Is ASS1 p.Ser18Leu (c.53C>T) pathogenic?

ASS1 p.Ser18Leu (c.53C>T) is classified Pathogenic/Likely pathogenic in ASS1 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-09-30). AlphaMissense: likely pathogenic (0.9546); Very rare (popmax 0.00333%, amr); Associated with citrullinemia.

What condition is associated with ASS1 p.Ser18Leu (c.53C>T)?

ASS1 p.Ser18Leu (c.53C>T) is associated with citrullinemia, citrullinemia type I (ClinVar).

How common is ASS1 p.Ser18Leu (c.53C>T) in the general population?

ASS1 p.Ser18Leu (c.53C>T) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about ASS1 p.Ser18Leu (c.53C>T)?

AlphaMissense predicts likely pathogenic (score 0.9546) — an in-silico prediction, not a clinical call.

ASS1 p.Ser18Leu

c.53C>T · rs121908643 · VCV6331

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.9546 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

citrullinemia

Computational evidence

Protein change
AlphaMissense	0.9546	likely pathogenic ✓ concordant with ClinVar
REVEL	0.979	strongly pathogenic-leaning
SaProt	LLR -15.49	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.8, 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 0.00333% Admixed American · 2/60,006 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.00062% 10/1,614,032 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,003
East Asian	0.00223%	44,886
African / African-American	0.00133%	74,932
South Asian	0.0011%	91,086
European (non-Finnish)	0.000424%	236,002

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.Ser18Leu
Coding: c.53C>T
MANE Select: NM_054012
dbSNP: rs121908643
Type: single nucleotide variant
Location: chr9:130452281 (GRCh38)
Gene constraint: LOEUF 1.14 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.64 · 1 PDB
Residue 18: a binding site; an α-helix; a UniProt-annotated variant site (in ctln1)

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

Disease context

citrullinemia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: citrullinemia type I

Similar variants

ASS1 p.Ser18= Likely benign ★ 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
ASS1 c.364-2A>T Likely 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-ser18leu (accessed [today's date]).

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