SPINK5

Chr 5AR

serine peptidase inhibitor Kazal type 5

Also known as: LEKTI, LETKI, NETS, NS, VAKTI

NCBI Gene: 11005ENSG00000133710UniProt: Q9NQ38

This gene encodes a multidomain serine protease inhibitor that contains 15 potential inhibitory domains. The encoded preproprotein is proteolytically processed to generate multiple protein products, which may exhibit unique activities and specificities. These proteins may play a role in skin and hair morphogenesis, as well as anti-inflammatory and antimicrobial protection of mucous epithelia. Mutations in this gene may result in Netherton syndrome, a disorder characterized by ichthyosis, defective cornification, and atopy. This gene is present in a gene cluster on chromosome 5. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2015]

Primary Disease Associations & Inheritance

Netherton syndromeMIM #256500
AR
576
ClinVar variants
98
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— SPINK5
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
98 Pathogenic / Likely Pathogenic· 156 VUS of 576 total submissions

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.
0.93LOEUF
pLI 0.000
Z-score 2.04
OE 0.74 (0.59–0.93)
Tolerant

Typical tolerance to LoF variation

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.
0.28Z-score
OE missense 0.97 (0.90–1.04)
562 obs / 580.9 exp
Tolerant

Mild missense constraint

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.0.74 (0.59–0.93)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.97 (0.90–1.04)
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.1.03
0≤1.21.6
LoF obs/exp: 53 / 71.7Missense obs/exp: 562 / 580.9Syn Z: -0.33

ClinVar Variant Classifications

576 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic67
Likely Pathogenic31
VUS156
Likely Benign234
Benign70
Conflicting18
67
Pathogenic
31
Likely Pathogenic
156
VUS
234
Likely Benign
70
Benign
18
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
35
0
32
0
67
Likely Pathogenic
25
0
5
1
31
VUS
1
132
20
3
156
Likely Benign
1
10
128
95
234
Benign
0
7
54
9
70
Conflicting
—18
Total62149239108576

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

View in ClinVar →

Protein Context — Lollipop Plot

SPINK5 · protein map & ClinVar variants

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

Gene2Phenotype Curations

SPINK5-related Netherton syndrome

definitive
ARLoss Of FunctionAbsent Gene Product
Skin
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Netherton syndrome

MIM #256500

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — SPINK5
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Hyper IgE syndromes: clinical and molecular characteristics.
Al-Shaikhly T et al.·Immunol Cell Biol
2019Review
Syndromic epidermal differentiation disorders: a new classification toward pathogenesis-based therapy.
Paller AS et al.·Br J Dermatol
2025Review
Clinical and genetic characterization of Netherton syndrome due to SPINK5 founder variant in Latvian population.
Nartisa I et al.·Pediatr Allergy Immunol
2023
Netherton Syndrome: A Genotype-Phenotype Review.
Sarri CA et al.·Mol Diagn Ther
2017Review
Successful infliximab treatment in siblings with Netherton syndrome: Unveiling a novel SPINK5 gene variant and literature review.
Salici NS et al.·Australas J Dermatol
2024Review
Clinical Manifestation of Hyper IgE Syndrome Including Otitis Media.
Wu J et al.·Curr Allergy Asthma Rep
2018Review
Otitis media susceptibility and shifts in the head and neck microbiome due to SPINK5 variants.
Frank DN et al.·J Med Genet
2021
Comparative analyses of Netherton syndrome patients and Spink5 conditional knock-out mice uncover disease-relevant pathways.
Petrova E et al.·Commun Biol
2024Cohort
Biologics and Small-Molecule Therapies in Netherton Syndrome: A Comprehensive Review.
Morizane S et al.·J Dermatol
2025Review
Could cellular and signaling abnormalities converge to provoke atopic dermatitis?
Elias PM et al.·J Dtsch Dermatol Ges
2020Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
SPINK5 Variants Drive Clinical Variability in Netherton Syndrome Through Th2/Th17 Skewing and Influence Therapeutic Outcomes.
Yorgun Altunbas M et al.·J Allergy Clin Immunol Pract
2026
KDM4A regulates microglial polarization after ischemic stroke by regulating SPINK5 signaling.
Min X et al.·Acta Biochim Biophys Sin (Shanghai)
2025
Clinical and immunological characterization of a Netherton syndrome infant with a large SPINK gene cluster deletion and a c.1258A>G polymorphism in SPINK5.
Guan Y et al.·Front Immunol
2025🔓 Open Access
[Clinical feature and genetic analysis of a preterm infant with Netherton syndrome due to variants of SPINK5 gene].
Hu L et al.·Zhonghua Yi Xue Yi Chuan Xue Za Zhi
2025
The role of SPINK5 mutation distribution in phenotypes of Netherton syndrome.
Xu M et al.·Front Genet
2025🔓 Open Access
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools