ASL

Chr 7AR

argininosuccinate lyase

Also known as: ASAL, ASLD

NCBI Gene: 435 ENSG00000126522 UniProt: P04424 OMIM: 608310

The protein catalyzes the reversible hydrolytic cleavage of argininosuccinate into arginine and fumarate as an essential step in the urea cycle for ammonia detoxification. Mutations cause argininosuccinic aciduria, an autosomal recessive disorder resulting from argininosuccinic acid lyase deficiency.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, Mechanism

This gene encodes a member of the lyase 1 family. The encoded protein forms a cytosolic homotetramer and primarily catalyzes the reversible hydrolytic cleavage of argininosuccinate into arginine and fumarate, an essential step in the liver in detoxifying ammonia via the urea cycle. Mutations in this gene result in the autosomal recessive disorder argininosuccinic aciduria, or argininosuccinic acid lyase deficiency. A nontranscribed pseudogene is also located on the long arm of chromosome 22. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Argininosuccinic aciduriaMIM #207900

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · argininosuccinic aciduria · AR · ClinGen 2018

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

863

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.94

LOEUF

LOF

Mechanism· G2P

📖

GeneReview available — ASL

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.94LOEUF

pLI 0.000

Z-score 1.83

OE 0.64 (0.44–0.94)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.75Z-score

OE missense 0.87 (0.79–0.97)

247 obs / 282.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.64 (0.44–0.94)

0≤0.351.4

Missense OE?0.87 (0.79–0.97)

0≤0.61.4

Synonymous OE?1.16

0≤1.21.6

LoF obs/exp: 19 / 29.8Missense obs/exp: 247 / 282.4Syn Z: -1.37

Background carrier burden — how many people carry a rare variant somewhere in ASL?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 120

575 rare PASS variants

Rare truncating (LoF)

1 in 970

97 rare PASS variants

Rare synonymous (reference)

1 in 120

254 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for ASL. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 130	1 in 840
South Asian	~43k	1 in 110	1 in 960
Remaining (unassigned)	~30k	1 in 98	1 in 1,500
European (Finnish)	~27k	1 in 170	1 in 4,800
Admixed American	~22k	1 in 88	1 in 4,400
African / African American	~21k	1 in 75	1 in 1,700
East Asian	~20k	1 in 140	1 in 570
Ashkenazi Jewish	~13k	1 in 340	≈ 1 in 3,300
Middle Eastern	~2,884	1 in 130	≈ 1 in 2,900

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 16 coding exons well covered in gnomAD exomes and genomes.? see exons ↓