Is CPS1 c.528+2T>C pathogenic?

CPS1 c.528+2T>C is classified Likely pathogenic in CPS1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-03-10). Very rare (popmax 8.48e-05%, nfe); Associated with pulmonary hypertension, neonatal, susceptibility to.

What condition is associated with CPS1 c.528+2T>C?

CPS1 c.528+2T>C is associated with pulmonary hypertension, neonatal, susceptibility to, carbamoyl phosphate synthetase I deficiency disease (ClinVar).

How common is CPS1 c.528+2T>C in the general population?

CPS1 c.528+2T>C is very rare (popmax 8.48e-05%, nfe) (gnomAD).

CPS1 c.528+2T>C

rs1574548003 · VCV656114

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

canonical splice-site (±1/±2)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

pulmonary hypertension, neonatal, susceptibility to

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	canonical splice-site (±1/±2)	predicted loss-of-function
Splicing
Splice region	donor +2	canonical splice dinucleotide (donor +2) · inside the BP7-excluded zone
SpliceAI	Δ0.97	donor loss · deltas
Pangolin	Δ0.81	loss · gain 0.20 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.9	GERP 2.6, phastCons 1
Non-coding constraint	Z 0.65	1 kb window · o/e 0.95 · regional · uncalibrated
Overall
CADD	29.4	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 8.48e-05% European (non-Finnish) · 1/1,178,588 alleles

Overall 6.85e-05% 1/1,459,256 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
Coding: c.528+2T>C
MANE Select: NM_001875
dbSNP: rs1574548003
Type: single nucleotide variant
Location: chr2:210579772 (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

Also linked: carbamoyl phosphate synthetase I deficiency disease

Similar variants

CPS1 c.1086+1G>A Likely pathogenic ★★ same condition
CPS1 c.1087-1G>T Pathogenic/Likely pathogenic ★★ same condition
CPS1 c.1165-2A>G Likely pathogenic ★★ same condition
CPS1 c.1263+5G>C Pathogenic/Likely pathogenic ★★ same condition
CPS1 c.1549+1G>A Pathogenic/Likely pathogenic ★★ same condition
CPS1 c.1549+1G>T Pathogenic/Likely pathogenic ★★ same condition
CPS1 c.1837-8A>G Pathogenic/Likely pathogenic ★★ same condition
CPS1 c.1981+1G>C 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-c-528-plus-2t-c (accessed [today's date]).

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