Is NLRP3 p.Pro880Ser (c.2638C>T) pathogenic?

NLRP3 p.Pro880Ser (c.2638C>T) is classified Uncertain significance in NLRP3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2020-11-05). AlphaMissense: likely benign (0.0965); Absent from gnomAD v4.1; Associated with cryopyrin-associated periodic syndrome.

What condition is associated with NLRP3 p.Pro880Ser (c.2638C>T)?

NLRP3 p.Pro880Ser (c.2638C>T) is associated with cryopyrin-associated periodic syndrome, Muckle-Wells syndrome (ClinVar).

How common is NLRP3 p.Pro880Ser (c.2638C>T) in the general population?

NLRP3 p.Pro880Ser (c.2638C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NLRP3 p.Pro880Ser (c.2638C>T)?

AlphaMissense predicts likely benign (score 0.0965) — an in-silico prediction, not a clinical call.

NLRP3 p.Pro880Ser

c.2638C>T · rs1663776046 · VCV933917

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0965 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cryopyrin-associated periodic syndrome

Computational evidence

Protein change
AlphaMissense	0.0965	likely benign
REVEL	0.153	moderately benign-leaning
SaProt	LLR -8.75	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 1.2	GERP -0.46, phastCons 0.28
Regional constraint	o/e 0.86	unconstrained · MANE · 19 kb · p 0.0049 · regional, not allelic
Overall
CADD	15.17	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 P882S vs ClinVar P880S) — 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.Pro880Ser
Coding: c.2638C>T
MANE Select: NM_001243133
dbSNP: rs1663776046
Type: single nucleotide variant
Location: chr1:247436115 (GRCh38)
Gene constraint: LOEUF 0.639 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.16 · 27 PDB

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

Also linked: Muckle-Wells syndrome

Similar variants

NLRP3 p.Pro880Thr 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-pro880ser (accessed [today's date]).

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