Is CPS1 p.Pro464fs (c.1390_1397del) pathogenic?

CPS1 p.Pro464fs (c.13901397del) is classified Pathogenic in CPS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-14). Ultra-rare (popmax 0.0166%, mid); Associated with pulmonary hypertension, neonatal, susceptibility to.

What condition is associated with CPS1 p.Pro464fs (c.1390_1397del)?

CPS1 p.Pro464fs (c.1390_1397del) is associated with pulmonary hypertension, neonatal, susceptibility to (ClinVar).

How common is CPS1 p.Pro464fs (c.1390_1397del) in the general population?

CPS1 p.Pro464fs (c.1390_1397del) is ultra-rare (popmax 0.0166%, mid) (gnomAD).

CPS1 p.Pro464fs

c.1390_1397del · rs2469146910 · VCV2680913

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, mid)

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 14 of 38
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.018	GERP 0.28, phastCons 0.79

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0166% Middle Eastern · 1/6,040 alleles

Overall 0.000137% 2/1,460,400 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0166%	6,040
European (non-Finnish)	8.48e-05%	1,178,920

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.Pro464fs
Coding: c.1390_1397del
MANE Select: NM_001875
dbSNP: rs2469146910
Type: Deletion
Location: chr2:210599402 (GRCh38)
Gene constraint: LOEUF 0.764 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.80 · 14 PDB

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

Similar variants

CPS1 p.Ala907fs Pathogenic/Likely pathogenic ★★ same condition
CPS1 p.Arg1228fs Pathogenic/Likely pathogenic ★★ same condition
CPS1 p.Arg932_Leu933insTer Pathogenic ★★ same condition
CPS1 p.Asp642fs Pathogenic/Likely pathogenic ★★ same condition
CPS1 p.Glu842fs Pathogenic/Likely pathogenic ★★ same condition
CPS1 p.Gly475fs Pathogenic/Likely pathogenic ★★ same condition
CPS1 p.Gly510fs Pathogenic ★★ same condition
CPS1 p.His974fs 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/cps1-p-pro464fs (accessed [today's date]).

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