NLRP1

Chr 17

NLR family pyrin domain containing 1

Also known as: AIADK, CARD7, CIDED, CLR17.1, DEFCAP, DEFCAP-L/S, JRRP, MSPC

NCBI Gene: 22861 ENSG00000091592 UniProt: Q9C000

The NLRP1 protein acts as a sensor component of the NLRP1 inflammasome, recognizing pathogen-associated signals and damage signals to initiate inflammatory responses and pyroptosis through caspase-1 activation. Mutations cause autoinflammation with arthritis and dyskeratosis, palmoplantar carcinoma with multiple self-healing lesions, and juvenile recurrent respiratory papillomatosis, with both autosomal dominant and autosomal recessive inheritance patterns reported. The gene shows low constraint against loss-of-function variants, suggesting tolerance to protein-truncating mutations.

ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the Ced-4 family of apoptosis proteins. Ced-family members contain a caspase recruitment domain (CARD) and are known to be key mediators of programmed cell death. The encoded protein contains a distinct N-terminal pyrin-like motif, which is possibly involved in protein-protein interactions. This protein interacts strongly with caspase 2 and weakly with caspase 9. Overexpression of this gene was demonstrated to induce apoptosis in cells. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene, but the biological validity of some variants has not been determined. [provided by RefSeq, Jul 2008]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.84

Clinical Summary— NLRP1

⚡

Population Constraint (gnomAD)

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

📋

ClinVar Variants

6 unique Pathogenic / Likely Pathogenic· 732 VUS of 1267 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.84LOEUF

pLI 0.000

Z-score 2.60

OE 0.64 (0.49–0.84)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.49Z-score

OE missense 0.85 (0.80–0.91)

685 obs / 803.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.64 (0.49–0.84)

0≤0.351.4

Missense OE?0.85 (0.80–0.91)

0≤0.61.4

Synonymous OE?0.96

0≤1.21.6

LoF obs/exp: 39 / 60.9Missense obs/exp: 685 / 803.8Syn Z: 0.62

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongNLRP1-related autoinflammation with arthritis and dyskeratosisOTHERAR

limitedNLRP1-related corneal intraepithelial dyskeratosisOTHERAD

This gene — mechanism propensity

0.78top 25%

GOF

0.6833th %ile

LOF

0.1697th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). The Badonyi & Marsh model scores dominant-negative highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports gain-of-function. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median · 1 literature citation

DNprediction 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.

Literature Evidence

GOFMoreover, gain-of-function mutations of NLRP1 cause inflammatory skin syndromes and a predisposition for the development of skin cancer.1

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

References

1.PMID 32640751 ↗

ClinVar Variant Classifications

1267 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4

Likely Pathogenic2

VUS732

Likely Benign424

Benign37

Conflicting27

Pathogenic

Likely Pathogenic

732

VUS

424

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	3	1	0	4
Likely Pathogenic	0	2	0	0	2
VUS	68	629	32	3	732
Likely Benign	0	38	105	281	424
Benign	0	2	13	22	37
Conflicting	—				27
Total	68	674	151	306	1,226

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

View in ClinVar →

22 pathogenic / likely-pathogenic (of 38) ClinVar copy-number / structural variants overlap NLRP1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →