Is NLRP3 p.Cys413Ser (c.1237T>A) pathogenic?

NLRP3 p.Cys413Ser (c.1237T>A) is classified Uncertain significance in NLRP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-30). AlphaMissense: ambiguous (0.4092); Absent from gnomAD v4.1; Associated with cryopyrin-associated periodic syndrome.

What condition is associated with NLRP3 p.Cys413Ser (c.1237T>A)?

NLRP3 p.Cys413Ser (c.1237T>A) is associated with cryopyrin-associated periodic syndrome (ClinVar).

How common is NLRP3 p.Cys413Ser (c.1237T>A) in the general population?

NLRP3 p.Cys413Ser (c.1237T>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NLRP3 p.Cys413Ser (c.1237T>A)?

AlphaMissense predicts ambiguous (score 0.4092) — an in-silico prediction, not a clinical call.

NLRP3 p.Cys413Ser

c.1237T>A · VCV4800143

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4092 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

cryopyrin-associated periodic syndrome

Computational evidence

Protein change
AlphaMissense	0.4092	ambiguous
REVEL	0.775	moderately pathogenic-leaning
SaProt	LLR -9.34	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 6,323 bp · p 5.5e-10 · regional, not allelic
Overall
CADD	23.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM C415S vs ClinVar C413S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: NLRP3
Protein: p.Cys413Ser
Coding: c.1237T>A
MANE Select: NM_001243133
Type: single nucleotide variant
Location: chr1:247424686 (GRCh38)
Gene constraint: LOEUF 0.639 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.16 · 27 PDB
Residue 413: an α-helix; the nacht domain

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

Disease context

cryopyrin-associated periodic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NLRP3 p.Cys413Gly Uncertain significance ★ ⚠ 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
NLRP3 p.Asp303Asn Pathogenic ★★ same condition
NLRP3 p.Glu304Lys 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-cys413ser (accessed [today's date]).

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