Is CPS1 p.Cys648fs (c.1941_1944del) pathogenic?

CPS1 p.Cys648fs (c.19411944del) is classified Pathogenic/Likely pathogenic in CPS1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-13). Very rare (popmax 0.00134%, afr); Associated with pulmonary hypertension, neonatal, susceptibility to.

What condition is associated with CPS1 p.Cys648fs (c.1941_1944del)?

CPS1 p.Cys648fs (c.1941_1944del) is associated with pulmonary hypertension, neonatal, susceptibility to, carbamoyl phosphate synthetase I deficiency disease (ClinVar).

How common is CPS1 p.Cys648fs (c.1941_1944del) in the general population?

CPS1 p.Cys648fs (c.1941_1944del) is very rare (popmax 0.00134%, afr) (gnomAD).

CPS1 p.Cys648fs

c.1941_1944del · rs1182802068 · VCV2680907

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Conditions

pulmonary hypertension, neonatal, susceptibility to

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 17 of 38
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 11	GERP 2.9, phastCons 1
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00134% African / African-American · 1/74,786 alleles

Overall 0.000658% 1/151,952 alleles · very rare

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: CPS1
Protein: p.Cys648fs
Coding: c.1941_1944del
MANE Select: NM_001875
dbSNP: rs1182802068
Type: Microsatellite
Location: chr2:210605202 (GRCh38)
Gene constraint: LOEUF 0.764 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.80 · 14 PDB
Residue 648: a UniProt-annotated variant site (in cps1d); the atp-grasp 1 domain; a β-strand

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

Disease context

pulmonary hypertension, neonatal, susceptibility to — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: carbamoyl phosphate synthetase I deficiency disease

Similar variants

CPS1 p.Val1013del Pathogenic/Likely pathogenic ★★ same condition
CPS1 c.1263+8TG[4] Likely benign ★★ same condition
CPS1 p.Ala724fs Pathogenic ★ same condition
CPS1 p.Arg1326fs Likely pathogenic ★ same condition
CPS1 p.Cys225fs Likely pathogenic ★ same condition
CPS1 p.Glu604fs Pathogenic ★ same condition
CPS1 p.Gly524fs Likely pathogenic ★ same condition
CPS1 p.Leu827fs 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-cys648fs (accessed [today's date]).

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