Is CPZ p.Pro480Ala (c.1438C>G) pathogenic?

CPZ p.Pro480Ala (c.1438C>G) is classified Benign in CPZ (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-10-29). AlphaMissense: likely benign (0.0699); Low-frequency (popmax 2.85%, mid); Associated with CPZ-related disorder.

What condition is associated with CPZ p.Pro480Ala (c.1438C>G)?

CPZ p.Pro480Ala (c.1438C>G) is associated with CPZ-related disorder (ClinVar).

How common is CPZ p.Pro480Ala (c.1438C>G) in the general population?

CPZ p.Pro480Ala (c.1438C>G) is low-frequency (popmax 2.85%, mid) (gnomAD).

What do computational predictors say about CPZ p.Pro480Ala (c.1438C>G)?

AlphaMissense predicts likely benign (score 0.0699) — an in-silico prediction, not a clinical call.

CPZ p.Pro480Ala

c.1438C>G · rs144878756 · VCV3041702

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0699 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.85%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CPZ-related disorder

Computational evidence

Protein change
AlphaMissense	0.0699	likely benign
REVEL	0.228	benign-leaning
SaProt	LLR -7.87	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.1	GERP -0.21, phastCons 0.99
Regional constraint	o/e 1.60	unconstrained · MANE · 27 kb · p 7.4e-73 · regional, not allelic
Overall
CADD	12.66	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.85% Middle Eastern · 173/6,060 alleles

Filtering AF 2.51% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.37%

Overall 0.507% 8,181/1,614,012 alleles · low-frequency

Ancestry group	Frequency	1 in
Middle Easterngrpmax	2.85%	35
Ashkenazi Jewishnot grpmax-eligible	2.53%	40
African / African-American	0.941%	106
Admixed American	0.777%	129
Remaining individualsnot grpmax-eligible	0.63%	159
European (non-Finnish)	0.457%	219
South Asian	0.324%	309
Finnishnot grpmax-eligible	0.0109%	9,140

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: CPZ
Protein: p.Pro480Ala
Coding: c.1438C>G
MANE Select: NM_001014447
dbSNP: rs144878756
Type: single nucleotide variant
Location: chr4:8614433 (GRCh38)
Gene constraint: LOEUF 1.966 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.33
Residue 480: the peptidase m14 domain

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

Disease context

CPZ-related disorder

Similar variants

CPZ p.Pro480His Uncertain significance ★ ⚠ same residue
CPZ p.Pro480Thr Uncertain significance ★ ⚠ same residue
CPZ p.Ala205Thr Uncertain significance ⚠ same condition
CPZ p.Gly575Arg Uncertain significance ⚠ same condition
CPZ c.1363+6G>T Benign same condition
CPZ c.1504-3C>T Benign same condition
CPZ c.497-5C>G Likely benign same condition
CPZ c.-10C>T Likely benign 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/cpz-p-pro480ala (accessed [today's date]).

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