NLRP12

Chr 19AD

NLR family pyrin domain containing 12

Also known as: CLR19.3, FCAS2, NALP12, PAN6, PYPAF7, RNO, RNO2

NCBI Gene: 91662 ENSG00000142405 OMIM: 609648

The protein functions as a potent anti-inflammatory regulator in immune cells, inhibiting NF-kappaB and ERK signaling pathways and suppressing inflammatory responses in activated monocytes and macrophages. Mutations cause familial cold autoinflammatory syndrome type 2, an inherited autoinflammatory disorder with autosomal dominant inheritance. The gene shows low constraint against loss-of-function variants, suggesting tolerance to complete protein loss.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a member of the CATERPILLER family of cytoplasmic proteins. The encoded protein, which contains an N-terminal pyrin domain, a NACHT domain, a NACHT-associated domain, and a C-terminus leucine-rich repeat region, functions as an attenuating factor of inflammation by suppressing inflammatory responses in activated monocytes. Mutations in this gene cause familial cold autoinflammatory syndrome type 2. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2013]

OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 1.351 OMIM phenotype

Clinical Summary— NLRP12

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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

12 unique Pathogenic / Likely Pathogenic· 926 VUS of 1489 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?

1.35LOEUF

pLI 0.000

Z-score -0.26

OE 1.04 (0.81–1.35)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-1.71Z-score

OE missense 1.20 (1.12–1.27)

729 obs / 610.0 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.04 (0.81–1.35)

0≤0.351.4

Missense OE?1.20 (1.12–1.27)

0≤0.61.4

Synonymous OE?1.19

0≤1.21.6

LoF obs/exp: 41 / 39.3Missense obs/exp: 729 / 610.0Syn Z: -2.50

This gene — mechanism propensity

0.6939th %ile

GOF

0.6931th %ile

LOF

0.2386th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function, dominant-negative and loss-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. 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

LOF1 literature citation · 92% of P/LP variants are LoF

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

GOFThis study also demonstrates, by means of functional assays, the deleterious effect of this recurrent missense mutation; the gain of function for speck formation and caspase 1 signaling associated with this NBS mutation is consistent with the inflammatory phenotype of PFS.1

LOFIn affected members of 2 unrelated families with familial cold autoinflammatory syndrome-2 (FCAS2; 611762), Jeru et al. (2008) identified heterozygous mutations in the NLRP12 gene (609648.0001 and 609648.0002). The findings indicated a dominant mode of expression through haploinsufficiency.2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

ClinVar Variant Classifications

1489 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic2

Likely Pathogenic10

VUS926

Likely Benign368

Benign65

Conflicting104

Pathogenic

Likely Pathogenic

926

VUS

368

Likely Benign

Benign

104

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	2	0	0	0	2
Likely Pathogenic	9	1	0	0	10
VUS	87	751	80	8	926
Likely Benign	1	20	76	271	368
Benign	0	3	49	13	65
Conflicting	—				104
Total	99	775	205	292	1,475

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

View in ClinVar →

16 pathogenic / likely-pathogenic (of 31) ClinVar copy-number / structural variants overlap NLRP12 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →