Is ADSL p.Arg125fs (c.372del) pathogenic?

ADSL p.Arg125fs (c.372del) is classified Pathogenic in ADSL (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-10). Very rare (popmax 0.00017%, nfe); Associated with adenylosuccinate lyase deficiency.

What condition is associated with ADSL p.Arg125fs (c.372del)?

ADSL p.Arg125fs (c.372del) is associated with adenylosuccinate lyase deficiency (ClinVar).

How common is ADSL p.Arg125fs (c.372del) in the general population?

ADSL p.Arg125fs (c.372del) is very rare (popmax 0.00017%, nfe) (gnomAD).

How is Adenylosuccinate lyase deficiency inherited?

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

ADSL p.Arg125fs

c.372del · rs2518096229 · VCV2854848

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

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	predicted	premature termination codon in exon 3 of 13
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 3.9	GERP 1.6, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,179,662 alleles

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

Overall 0.000137% 2/1,461,442 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: ADSL
Protein: p.Arg125fs
Coding: c.372del
MANE Select: NM_000026
dbSNP: rs2518096229
Type: Deletion
Location: chr22:40353086 (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 125: an α-helix

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.Asn421del Uncertain significance ★★ same condition
ADSL c.1368+8del Likely benign ★★ same condition
ADSL p.Arg396fs Pathogenic ★ same condition
ADSL p.Asp223fs Pathogenic ★ same condition
ADSL p.Gln63fs Pathogenic ★ same condition
ADSL p.Glu343fs Pathogenic ★ same condition
ADSL p.Leu319fs Pathogenic ★ same condition
ADSL c.655-42_655-8del 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/adsl-p-arg125fs (accessed [today's date]).

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