Is NLRP3 p.Pro281Ala (c.841C>G) pathogenic?

NLRP3 p.Pro281Ala (c.841C>G) is classified Uncertain significance in NLRP3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-05). AlphaMissense: likely benign (0.0792); Very rare (popmax 0.004%, afr); Associated with cryopyrin-associated periodic syndrome.

What condition is associated with NLRP3 p.Pro281Ala (c.841C>G)?

NLRP3 p.Pro281Ala (c.841C>G) is associated with cryopyrin-associated periodic syndrome (ClinVar).

How common is NLRP3 p.Pro281Ala (c.841C>G) in the general population?

NLRP3 p.Pro281Ala (c.841C>G) is very rare (popmax 0.004%, afr) (gnomAD).

What do computational predictors say about NLRP3 p.Pro281Ala (c.841C>G)?

AlphaMissense predicts likely benign (score 0.0792) — an in-silico prediction, not a clinical call.

NLRP3 p.Pro281Ala

c.841C>G · rs1662692979 · VCV2570760

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0792 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

cryopyrin-associated periodic syndrome

Computational evidence

Protein change
AlphaMissense	0.0792	likely benign
REVEL	0.314	indeterminate
SaProt	LLR -5.53	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.2	GERP 0.9
Regional constraint	o/e 0.77	unconstrained · MANE · 6,323 bp · p 5.5e-10 · regional, not allelic
Overall
CADD	9.964	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 P283A vs ClinVar P281A) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.004% African / African-American · 3/75,000 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000205% 3/1,461,816 alleles · very rare

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.Pro281Ala
Coding: c.841C>G
MANE Select: NM_001243133
dbSNP: rs1662692979
Type: single nucleotide variant
Location: chr1:247424290 (GRCh38)
Gene constraint: LOEUF 0.639 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.16 · 27 PDB
Residue 281: a β-strand; 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.Pro281Leu Uncertain significance ★ ⚠ same residue
NLRP3 p.Pro281= 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
NLRP3 p.Asp303Asn 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-pro281ala (accessed [today's date]).

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