SPINK5

Chr 5AR

serine peptidase inhibitor Kazal type 5

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

NCBI Gene: 11005 ENSG00000133710 UniProt: Q9NQ38 OMIM: 605010

The protein is a serine protease inhibitor that regulates skin barrier function by inhibiting proteases involved in desquamation and defense, particularly KLK5, KLK7, KLK14, and CASP14. Mutations cause Netherton syndrome, an autosomal recessive disorder characterized by severe ichthyosis, hair shaft abnormalities, and atopic manifestations that typically present in the neonatal period. The gene shows very low constraint against loss-of-function variants, consistent with its recessive inheritance pattern.

GeneReviews OMIM ResearchSummary from OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.931 OMIM phenotype

Clinical Summary— SPINK5

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Gene-Disease Validity (ClinGen)

Netherton syndrome · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

132 unique Pathogenic / Likely Pathogenic· 432 VUS of 1201 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — SPINK5

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.93LOEUF

pLI 0.000

Z-score 2.04

OE 0.74 (0.59–0.93)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.28Z-score

OE missense 0.97 (0.90–1.04)

562 obs / 580.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.74 (0.59–0.93)

0≤0.351.4

Missense OE?0.97 (0.90–1.04)

0≤0.61.4

Synonymous OE?1.03

0≤1.21.6

LoF obs/exp: 53 / 71.7Missense obs/exp: 562 / 580.9Syn Z: -0.33

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveSPINK5-related Netherton syndromeLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6453th %ile

GOF

0.4184th %ile

LOF

0.3842th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

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

ClinVar Variant Classifications

1201 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic90

Likely Pathogenic42

VUS432

Likely Benign381

Benign200

Conflicting33

Pathogenic

Likely Pathogenic

432

VUS

381

Likely Benign

200

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	83	1	6	0	90
Likely Pathogenic	36	1	4	1	42
VUS	1	385	37	9	432
Likely Benign	2	17	216	146	381
Benign	0	10	176	14	200
Conflicting	—				33
Total	122	414	439	170	1,178

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

View in ClinVar →

13 pathogenic / likely-pathogenic (of 20) ClinVar copy-number / structural variants overlap SPINK5 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →