Is ASL p.Arg94fs (c.280_281insTGAAG) pathogenic?

ASL p.Arg94fs (c.280281insTGAAG) is classified Pathogenic in ASL (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-06). Very rare (popmax 0.00447%, eas); Associated with argininosuccinic aciduria.

What condition is associated with ASL p.Arg94fs (c.280_281insTGAAG)?

ASL p.Arg94fs (c.280_281insTGAAG) is associated with argininosuccinic aciduria (ClinVar).

How common is ASL p.Arg94fs (c.280_281insTGAAG) in the general population?

ASL p.Arg94fs (c.280_281insTGAAG) is very rare (popmax 0.00447%, eas) (gnomAD).

How is Argininosuccinic aciduria inherited?

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

ASL p.Arg94fs

c.280_281insTGAAG · rs2484995776 · VCV2123808

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00447%, eas)

Conditions

argininosuccinic aciduria

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 4 of 17
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.4	GERP -1, phastCons 1
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00447% East Asian · 2/44,762 alleles

Filtering AF 0.000741% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000277%

Overall 0.000124% 2/1,610,156 alleles · very rare

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: ASL
Protein: p.Arg94fs
Coding: c.280_281insTGAAG
MANE Select: NM_000048
dbSNP: rs2484995776
Type: Insertion
Location: chr7:66082440 (GRCh38)
Gene constraint: LOEUF 0.937 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 96.51 · 2 PDB
Residue 94: a UniProt-annotated variant site (in arginsa; severe); a UniProt-annotated variant site (in arginsa); an α-helix

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

Disease context

argininosuccinic aciduria — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Argininosuccinic aciduria (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages
Prevalence: 1-9 / 1 000 000 (United States)

Similar variants

ASL p.Arg94Cys Pathogenic/Likely pathogenic ★★ ⚠ same residue
ASL p.Arg94His Likely pathogenic ★★ ⚠ same residue
ASL p.Arg94Ser Likely pathogenic ★ same residue
ASL p.Arg94= Likely benign ★ same residue
ASL p.Leu135fs Likely pathogenic ★ same condition
ASL c.1045_1062+7del Pathogenic ★★ same condition
ASL c.1062+5G>C Likely pathogenic ★★ same condition
ASL c.1143+1del 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/asl-p-arg94fs (accessed [today's date]).

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