ASS1

Chr 9AR

argininosuccinate synthase 1

Also known as: ASS, CTLN1

NCBI Gene: 445 ENSG00000130707 UniProt: P00966 OMIM: 603470

The protein catalyzes the penultimate step of arginine biosynthesis by synthesizing argininosuccinate from citrulline and aspartate. Mutations cause citrullinemia, an autosomal recessive disorder of the urea cycle that results in hyperammonemia and elevated plasma citrulline levels. The pathogenic mechanism involves loss of enzyme function leading to impaired conversion of citrulline to argininosuccinate in the cytosol.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

The protein encoded by this gene catalyzes the penultimate step of the arginine biosynthetic pathway. There are approximately 10 to 14 copies of this gene including the pseudogenes scattered across the human genome, among which the one located on chromosome 9 appears to be the only functional gene for argininosuccinate synthetase. Mutations in the chromosome 9 copy of this gene cause citrullinemia. Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Aug 2012]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.981 OMIM phenotype

VCEP Guidelines: Urea Cycle DisordersReleased

ClinGen Panel

Clinical Summary— ASS1

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Gene-Disease Validity (ClinGen)

citrullinemia type I · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

250 unique Pathogenic / Likely Pathogenic· 216 VUS of 965 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — ASS1

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?

0.98LOEUF

pLI 0.000

Z-score 1.62

OE 0.66 (0.46–0.98)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.76Z-score

OE missense 0.86 (0.77–0.97)

211 obs / 244.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.66 (0.46–0.98)

0≤0.351.4

Missense OE?0.86 (0.77–0.97)

0≤0.61.4

Synonymous OE?1.14

0≤1.21.6

LoF obs/exp: 18 / 27.1Missense obs/exp: 211 / 244.3Syn Z: -1.11

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveASS1-related citrullinemiaLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.7035th %ile

GOF

0.5660th %ile

LOF

0.3454th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

965 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic87

Likely Pathogenic163

VUS216

Likely Benign381

Benign51

Conflicting48

Pathogenic

163

Likely Pathogenic

216

VUS

381

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	48	20	19	0	87
Likely Pathogenic	95	58	10	0	163
VUS	2	159	48	7	216
Likely Benign	1	5	186	189	381
Benign	0	0	49	2	51
Conflicting	—				48
Total	146	242	312	198	946

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

29 pathogenic / likely-pathogenic (of 39) ClinVar copy-number / structural variants overlap ASS1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →