Is CPA1 p.Arg66Pro (c.197G>C) pathogenic?

CPA1 p.Arg66Pro (c.197G>C) is classified Uncertain significance in CPA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-10). AlphaMissense: likely pathogenic (0.9714); Very rare (popmax 0.00133%, afr); Associated with hereditary chronic pancreatitis.

What condition is associated with CPA1 p.Arg66Pro (c.197G>C)?

CPA1 p.Arg66Pro (c.197G>C) is associated with hereditary chronic pancreatitis (ClinVar).

How common is CPA1 p.Arg66Pro (c.197G>C) in the general population?

CPA1 p.Arg66Pro (c.197G>C) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about CPA1 p.Arg66Pro (c.197G>C)?

AlphaMissense predicts likely pathogenic (score 0.9714) — an in-silico prediction, not a clinical call.

CPA1 p.Arg66Pro

Q: How is Autosomal dominant hereditary chronic pancreatitis inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.197G>C · rs201332778 · VCV1783784

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9714 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary chronic pancreatitis

Computational evidence

Protein change
AlphaMissense	0.9714	likely pathogenic · top 5% in CPA1
REVEL	0.379	indeterminate
SaProt	LLR -11.43	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 12	GERP 2.5, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 7,487 bp · p 0.0037 · regional, not allelic
Overall
CADD	33.0	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

Grpmax group 0.00133% African / African-American · 1/75,042 alleles

Overall 6.84e-05% 1/1,461,790 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: CPA1
Protein: p.Arg66Pro
Coding: c.197G>C
MANE Select: NM_001868
dbSNP: rs201332778
Type: single nucleotide variant
Location: chr7:130381679 (GRCh38)
Gene constraint: LOEUF 1.14 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.41 · 6 PDB
Residue 66: a β-strand

Full CPA1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary chronic pancreatitis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal dominant hereditary chronic pancreatitis (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Childhood
Prevalence: 1-9 / 1 000 000 (France)

Similar variants

CPA1 p.Arg66Gln Uncertain significance ★★ ⚠ same residue
CPA1 p.Arg66Ter Conflicting classifications of pathogenicity ★ same residue
CPA1 p.Arg66= Likely benign ★ same residue
CPA1 c.1072+1G>T Uncertain significance ★★ same condition
CPA1 c.147+4A>C Uncertain significance ★★ same condition
CPA1 c.586-2A>G Uncertain significance ★★ same condition
CPA1 c.696+5C>T Uncertain significance ★★ same condition
CPA1 p.Ala111Glu Uncertain significance ★★ ⚠ 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/cpa1-p-arg66pro (accessed [today's date]).

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