Is NAGS p.Pro178= (c.534G>A) pathogenic?

NAGS p.Pro178= (c.534G>A) is classified Likely benign in NAGS (ClinVar, Single submitter, 2 submitters; last evaluated 2024-01-07). Ultra-rare (popmax 0.0843%, eas); Associated with hyperammonemia due to N-acetylglutamate synthase deficiency.

What condition is associated with NAGS p.Pro178= (c.534G>A)?

NAGS p.Pro178= (c.534G>A) is associated with hyperammonemia due to N-acetylglutamate synthase deficiency (ClinVar).

How common is NAGS p.Pro178= (c.534G>A) in the general population?

NAGS p.Pro178= (c.534G>A) is ultra-rare (popmax 0.0843%, eas) (gnomAD).

NAGS p.Pro178=

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.534G>A · rs539061299 · VCV648992

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0843%, 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	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -6.6	GERP -3.8
Overall
CADD	1.244	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0843% East Asian · 37/43,872 alleles

Filtering AF 0.0628% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0554%

Overall 0.00333% 53/1,591,428 alleles · ultra-rare exomes 51/1,439,070 · genomes 2/152,358 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0843%	1,186
South Asian	0.00229%	43,751
Remaining individualsnot grpmax-eligible	0.00162%	61,620
European (non-Finnish)	0.00111%	89,975

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.Pro178=
Coding: c.534G>A
MANE Select: NM_153006
dbSNP: rs539061299
Type: single nucleotide variant
Location: chr17:44005744 (GRCh38)
Gene constraint: LOEUF 1.178 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.38 · 1 PDB
Residue 178: 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.Pro178Ser Uncertain significance ★ ⚠ 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
NAGS p.Gln247Ter 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-pro178 (accessed [today's date]).

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