Is ASS1 p.Ser2Pro (c.4T>C) pathogenic?

ASS1 p.Ser2Pro (c.4T>C) is classified Uncertain significance in ASS1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2025-05-05). AlphaMissense: likely benign (0.0963); Absent from gnomAD v4.1; Associated with citrullinemia type I.

What condition is associated with ASS1 p.Ser2Pro (c.4T>C)?

ASS1 p.Ser2Pro (c.4T>C) is associated with citrullinemia type I (ClinVar).

How common is ASS1 p.Ser2Pro (c.4T>C) in the general population?

ASS1 p.Ser2Pro (c.4T>C) is absent from gnomAD v4.1 (gnomAD).

How is Citrullinemia type I inherited?

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

What do computational predictors say about ASS1 p.Ser2Pro (c.4T>C)?

AlphaMissense predicts likely benign (score 0.0963) — an in-silico prediction, not a clinical call.

ASS1 p.Ser2Pro

c.4T>C · VCV4062509

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0963 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

citrullinemia type I

Computational evidence

Protein change
AlphaMissense	0.0963	likely benign
REVEL	0.475	indeterminate
SaProt	LLR -4.00	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP 0.81, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 49 kb · p 6.7e-05 · regional, not allelic
Overall
CADD	21.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ASS1
Protein: p.Ser2Pro
Coding: c.4T>C
MANE Select: NM_054012
Type: single nucleotide variant
Location: chr9:130452232 (GRCh38)
Gene constraint: LOEUF 1.14 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.64 · 1 PDB

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

Disease context

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

For Citrullinemia type I (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

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
ASS1 c.420+1G>T Pathogenic/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-ser2pro (accessed [today's date]).

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