Is NLRP3 p.Phe207Ser (c.620T>C) pathogenic?

NLRP3 p.Phe207Ser (c.620T>C) is classified Uncertain significance in NLRP3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-27). AlphaMissense: likely pathogenic (0.9424); Absent from gnomAD v4.1; Associated with Muckle-Wells syndrome.

What condition is associated with NLRP3 p.Phe207Ser (c.620T>C)?

NLRP3 p.Phe207Ser (c.620T>C) is associated with Muckle-Wells syndrome, familial cold autoinflammatory syndrome 1, keratitis fugax hereditaria (ClinVar).

How common is NLRP3 p.Phe207Ser (c.620T>C) in the general population?

NLRP3 p.Phe207Ser (c.620T>C) is absent from gnomAD v4.1 (gnomAD).

How is Muckle-Wells syndrome inherited?

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

What do computational predictors say about NLRP3 p.Phe207Ser (c.620T>C)?

AlphaMissense predicts likely pathogenic (score 0.9424) — an in-silico prediction, not a clinical call.

NLRP3 p.Phe207Ser

c.620T>C · VCV3583103

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9424 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Muckle-Wells syndrome

Computational evidence

Protein change
AlphaMissense	0.9424	likely pathogenic · top 5% in NLRP3
REVEL	0.782	moderately pathogenic-leaning
SaProt	LLR -13.73	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.7, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 6,323 bp · p 5.5e-10 · regional, not allelic
Overall
CADD	23.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 F209S vs ClinVar F207S) — 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.Phe207Ser
Coding: c.620T>C
MANE Select: NM_001243133
Type: single nucleotide variant
Location: chr1:247424069 (GRCh38)
Gene constraint: LOEUF 0.639 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.16 · 27 PDB
Residue 209 UniProt numbering: an α-helix; the fisna domain

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

NLRP3 p.Phe207Leu 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-phe207ser (accessed [today's date]).

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