SPINK4

Chr 9

serine peptidase inhibitor Kazal type 4

Also known as: HEL136, PEC-60, PEC60

NCBI Gene: 27290ENSG00000122711UniProt: O60575OMIM: 613929

The protein is predicted to function as a serine-type endopeptidase inhibitor in the extracellular region. Currently, no established human diseases have been definitively linked to SPINK4 mutations in clinical practice. The gene shows tolerance to loss-of-function variants with a low constraint score (pLI 0.30, LOEUF 1.19).

OMIMResearchSummary from RefSeq
MultiplemechanismLOEUF 1.19
Clinical Summary— SPINK4
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.25) despite low pLI — interpret in context.
📋
ClinVar Variants
69 unique Pathogenic / Likely Pathogenic· 33 VUS of 105 total submissions
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint
1.19LOEUF
pLI 0.296
Z-score 1.37
OE 0.25 (0.09–1.19)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint
0.34Z-score
OE missense 0.86 (0.67–1.12)
41 obs / 47.6 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.25 (0.09–1.19)
0≤0.351.4
Missense OE0.86 (0.67–1.12)
0≤0.61.4
Synonymous OE0.75
0≤1.21.6
LoF obs/exp: 1 / 3.9Missense obs/exp: 41 / 47.6Syn Z: 0.84
DN
0.90top 5%
GOF
0.6540th %ile
LOF
0.09100th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median
GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

105 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic61
Likely Pathogenic8
VUS33
Likely Benign1
Benign1
61
Pathogenic
8
Likely Pathogenic
33
VUS
1
Likely Benign
1
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
61
0
61
Likely Pathogenic
0
0
8
0
8
VUS
0
21
12
0
33
Likely Benign
0
1
0
0
1
Benign
0
0
1
0
1
Total022820104

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

View in ClinVar →

Protein Context — Lollipop Plot

SPINK4 · protein map & ClinVar variants

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

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 4 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Leveraging a KRAS-based signature to predict the prognosis and drug sensitivity of colon cancer and identifying SPINK4 as a new biomarker.
Huo JT et al.·Sci Rep
2023
Single-cell profiling reveals differences between human classical adenocarcinoma and mucinous adenocarcinoma.
Hu FJ et al.·Commun Biol
2023
Baseline Serum and Stool Microbiome Biomarkers Predict Clinical Efficacy and Tissue Molecular Response After Ritlecitinib Induction Therapy in Ulcerative Colitis.
Hassan-Zahraee M et al.·J Crohns Colitis
2024Clinical trial
[Identification of potential pathogenic genes of intestinal metaplasia based on transcriptomic sequencing and bioinformatics analysis].
Pei B et al.·Nan Fang Yi Ke Da Xue Xue Bao
2024
Downregulated SPINK4 is associated with poor survival in colorectal cancer.
Wang X et al.·BMC Cancer
2019
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients