Is ASL p.Ser133Ter (c.398C>A) pathogenic?

ASL p.Ser133Ter (c.398C>A) is classified Likely pathogenic in ASL (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-04). Absent from gnomAD v4.1; Associated with argininosuccinic aciduria.

What condition is associated with ASL p.Ser133Ter (c.398C>A)?

ASL p.Ser133Ter (c.398C>A) is associated with argininosuccinic aciduria (ClinVar).

How common is ASL p.Ser133Ter (c.398C>A) in the general population?

ASL p.Ser133Ter (c.398C>A) is absent from gnomAD v4.1 (gnomAD).

How is Argininosuccinic aciduria inherited?

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

ASL p.Ser133Ter

c.398C>A · rs748203708 · VCV1724986

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

argininosuccinic aciduria

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 6 of 17
Splicing
SpliceAI	Δ0.43	donor loss, 48 bp away · masked 0 · deltas
Pangolin	Δ0.37	loss · gain 0.01 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 2.3	GERP -2.7, phastCons 0.94
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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ASL
Protein: p.Ser133Ter
Coding: c.398C>A
MANE Select: NM_000048
dbSNP: rs748203708
Type: single nucleotide variant
Location: chr7:66083126 (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 133: 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.Ser133Leu Uncertain significance ★ ⚠ same residue
ASL p.Ser133Trp Uncertain significance ★ ⚠ same residue
ASL p.Ser133= Likely benign ★ same residue
ASL c.1062+5G>C Likely pathogenic ★★ same condition
ASL c.1143+1G>T Pathogenic/Likely pathogenic ★★ same condition
ASL c.13-1G>C Pathogenic/Likely pathogenic ★★ same condition
ASL c.291+1G>T Likely pathogenic ★★ same condition
ASL c.348+1G>A 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/asl-p-ser133ter (accessed [today's date]).

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