated with acromesomelic dysplasia 1, Maroteaux type.

What condition is associated with NPR2 p.Ala48Ser (c.142G>T)?

NPR2 p.Ala48Ser (c.142G>T) is associated with acromesomelic dysplasia 1, Maroteaux type, tall stature-scoliosis-macrodactyly of the great toes syndrome (ClinVar).

How common is NPR2 p.Ala48Ser (c.142G>T) in the general population?

NPR2 p.Ala48Ser (c.142G>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about NPR2 p.Ala48Ser (c.142G>T)?

AlphaMissense predicts ambiguous (score 0.4191) — an in-silico prediction, not a clinical call.

NPR2 p.Ala48Ser

c.142G>T · VCV3759141

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4191 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

acromesomelic dysplasia 1, Maroteaux type

Computational evidence

Protein change
AlphaMissense	0.4191	ambiguous
REVEL	0.916	moderately pathogenic-leaning
SaProt	LLR -9.70	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Overall
CADD	32.0	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

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,938 alleles

Overall 0.000206% 3/1,459,472 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,244
European (non-Finnish)grpmax	8.48e-05%	1,179,938

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala48Ser
Coding: c.142G>T
MANE Select: NM_003995
Type: single nucleotide variant
Location: chr9:35792550 (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 p.Ala48Thr 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
NPR2 p.Arg749Trp 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-ala48ser (accessed [today's date]).

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