Is SPINK1 p.Pro45= (c.135T>C) pathogenic?

SPINK1 p.Pro45= (c.135T>C) is classified Likely benign in SPINK1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-23). Very rare (popmax 0.00223%, eas); Associated with hereditary chronic pancreatitis.

What condition is associated with SPINK1 p.Pro45= (c.135T>C)?

SPINK1 p.Pro45= (c.135T>C) is associated with hereditary chronic pancreatitis (ClinVar).

How common is SPINK1 p.Pro45= (c.135T>C) in the general population?

SPINK1 p.Pro45= (c.135T>C) is very rare (popmax 0.00223%, eas) (gnomAD).

SPINK1 p.Pro45=

Q: How is Autosomal dominant hereditary chronic pancreatitis inherited?

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

c.135T>C · VCV4173712

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

hereditary chronic pancreatitis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.066
Overall
CADD	4.949	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,792 alleles

Overall 6.2e-05% 1/1,613,652 alleles · very rare exomes 1/1,461,318 · genomes 0/152,334 · 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: SPINK1
Protein: p.Pro45=
Coding: c.135T>C
MANE Select: NM_001379610
Type: single nucleotide variant
Location: chr5:147828081 (GRCh38)
Gene constraint: LOEUF 1.03 · pLI 0.22 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 88.70 · 5 PDB
Residue 45: the kazal-like domain

Full SPINK1 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

SPINK1 p.Pro45Arg Uncertain significance ★★ ⚠ same residue
SPINK1 p.Pro45Thr Uncertain significance ★ ⚠ same residue
SPINK1 c.194+2T>C Pathogenic/Likely pathogenic ★★ same condition
SPINK1 p.Glu35Ter Pathogenic ★★ same condition
SPINK1 c.194+5G>A Uncertain significance ★★ same condition
SPINK1 c.55+5G>A Uncertain significance ★★ same condition
SPINK1 c.-142T>C Uncertain significance ★★ same condition
SPINK1 c.-53C>T 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/spink1-p-pro45 (accessed [today's date]).

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