Is NAGS p.Ser280= (c.840G>A) pathogenic?

NAGS p.Ser280= (c.840G>A) is classified Likely benign in NAGS (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-18). Very rare (popmax 0.00223%, eas); Associated with hyperammonemia due to N-acetylglutamate synthase deficiency.

What condition is associated with NAGS p.Ser280= (c.840G>A)?

NAGS p.Ser280= (c.840G>A) is associated with hyperammonemia due to N-acetylglutamate synthase deficiency (ClinVar).

How common is NAGS p.Ser280= (c.840G>A) in the general population?

NAGS p.Ser280= (c.840G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

NAGS p.Ser280=

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.840G>A · rs202173320 · VCV2031068

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

hyperammonemia due to N-acetylglutamate synthase deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.65	GERP -3.5, phastCons 0.003
Overall
CADD	9.568	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,878 alleles

Overall 0.000124% 2/1,613,374 alleles · very rare exomes 1/1,461,026 · genomes 1/152,348 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,878
European (non-Finnish)	8.47e-05%	1,180,008

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: NAGS
Protein: p.Ser280=
Coding: c.840G>A
MANE Select: NM_153006
dbSNP: rs202173320
Type: single nucleotide variant
Location: chr17:44006162 (GRCh38)
Gene constraint: LOEUF 1.178 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.38 · 1 PDB
Residue 280: the 'amino-acid kinase domain (aak)' 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.Ser280Ter Likely pathogenic ★ same residue
NAGS p.Ser280fs Likely pathogenic ★ 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-ser280 (accessed [today's date]).

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