Is ASL p.Thr103fs (c.305dup) pathogenic?

ASL p.Thr103fs (c.305dup) is classified Likely pathogenic in ASL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-12-01). Very rare (popmax 0.000169%, nfe); Associated with argininosuccinic aciduria.

What condition is associated with ASL p.Thr103fs (c.305dup)?

ASL p.Thr103fs (c.305dup) is associated with argininosuccinic aciduria (ClinVar).

How common is ASL p.Thr103fs (c.305dup) in the general population?

ASL p.Thr103fs (c.305dup) is very rare (popmax 0.000169%, nfe) (gnomAD).

How is Argininosuccinic aciduria inherited?

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

ASL p.Thr103fs

c.305dup · rs2484997333 · VCV2678788

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

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 5 of 17
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 8.7	GERP 1.4, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,179,990 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,592 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.Thr103fs
Coding: c.305dup
MANE Select: NM_000048
dbSNP: rs2484997333
Type: Duplication
Location: chr7:66082892 (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 103: 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.Thr103= Likely benign ★ same residue
ASL p.Thr103Met Likely benign ★ ⚠ same residue
ASL p.Arg186_Leu187insGlyThrAspProArgLeuTer Pathogenic ★★ same condition
ASL p.Met256fs Pathogenic ★★ same condition
ASL c.656-3dup Benign/Likely benign ★★ same condition
ASL c.978+15dup Benign/Likely benign ★★ same condition
ASL c.656-1dup Likely pathogenic ★ same condition
ASL p.Arg111fs 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-thr103fs (accessed [today's date]).

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