NLRP12

Chr 19AD

NLR family pyrin domain containing 12

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

NCBI Gene: 91662 ENSG00000142405 UniProt: P59046 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

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

4 unique Pathogenic / Likely Pathogenic· 228 VUS of 400 total submissions

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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 OE1.04 (0.81–1.35)

0≤0.351.4

Missense OE1.20 (1.12–1.27)

0≤0.61.4

Synonymous OE1.19

0≤1.21.6

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

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

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.PMID:21538323

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.PMID:18230725

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