Is NLRP3 p.Ile415= (c.1245C>T) pathogenic?

NLRP3 p.Ile415= (c.1245C>T) is classified Conflicting classifications of pathogenicity in NLRP3 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2025-12-10). Rare (popmax 0.129%, afr); Associated with autoinflammatory syndrome.

What condition is associated with NLRP3 p.Ile415= (c.1245C>T)?

NLRP3 p.Ile415= (c.1245C>T) is associated with autoinflammatory syndrome, familial cold autoinflammatory syndrome 1, Muckle-Wells syndrome (ClinVar).

How common is NLRP3 p.Ile415= (c.1245C>T) in the general population?

NLRP3 p.Ile415= (c.1245C>T) is rare (popmax 0.129%, afr) (gnomAD).

NLRP3 p.Ile415=

c.1245C>T · rs139852370 · VCV296946

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

rare (popmax 0.129%, afr)

Conditions

autoinflammatory syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -8.7	GERP -3.7
Overall
CADD	0.73	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.129% African / African-American · 97/75,070 alleles

Filtering AF 0.108% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.101%

Overall 0.00818% 132/1,614,224 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.129%	774
Admixed American	0.035%	2,858
Middle Eastern	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.0128%	7,813
South Asian	0.0022%	45,545
European (non-Finnish)	0.000254%	393,349

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.Ile415=
Coding: c.1245C>T
MANE Select: NM_001243133
dbSNP: rs139852370
Type: single nucleotide variant
Location: chr1:247424694 (GRCh38)
Gene constraint: LOEUF 0.639 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.16 · 27 PDB
Residue 415: an α-helix; the nacht domain

Full NLRP3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autoinflammatory syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial cold autoinflammatory syndrome 1 Muckle-Wells syndrome CINCA syndrome cryopyrin-associated periodic syndrome

Similar variants

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
NLRP3 p.Asp303Asn Pathogenic ★★ ⚠ same condition
NLRP3 p.Glu304Lys Pathogenic ★★ same condition
NLRP3 p.Glu311Lys 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-ile415 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown