SPINK1

Chr 5ADAR

serine peptidase inhibitor Kazal type 1

Also known as: PCTT, PSTI, Spink3, TATI, TCP

NCBI Gene: 6690ENSG00000164266UniProt: P00995

The protein encoded by this gene is a trypsin inhibitor, which is secreted from pancreatic acinar cells into pancreatic juice. It is thought to function in the prevention of trypsin-catalyzed premature activation of zymogens within the pancreas and the pancreatic duct. Mutations in this gene are associated with hereditary pancreatitis and tropical calcific pancreatitis. [provided by RefSeq, Oct 2008]

Primary Disease Associations & Inheritance

{Fibrocalculous pancreatic diabetes, susceptibility to}MIM #608189
ADAR
Pancreatitis, hereditaryMIM #167800
AD
Tropical calcific pancreatitisMIM #608189
ADAR
261
ClinVar variants
31
Pathogenic / LP
0.31
pLI score
2
Active trials
Clinical Summary— SPINK1
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.24) despite low pLI — interpret in context.
📋
ClinVar Variants
31 Pathogenic / Likely Pathogenic· 111 VUS of 261 total submissions
💊
Clinical Trials
2 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
1.13LOEUF
pLI 0.315
Z-score 1.43
OE 0.24 (0.09–1.13)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
-0.12Z-score
OE missense 1.05 (0.83–1.35)
45 obs / 42.7 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.24 (0.09–1.13)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.05 (0.83–1.35)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.26
0≤1.21.6
LoF obs/exp: 1 / 4.1Missense obs/exp: 45 / 42.7Syn Z: -0.77

ClinVar Variant Classifications

261 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic26
Likely Pathogenic5
VUS111
Likely Benign92
Benign4
Conflicting23
26
Pathogenic
5
Likely Pathogenic
111
VUS
92
Likely Benign
4
Benign
23
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
3
2
21
0
26
Likely Pathogenic
4
1
0
0
5
VUS
2
79
30
0
111
Likely Benign
0
11
28
53
92
Benign
0
0
4
0
4
Conflicting
—23
Total9938353261

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

SPINK1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

{Fibrocalculous pancreatic diabetes, susceptibility to}

MIM #608189

Molecular basis of disorder known

Autosomal dominantAutosomal recessive

Pancreatitis, hereditary

MIM #167800

Molecular basis of disorder known

Autosomal dominant

Tropical calcific pancreatitis

MIM #608189

Molecular basis of disorder known

Autosomal dominantAutosomal recessive
📖
GeneReview available — SPINK1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Expanding ACMG variant classification guidelines into a general framework.
Masson E et al.·Hum Genomics
2022
Prevalence of Germline Sequence Variations Among Patients With Pancreatic Cancer in China.
Yin L et al.·JAMA Netw Open
2022Cohort
SPINK1, PRSS1, CTRC, and CFTR Genotypes Influence Disease Onset and Clinical Outcomes in Chronic Pancreatitis.
Zou WB et al.·Clin Transl Gastroenterol
2018
Prostate cancer.
Attard G et al.·Lancet
2016Review
Hereditary pancreatic cancer.
Abe K et al.·Int J Clin Oncol
2021Review
Pancreas divisum.
DiMagno MJ et al.·Curr Gastroenterol Rep
2011Review
Chronic pancreatitis.
DiMagno MJ et al.·Curr Opin Gastroenterol
2011Review
Functional Roles of SPINK1 in Cancers.
Lin TC·Int J Mol Sci
2021Review
Clinical interpretation of SPINK1 and CTRC variants in pancreatitis.
Girodon E et al.·Pancreatology
2020
Hereditary chronic pancreatitis.
Rosendahl J et al.·Orphanet J Rare Dis
2007Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Single-Cell and Bulk RNA Sequencing Reveal SPINK1 and TIMP1 as Epithelial Cell Marker Genes Linked to Colorectal Cancer Survival and Tumor Immune Microenvironment Profiles.
Al-Bzour NN et al.·Int J Mol Sci
2025🔓 Open Access
SPINK1-driven cellular heterogeneity and interaction networks in intrahepatic cholangiocarcinoma revealed by integrated multi-omics analysis.
Rong X et al.·J Adv Res
2025
[194 + 2T>C;-215G>A] mutation of SPINK1 gene is associated with fibrocalculous pancreatic diabetes: A rare case report.
Li Y et al.·Medicine (Baltimore)
2025🔓 Open AccessCase report
Case Report: a family report of hereditary pancreatitis caused by SPINK1 and PRSS1 gene mutations.
Xu J et al.·Front Genet
2025🔓 Open AccessCase report
PRSS1, SPINK1 Mutations and Associated Factors in Vietnamese Patients With Chronic Pancreatitis.
Vo TTL et al.·JGH Open
2025🔓 Open AccessCohort
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Chronic PancreatitisGenetic MutationSmoking, Tobacco

An Observational Study on the Natural Course of Chronic Pancreatitis

ACTIVE NOT RECRUITING
NCT04574297Changhai HospitalStarted 2011-01-01
smoking and alcohol assumptiongenetic sequencing
Prostate CancerNeoadjuvant TherapyAndrogen Antagonists

Neoadjuvant Degarelix With or Without Apalutamide (ARN-509) Followed by Radical Prostatectomy

ACTIVE NOT RECRUITING
NCT03080116Phase PHASE2Universitaire Ziekenhuizen KU LeuvenStarted 2019-03-28
ARN-509DegarelixPlacebo

External Resources

Links to major genomics databases and tools