Is CPS1 p.Ser1216fs (c.3646dup) pathogenic?

CPS1 p.Ser1216fs (c.3646dup) is classified Likely pathogenic in CPS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-11). Associated with carbamoyl phosphate synthetase I deficiency disease.

What condition is associated with CPS1 p.Ser1216fs (c.3646dup)?

CPS1 p.Ser1216fs (c.3646dup) is associated with carbamoyl phosphate synthetase I deficiency disease (ClinVar).

How is Carbamoyl-phosphate synthetase 1 deficiency inherited?

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

CPS1 p.Ser1216fs

c.3646dup · VCV4814962

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

carbamoyl phosphate synthetase I deficiency disease

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 30 of 38
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 4.9	GERP 1.9, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Variant & gene context

Gene: CPS1
Protein: p.Ser1216fs
Coding: c.3646dup
MANE Select: NM_001875
Type: Duplication
Location: chr2:210656611 (GRCh38)
Gene constraint: LOEUF 0.764 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.80 · 14 PDB
Residue 1216: the atp-grasp 2 domain

Full CPS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

carbamoyl phosphate synthetase I deficiency disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Carbamoyl-phosphate synthetase 1 deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages

Similar variants

CPS1 p.Asn103_Gly104dup Pathogenic/Likely pathogenic ★★ same condition
CPS1 p.Asp442Ter Pathogenic/Likely pathogenic ★★ same condition
CPS1 p.Gly802fs Pathogenic/Likely pathogenic ★★ same condition
CPS1 p.Leu290fs Pathogenic/Likely pathogenic ★★ same condition
CPS1 c.3666+77dup Benign ★★ same condition
CPS1 c.3928-8dup Likely benign ★★ same condition
CPS1 p.Ala1102fs Pathogenic ★ same condition
CPS1 p.Asn472fs 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/cps1-p-ser1216fs (accessed [today's date]).

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