Is CPA1 p.Pro70Ser (c.208C>T) pathogenic?

CPA1 p.Pro70Ser (c.208C>T) is classified Conflicting classifications of pathogenicity in CPA1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-06-05). AlphaMissense: likely benign (0.0835); Very rare (popmax 0.0022%, sas); Associated with hereditary chronic pancreatitis.

What condition is associated with CPA1 p.Pro70Ser (c.208C>T)?

CPA1 p.Pro70Ser (c.208C>T) is associated with hereditary chronic pancreatitis (ClinVar).

How common is CPA1 p.Pro70Ser (c.208C>T) in the general population?

CPA1 p.Pro70Ser (c.208C>T) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about CPA1 p.Pro70Ser (c.208C>T)?

AlphaMissense predicts likely benign (score 0.0835) — an in-silico prediction, not a clinical call.

CPA1 p.Pro70Ser

Q: How is Autosomal dominant hereditary chronic pancreatitis inherited?

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

c.208C>T · rs1796406634 · VCV1437439

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0835 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary chronic pancreatitis

Computational evidence

Protein change
AlphaMissense	0.0835	likely benign
REVEL	0.038	moderately benign-leaning
SaProt	LLR -5.50	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.37 · evaluated, not missing
Constraint at this position
Conservation	phyloP -8.7	GERP -5
Regional constraint	o/e 0.88	unconstrained · MANE · 7,487 bp · p 0.0037 · regional, not allelic
Overall
CADD	0.165	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 0.0022% South Asian · 2/91,082 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000248% 4/1,613,992 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,541
European (non-Finnish)	0.000169%	590,012

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.Pro70Ser
Coding: c.208C>T
MANE Select: NM_001868
dbSNP: rs1796406634
Type: single nucleotide variant
Location: chr7:130381690 (GRCh38)
Gene constraint: LOEUF 1.14 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.41 · 6 PDB
Residue 70: an α-helix

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.Pro70Leu 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
CPA1 p.Ala193Ser 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-pro70ser (accessed [today's date]).

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