Is CPZ p.Ile348Ser (c.1043T>G) pathogenic?

CPZ p.Ile348Ser (c.1043T>G) is classified Uncertain significance in CPZ (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-08). AlphaMissense: likely pathogenic (0.8921); Absent from gnomAD v4.1.

How common is CPZ p.Ile348Ser (c.1043T>G) in the general population?

CPZ p.Ile348Ser (c.1043T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CPZ p.Ile348Ser (c.1043T>G)?

AlphaMissense predicts likely pathogenic (score 0.8921) — an in-silico prediction, not a clinical call.

CPZ p.Ile348Ser

c.1043T>G · VCV3496740

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8921 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8921	likely pathogenic
REVEL	0.364	indeterminate
SaProt	LLR -11.19	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.2, phastCons 1
Regional constraint	o/e 1.60	unconstrained · MANE · 27 kb · p 7.4e-73 · regional, not allelic
Overall
CADD	26.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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: CPZ
Protein: p.Ile348Ser
Coding: c.1043T>G
MANE Select: NM_001014447
Type: single nucleotide variant
Location: chr4:8606873 (GRCh38)
Gene constraint: LOEUF 1.966 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.33
Residue 348: the peptidase m14 domain

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

Similar variants

CPZ p.Gln317Ter Uncertain significance ★★ same type
CPZ c.1068+9C>T Benign ★★ same type
CPZ c.1604-8G>T Benign ★★ same type
CPZ p.Arg522= Benign ★★ same type
CPZ p.Arg647= Likely benign ★★ same type
CPZ p.Asn250= Benign ★★ same type
CPZ p.Gln263Arg Benign ★★ ⚠ same type
CPZ p.Pro618= Benign ★★ same type

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/cpz-p-ile348ser (accessed [today's date]).

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