Is PRSS1 p.Pro129Arg (c.386C>G) pathogenic?

PRSS1 p.Pro129Arg (c.386C>G) is classified Uncertain significance in PRSS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-26). AlphaMissense: likely pathogenic (0.9249); Absent from gnomAD v4.1; Associated with hereditary chronic pancreatitis.

What condition is associated with PRSS1 p.Pro129Arg (c.386C>G)?

PRSS1 p.Pro129Arg (c.386C>G) is associated with hereditary chronic pancreatitis (ClinVar).

How common is PRSS1 p.Pro129Arg (c.386C>G) in the general population?

PRSS1 p.Pro129Arg (c.386C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PRSS1 p.Pro129Arg (c.386C>G)?

AlphaMissense predicts likely pathogenic (score 0.9249) — an in-silico prediction, not a clinical call.

PRSS1 p.Pro129Arg

Q: How is Autosomal dominant hereditary chronic pancreatitis inherited?

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

c.386C>G · rs768673799 · VCV1735674

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9249 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary chronic pancreatitis

Computational evidence

Protein change
AlphaMissense	0.9249	likely pathogenic
REVEL	0.792	moderately pathogenic-leaning
SaProt	LLR -17.10	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 1.9, phastCons 1
Regional constraint	o/e 1.20	unconstrained · MANE · 3,532 bp · p 0.00039 · regional, not allelic
Overall
CADD	23.2	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PRSS1
Protein: p.Pro129Arg
Coding: c.386C>G
MANE Select: NM_002769
dbSNP: rs768673799
Type: single nucleotide variant
Location: chr7:142751959 (GRCh38)
Gene constraint: LOEUF 1.301 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 92.24 · 12 PDB
Residue 129: an α-helix; the peptidase s1 domain

Full PRSS1 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

PRSS1 p.Pro129Leu Uncertain significance ★★ ⚠ same residue
PRSS1 p.Pro129Ser Uncertain significance ★ ⚠ same residue
PRSS1 p.Pro129Thr Uncertain significance ★ ⚠ same residue
PRSS1 p.Pro129= Likely benign ★ same residue
PRSS1 p.Ala16Val Pathogenic/Likely pathogenic ★★ ⚠ same condition
PRSS1 p.Arg116Cys Pathogenic/Likely pathogenic ★★ same condition
PRSS1 p.Arg122Cys Pathogenic ★★ same condition
PRSS1 p.Arg122His Pathogenic/Likely pathogenic ★★ ⚠ 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/prss1-p-pro129arg (accessed [today's date]).

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