Is ASS1 p.Arg265Cys (c.793C>T) pathogenic?

ASS1 p.Arg265Cys (c.793C>T) is classified Pathogenic/Likely pathogenic in ASS1 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-09-26). AlphaMissense: ambiguous (0.5502); Very rare (popmax 0.00223%, eas); Associated with ASS1-related disorder.

What condition is associated with ASS1 p.Arg265Cys (c.793C>T)?

ASS1 p.Arg265Cys (c.793C>T) is associated with ASS1-related disorder, citrullinemia type I, citrullinemia (ClinVar).

How common is ASS1 p.Arg265Cys (c.793C>T) in the general population?

ASS1 p.Arg265Cys (c.793C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about ASS1 p.Arg265Cys (c.793C>T)?

AlphaMissense predicts ambiguous (score 0.5502) — an in-silico prediction, not a clinical call.

ASS1 p.Arg265Cys

c.793C>T · rs148918985 · VCV92373

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

ambiguous

0.5502 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

ASS1-related disorder

Computational evidence

Protein change
AlphaMissense	0.5502	ambiguous
REVEL	0.887	moderately pathogenic-leaning
SaProt	LLR -9.65	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.6, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 49 kb · p 6.7e-05 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,896 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000682% 11/1,614,054 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,896
Remaining individualsnot grpmax-eligible	0.0016%	62,490
African / African-American	0.00133%	74,926
South Asian	0.0011%	91,090
European (non-Finnish)	0.000593%	168,577

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: ASS1
Protein: p.Arg265Cys
Coding: c.793C>T
MANE Select: NM_054012
dbSNP: rs148918985
Type: single nucleotide variant
Location: chr9:130480404 (GRCh38)
Gene constraint: LOEUF 1.14 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.64 · 1 PDB
Residue 265: a β-strand; a UniProt-annotated variant site (in ctln1); a UniProt-annotated variant site (in ctln1; severe clinical course; loss of argininosuccinate synthase activity)

Full ASS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ASS1-related disorder

Also linked: citrullinemia type I citrullinemia

Similar variants

ASS1 p.Arg265His Pathogenic/Likely pathogenic ★★ same residue
ASS1 p.Arg265Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
ASS1 c.1194-1G>C Pathogenic/Likely pathogenic ★★ same condition
ASS1 c.174+1G>A Pathogenic/Likely pathogenic ★★ same condition
ASS1 c.174+1G>T Pathogenic/Likely pathogenic ★★ same condition
ASS1 c.175-1119G>A Pathogenic/Likely pathogenic ★★ same condition
ASS1 c.364-2A>C Pathogenic/Likely pathogenic ★★ same condition
ASS1 c.364-2A>G 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/ass1-p-arg265cys (accessed [today's date]).

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