Is NAGS p.Asp68= (c.204C>T) pathogenic?

NAGS p.Asp68= (c.204C>T) is classified Likely benign in NAGS (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-25). Very rare (popmax 8.73e-05%, nfe); Associated with hyperammonemia due to N-acetylglutamate synthase deficiency.

What condition is associated with NAGS p.Asp68= (c.204C>T)?

NAGS p.Asp68= (c.204C>T) is associated with hyperammonemia due to N-acetylglutamate synthase deficiency (ClinVar).

How common is NAGS p.Asp68= (c.204C>T) in the general population?

NAGS p.Asp68= (c.204C>T) is very rare (popmax 8.73e-05%, nfe) (gnomAD).

NAGS p.Asp68=

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.204C>T · rs1219764962 · VCV2771726

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 8.73e-05%, nfe)

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	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.74	GERP -1.8
Overall
CADD	4.975	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.73e-05% European (non-Finnish) · 1/1,144,896 alleles

Overall 0.000131% 2/1,530,540 alleles · very rare exomes 2/1,378,280 · genomes 0/152,260 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00351%	28,484
European (non-Finnish)grpmax	8.73e-05%	1,144,896

Ashkenazi Jewish 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: NAGS
Protein: p.Asp68=
Coding: c.204C>T
MANE Select: NM_153006
dbSNP: rs1219764962
Type: single nucleotide variant
Location: chr17:44004867 (GRCh38)
Gene constraint: LOEUF 1.178 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.38 · 1 PDB
Residue 68: 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 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
NAGS p.Gln247Ter Pathogenic/Likely pathogenic ★★ same condition
NAGS p.Glu142Ter 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-asp68 (accessed [today's date]).

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