Is NAGS p.Pro434= (c.1302C>T) pathogenic?

NAGS p.Pro434= (c.1302C>T) is classified Conflicting classifications of pathogenicity in NAGS (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-01-20). Rare (popmax 0.232%, sas); Associated with hyperammonemia due to N-acetylglutamate synthase deficiency.

What condition is associated with NAGS p.Pro434= (c.1302C>T)?

NAGS p.Pro434= (c.1302C>T) is associated with hyperammonemia due to N-acetylglutamate synthase deficiency (ClinVar).

How common is NAGS p.Pro434= (c.1302C>T) in the general population?

NAGS p.Pro434= (c.1302C>T) is rare (popmax 0.232%, sas) (gnomAD).

NAGS p.Pro434=

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.1302C>T · rs150004962 · VCV323450

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

rare (popmax 0.232%, sas)

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 -8.8	GERP -4
Overall
CADD	1.377	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.232% South Asian · 209/90,132 alleles

Filtering AF 0.206% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.196%

Overall 0.114% 1,825/1,606,326 alleles · rare exomes 1,712/1,453,978 · genomes 113/152,348 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.232%	431
European (non-Finnish)	0.125%	803
Remaining individualsnot grpmax-eligible	0.119%	839
Ashkenazi Jewishnot grpmax-eligible	0.0919%	1,088
Middle Eastern	0.0331%	3,023
Finnishnot grpmax-eligible	0.0301%	3,326
African / African-American	0.024%	4,159
Admixed American	0.0187%	5,341

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.Pro434=
Coding: c.1302C>T
MANE Select: NM_153006
dbSNP: rs150004962
Type: single nucleotide variant
Location: chr17:44007624 (GRCh38)
Gene constraint: LOEUF 1.178 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.38 · 1 PDB
Residue 434: a β-strand; the n-acetyltransferase domain

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-pro434 (accessed [today's date]).

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