Is CPA1 p.Arg2Trp (c.4C>T) pathogenic?

CPA1 p.Arg2Trp (c.4C>T) is classified Uncertain significance in CPA1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-26). AlphaMissense: likely benign (0.2525); Very rare (popmax 0.0056%, eas); Associated with hereditary chronic pancreatitis.

What condition is associated with CPA1 p.Arg2Trp (c.4C>T)?

CPA1 p.Arg2Trp (c.4C>T) is associated with hereditary chronic pancreatitis (ClinVar).

How common is CPA1 p.Arg2Trp (c.4C>T) in the general population?

CPA1 p.Arg2Trp (c.4C>T) is very rare (popmax 0.0056%, eas) (gnomAD).

What do computational predictors say about CPA1 p.Arg2Trp (c.4C>T)?

AlphaMissense predicts likely benign (score 0.2525) — an in-silico prediction, not a clinical call.

CPA1 p.Arg2Trp

Q: How is Autosomal dominant hereditary chronic pancreatitis inherited?

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

c.4C>T · rs541913287 · VCV1000164

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2525 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0056%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary chronic pancreatitis

Computational evidence

Protein change
AlphaMissense	0.2525	likely benign
REVEL	0.102	moderately benign-leaning
SaProt	LLR -8.43	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 -0.43	GERP -4.5
Regional constraint	o/e 0.88	unconstrained · MANE · 7,487 bp · p 0.0037 · regional, not allelic
Overall
CADD	15.13	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0056% East Asian · 2/35,726 alleles

Filtering AF 0.000927% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000347%

Overall 0.000837% 11/1,314,664 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0056%	17,863
African / African-American	0.00301%	33,191
Finnishnot grpmax-eligible	0.00197%	50,876
European (non-Finnish)	0.000586%	170,585

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.Arg2Trp
Coding: c.4C>T
MANE Select: NM_001868
dbSNP: rs541913287
Type: single nucleotide variant
Location: chr7:130380524 (GRCh38)
Gene constraint: LOEUF 1.14 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.41 · 6 PDB

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.Arg2Gln Benign/Likely benign ★★ ⚠ same residue
CPA1 p.Arg2Pro Uncertain significance ★ ⚠ 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
CPA1 p.Ala120Thr 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-arg2trp (accessed [today's date]).

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