Is NAGS p.Ser97Pro (c.289T>C) pathogenic?

NAGS p.Ser97Pro (c.289T>C) is classified Uncertain significance in NAGS (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-18). AlphaMissense: likely benign (0.0591); Absent from gnomAD v4.1; Associated with hyperammonemia due to N-acetylglutamate synthase deficiency.

What condition is associated with NAGS p.Ser97Pro (c.289T>C)?

NAGS p.Ser97Pro (c.289T>C) is associated with hyperammonemia due to N-acetylglutamate synthase deficiency (ClinVar).

How common is NAGS p.Ser97Pro (c.289T>C) in the general population?

NAGS p.Ser97Pro (c.289T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NAGS p.Ser97Pro (c.289T>C)?

AlphaMissense predicts likely benign (score 0.0591) — an in-silico prediction, not a clinical call.

NAGS p.Ser97Pro

Q: How is Hyperammonemia due to N-acetylglutamate synthase deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.289T>C · rs2509277790 · VCV1998875

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0591 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hyperammonemia due to N-acetylglutamate synthase deficiency

Computational evidence

Protein change
AlphaMissense	0.0591	likely benign
REVEL	0.252	benign-leaning
SaProt	LLR -5.44	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Regional constraint	o/e 0.89	unconstrained · MANE · 3,934 bp · p 0.0027 · regional, not allelic
Overall
CADD	15.76	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

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: NAGS
Protein: p.Ser97Pro
Coding: c.289T>C
MANE Select: NM_153006
dbSNP: rs2509277790
Type: single nucleotide variant
Location: chr17:44004952 (GRCh38)
Gene constraint: LOEUF 1.178 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.38 · 1 PDB
Residue 97: the 'amino-acid kinase domain (aak)' region; the 'disordered' region

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

Disease context

hyperammonemia due to N-acetylglutamate synthase deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hyperammonemia due to N-acetylglutamate synthase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages
Prevalence: <1 / 1 000 000 (Europe)

Similar variants

NAGS p.Ser97Leu Uncertain significance ★★ ⚠ same residue
NAGS p.Ser97= Likely benign ★ same residue
NAGS c.1097-1G>C Pathogenic ★★ same condition
NAGS c.1097-2A>G Pathogenic/Likely pathogenic ★★ same condition
NAGS c.701+1G>A Likely pathogenic ★★ same condition
NAGS c.915+1G>T Likely pathogenic ★★ same condition
NAGS c.916-2A>T Pathogenic/Likely pathogenic ★★ same condition
NAGS p.Arg208Ter 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/nags-p-ser97pro (accessed [today's date]).

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