Is PRSS1 p.Pro176fs (c.527del) pathogenic?

PRSS1 p.Pro176fs (c.527del) is classified Uncertain significance in PRSS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-29). Very rare (popmax 8.47e-05%, nfe); Associated with hereditary chronic pancreatitis.

What condition is associated with PRSS1 p.Pro176fs (c.527del)?

PRSS1 p.Pro176fs (c.527del) is associated with hereditary chronic pancreatitis (ClinVar).

How common is PRSS1 p.Pro176fs (c.527del) in the general population?

PRSS1 p.Pro176fs (c.527del) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

PRSS1 p.Pro176fs

Q: How is Autosomal dominant hereditary chronic pancreatitis inherited?

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

c.527del · rs1181629887 · VCV2560444

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

hereditary chronic pancreatitis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 4 of 5
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.8	GERP 0.69, phastCons 1
Overall
CADD	23.3	PHRED · no single calibrated threshold — expert panels disagree
Region caveats
Repeat context	seg dup	· reads may not map uniquely · confidence, not pathogenicity

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,016 alleles

Overall 6.2e-05% 1/1,614,046 alleles · very rare exomes 0/1,461,862 · genomes 1/152,184 · joint denominator

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: PRSS1
Protein: p.Pro176fs
Coding: c.527del
MANE Select: NM_002769
dbSNP: rs1181629887
Type: Deletion
Location: chr7:142752501 (GRCh38)
Gene constraint: LOEUF 1.301 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 92.24 · 12 PDB
Residue 176: the peptidase s1 domain; a turn

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.Pro176= Likely benign ★ same residue
PRSS1 c.-28_-8del21 Uncertain significance ★★ same condition
PRSS1 p.Phe18fs Uncertain significance ★★ same condition
PRSS1 c.41-5del Uncertain significance ★ same condition
PRSS1 p.Gly217del Uncertain significance ★ same condition
PRSS1 p.Ser115fs Uncertain significance ★ same condition
PRSS1 c.591+12_591+14del Likely benign ★ same condition
PRSS1 p.Ala16Val 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-pro176fs (accessed [today's date]).

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