Is ADSL p.Thr450fs (c.1346dup) pathogenic?

ADSL p.Thr450fs (c.1346dup) is classified Pathogenic in ADSL (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-14). Absent from gnomAD; Associated with adenylosuccinate lyase deficiency.

What condition is associated with ADSL p.Thr450fs (c.1346dup)?

ADSL p.Thr450fs (c.1346dup) is associated with adenylosuccinate lyase deficiency (ClinVar).

How common is ADSL p.Thr450fs (c.1346dup) in the general population?

ADSL p.Thr450fs (c.1346dup) is absent from gnomAD (gnomAD).

How is Adenylosuccinate lyase deficiency inherited?

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

ADSL p.Thr450fs

c.1346dup · rs2518130804 · VCV2752273

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

adenylosuccinate lyase 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	escapes	premature termination codon within the last 50 nt of the penultimate exon (12 of 13, 25 nt from its 3' end) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 6	GERP 2.5, phastCons 1

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

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: ADSL
Protein: p.Thr450fs
Coding: c.1346dup
MANE Select: NM_000026
dbSNP: rs2518130804
Type: Duplication
Location: chr22:40365031 (GRCh38)
Gene constraint: LOEUF 0.915 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 96.82 · 4 PDB
Residue 450: a UniProt-annotated variant site (in adsld; moderate)

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

Disease context

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

For Adenylosuccinate lyase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy, Neonatal

Similar variants

ADSL p.Thr450Ser Pathogenic/Likely pathogenic ★★ ⚠ same residue
ADSL p.Thr450Ile Uncertain significance ★ ⚠ same residue
ADSL p.Thr450= Likely benign ★ same residue
ADSL p.Arg270fs Pathogenic ★★ same condition
ADSL p.Gln456fs Uncertain significance ★ same condition
ADSL p.Gln458fs Uncertain significance ★ same condition
ADSL c.1102-15dup Likely benign ★ same condition
ADSL c.1191+12dup Likely benign ★ 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/adsl-p-thr450fs (accessed [today's date]).

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