Is NLRP3 p.Cys461= (c.1383C>T) pathogenic?

NLRP3 p.Cys461= (c.1383C>T) is classified Conflicting classifications of pathogenicity in NLRP3 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-01-29). Ultra-rare (popmax 0.0293%, afr); Associated with cryopyrin-associated periodic syndrome.

What condition is associated with NLRP3 p.Cys461= (c.1383C>T)?

NLRP3 p.Cys461= (c.1383C>T) is associated with cryopyrin-associated periodic syndrome, familial cold autoinflammatory syndrome 1, autoinflammatory syndrome (ClinVar).

How common is NLRP3 p.Cys461= (c.1383C>T) in the general population?

NLRP3 p.Cys461= (c.1383C>T) is ultra-rare (popmax 0.0293%, afr) (gnomAD).

NLRP3 p.Cys461=

c.1383C>T · rs104895398 · VCV97930

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0293%, afr)

Conditions

cryopyrin-associated periodic 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 -3.9	GERP -3.4
Overall
CADD	1.383	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0293% African / African-American · 22/75,034 alleles

Filtering AF 0.0198% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0184%

Overall 0.0182% 292/1,607,918 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0293%	3,411
European (non-Finnish)	0.0214%	4,664
Remaining individualsnot grpmax-eligible	0.0144%	6,940
Finnishnot grpmax-eligible	0.00691%	14,468
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,602
Admixed American	0.00333%	30,012
South Asian	0.0011%	91,080

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.Cys461=
Coding: c.1383C>T
MANE Select: NM_001243133
dbSNP: rs104895398
Type: single nucleotide variant
Location: chr1:247424832 (GRCh38)
Gene constraint: LOEUF 0.639 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.16 · 27 PDB
Residue 461: 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

Also linked: familial cold autoinflammatory syndrome 1 autoinflammatory syndrome

Similar variants

NLRP3 p.Cys461Tyr 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-cys461 (accessed [today's date]).

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