NLRP3 p.Arg135Pro
c.404G>C · VCV3583089
Computational evidence
| Protein change | ||
| AlphaMissense | 0.1864 | likely benign |
|---|---|---|
| REVEL | 0.246 | benign-leaning |
| SaProt | LLR -9.33 | tolerated |
| ⇒ AlphaMissense, REVEL and SaProt all call this tolerated. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 5.6 | GERP -0.43, phastCons 0.99 |
| Regional constraint | o/e 0.77 | unconstrained · MANE · 6,323 bp · p 5.5e-10 · regional, not allelic |
| Overall | ||
| CADD | 16.06 | PHRED · no single calibrated threshold — expert panels disagree |
ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R137P vs ClinVar R135P) — verify the residue.
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Remaining individualsnot grpmax-eligible | 0.0016% | 62,504 |
| European (non-Finnish)grpmax | 0.000254% | 393,289 |
Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.
Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.
Variant & gene context
- Gene
- NLRP3
- Protein
- p.Arg135Pro
- Coding
- c.404G>C
- MANE Select
- NM_001243133
- Type
- single nucleotide variant
- Location
- chr1:247423853 (GRCh38)
- Gene constraint
- LOEUF 0.639 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 81.16 · 27 PDB
- Residue 137 UniProt numbering
- an α-helix
Disease context
Muckle-Wells syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatmentsAlso linked: familial cold autoinflammatory syndrome 1keratitis fugax hereditariaCINCA syndromehearing loss, autosomal dominant 34, with or without inflammation
For Muckle-Wells syndrome (Orphanet):
- Inheritance
- Autosomal dominant
- Onset
- Childhood, Infancy, Neonatal
Similar variants
- NLRP3 p.Arg135His Conflicting classifications of pathogenicity ★ ⚠ same residue
- NLRP3 p.Arg135Gly Uncertain significance ★ ⚠ same residue
- AVP p.Leu135= Likely benign ★ same residue
- NLRP3 p.Ala352Thr Likely pathogenic ★★ same condition
- NLRP3 p.Ala352Val Pathogenic/Likely pathogenic ★★ ⚠ same condition
- NLRP3 p.Ala439Thr Pathogenic/Likely pathogenic ★★ ⚠ same condition
- NLRP3 p.Ala439Val Pathogenic/Likely pathogenic ★★ same condition
- NLRP3 p.Arg260Ter Pathogenic ★★ same condition
Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →
Cite Sugi Variant
Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/nlrp3-p-arg135pro (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown