Is NAGS p.Phe362= (c.1086T>C) pathogenic?

NAGS p.Phe362= (c.1086T>C) is classified Benign/Likely benign in NAGS (ClinVar, Multiple submitters, 11 submitters; last evaluated 2026-02-04). Common (popmax 20.5%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with hyperammonemia due to N-acetylglutamate synthase deficiency.

What condition is associated with NAGS p.Phe362= (c.1086T>C)?

NAGS p.Phe362= (c.1086T>C) is associated with hyperammonemia due to N-acetylglutamate synthase deficiency (ClinVar).

NAGS p.Phe362=

Q: How common is NAGS p.Phe362= (c.1086T>C) in the general population?

NAGS p.Phe362= (c.1086T>C) is common (popmax 20.5%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

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.1086T>C · rs55708447 · VCV203863

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

gnomAD v4.1

Common

common (popmax 20.5%, nfe) — too common for a highly-penetrant pathogenic allele

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 1.1	GERP -3.5, phastCons 1
Overall
CADD	13.12	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 20.5% European (non-Finnish) · 240,617/1,175,218 alleles

Filtering AF 20.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 20.4%

Overall 18.5% 297,678/1,606,072 alleles · common exomes 273,268/1,453,896 · genomes 24,410/152,176 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	23.5%	4
Amishnot grpmax-eligible	23.2%	4
European (non-Finnish)grpmax	20.5%	5
Remaining individualsnot grpmax-eligible	17%	6
Ashkenazi Jewishnot grpmax-eligible	14.7%	7
Admixed American	13.1%	8
South Asian	12.1%	8
African / African-American	9.65%	10
Middle Eastern	8.51%	12
East Asian	1.61%	62

Finnish 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.Phe362=
Coding: c.1086T>C
MANE Select: NM_153006
dbSNP: rs55708447
Type: single nucleotide variant
Location: chr17:44006699 (GRCh38)
Gene constraint: LOEUF 1.178 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.38 · 1 PDB
Residue 362: 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.Phe362Ser 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-phe362 (accessed [today's date]).

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