Is NLRP3 p.Phe73= (c.219C>T) pathogenic?

NLRP3 p.Phe73= (c.219C>T) is classified Likely benign in NLRP3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-03). Very rare (popmax 0.00593%, nfe); Associated with Muckle-Wells syndrome.

What condition is associated with NLRP3 p.Phe73= (c.219C>T)?

NLRP3 p.Phe73= (c.219C>T) is associated with Muckle-Wells syndrome, familial cold autoinflammatory syndrome 1, keratitis fugax hereditaria (ClinVar).

How common is NLRP3 p.Phe73= (c.219C>T) in the general population?

NLRP3 p.Phe73= (c.219C>T) is very rare (popmax 0.00593%, nfe) (gnomAD).

How is Muckle-Wells syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

NLRP3 p.Phe73=

c.219C>T · rs201980166 · VCV469049

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00593%, nfe)

Conditions

Muckle-Wells 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 -0.44	GERP -3.7, phastCons 0.2
Overall
CADD	8.21	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00593% European (non-Finnish) · 70/1,179,976 alleles

Filtering AF 0.00478% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00439%

Overall 0.00452% 73/1,613,468 alleles · very rare exomes 68/1,461,568 · genomes 5/151,900 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00593%	16,857
South Asian	0.0022%	45,530
Remaining individualsnot grpmax-eligible	0.0016%	62,506

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.Phe73=
Coding: c.219C>T
MANE Select: NM_001243133
dbSNP: rs201980166
Type: single nucleotide variant
Location: chr1:247419019 (GRCh38)
Gene constraint: LOEUF 0.639 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.16 · 27 PDB
Residue 73: the pyrin domain; an α-helix

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

Disease context

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

Also linked: familial cold autoinflammatory syndrome 1 keratitis fugax hereditaria CINCA syndrome cryopyrin-associated periodic syndrome hearing loss, autosomal dominant 34, with or without inflammation

For Muckle-Wells syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood, Infancy, Neonatal

Similar variants

AVP p.Leu73Pro 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.Asp19His Pathogenic/Likely 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-phe73 (accessed [today's date]).

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