Is ARG1 p.Ser199fs (c.594_595dup) pathogenic?

ARG1 p.Ser199fs (c.594595dup) is classified Pathogenic in ARG1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-19). Very rare (popmax 0.000424%, nfe); Associated with arginase deficiency.

What condition is associated with ARG1 p.Ser199fs (c.594_595dup)?

ARG1 p.Ser199fs (c.594_595dup) is associated with arginase deficiency (ClinVar).

How common is ARG1 p.Ser199fs (c.594_595dup) in the general population?

ARG1 p.Ser199fs (c.594_595dup) is very rare (popmax 0.000424%, nfe) (gnomAD).

How is Argininemia inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

ARG1 p.Ser199fs

c.594_595dup · rs1337890012 · VCV2064930

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Conditions

arginase deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 6 of 8
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.37	GERP -1.7, phastCons 0.96

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000424% European (non-Finnish) · 5/1,179,648 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.00031% 5/1,613,544 alleles · very rare exomes 5/1,461,376 · genomes 0/152,168 · joint denominator

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: ARG1
Protein: p.Ser199fs
Coding: c.594_595dup
MANE Select: NM_000045
dbSNP: rs1337890012
Type: Duplication
Location: chr6:131583090 (GRCh38)
Gene constraint: LOEUF 0.833 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.01 · 60 PDB
Residue 199: a β-strand

Full ARG1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

arginase deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Argininemia (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy
Prevalence: <1 / 1 000 000 (Finland)

Similar variants

ARG1 p.Ser199Ala Uncertain significance ★ ⚠ same residue
ARG1 p.Ala125fs Pathogenic/Likely pathogenic ★★ same condition
ARG1 p.Arg92fs Pathogenic ★★ same condition
ARG1 p.Asp117fs Pathogenic/Likely pathogenic ★★ same condition
ARG1 p.Asp237fs Pathogenic/Likely pathogenic ★★ same condition
ARG1 p.Ile227fs Pathogenic/Likely pathogenic ★★ same condition
ARG1 p.Phe147fs Pathogenic/Likely pathogenic ★★ same condition
ARG1 c.306-1_307dup Uncertain significance ★★ 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/arg1-p-ser199fs (accessed [today's date]).

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