Is CPZ p.Arg19Pro (c.56G>C) pathogenic?

CPZ p.Arg19Pro (c.56G>C) is classified Benign in CPZ (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-11-25). AlphaMissense: likely benign (0.0858); Common (popmax 19.8%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with CPZ-related disorder.

What condition is associated with CPZ p.Arg19Pro (c.56G>C)?

CPZ p.Arg19Pro (c.56G>C) is associated with CPZ-related disorder (ClinVar).

What do computational predictors say about CPZ p.Arg19Pro (c.56G>C)?

AlphaMissense predicts likely benign (score 0.0858) — an in-silico prediction, not a clinical call.

CPZ p.Arg19Pro

Q: How common is CPZ p.Arg19Pro (c.56G>C) in the general population?

CPZ p.Arg19Pro (c.56G>C) is common (popmax 19.8%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.56G>C · rs79736750 · VCV3056352

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0858 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 19.8%, nfe) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CPZ-related disorder

Computational evidence

Protein change
AlphaMissense	0.0858	likely benign
REVEL	0.071	moderately benign-leaning
SaProt	LLR -6.45	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 0.27	GERP -0.46, phastCons 0.005
Regional constraint	o/e 1.60	unconstrained · MANE · 27 kb · p 7.4e-73 · regional, not allelic
Overall
CADD	8.397	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 19.8% European (non-Finnish) · 226,648/1,142,122 alleles

Filtering AF 19.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 19.7%

Overall 18% 274,965/1,531,574 alleles · common

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	19.8%	5
Finnishnot grpmax-eligible	19%	5
South Asian	18.9%	5
Remaining individualsnot grpmax-eligible	16.3%	6
Middle Eastern	14.1%	7
Ashkenazi Jewishnot grpmax-eligible	12.2%	8
Amishnot grpmax-eligible	11.6%	9
Admixed American	8.29%	12
East Asian	4.86%	21
African / African-American	4.34%	23

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.Arg19Pro
Coding: c.56G>C
MANE Select: NM_001014447
dbSNP: rs79736750
Type: single nucleotide variant
Location: chr4:8592889 (GRCh38)
Gene constraint: LOEUF 1.966 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.33

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

Disease context

CPZ-related disorder

Similar variants

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
CPZ c.*4C>T Benign same condition
CPZ c.*7C>G 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-arg19pro (accessed [today's date]).

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