Is NLRP3 p.Ser434= (c.1302C>T) pathogenic?

NLRP3 p.Ser434= (c.1302C>T) is classified Benign/Likely benign in NLRP3 (ClinVar, Multiple submitters, 15 submitters; last evaluated 2026-02-04). Common (popmax 17.7%, mid) — too common for a highly-penetrant pathogenic allele; Associated with familial cold autoinflammatory syndrome 1.

What condition is associated with NLRP3 p.Ser434= (c.1302C>T)?

NLRP3 p.Ser434= (c.1302C>T) is associated with familial cold autoinflammatory syndrome 1, keratitis fugax hereditaria, Muckle-Wells syndrome (ClinVar).

How is Familial cold urticaria inherited?

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

NLRP3 p.Ser434=

Q: How common is NLRP3 p.Ser434= (c.1302C>T) in the general population?

NLRP3 p.Ser434= (c.1302C>T) is common (popmax 17.7%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1302C>T · rs34298354 · VCV259560

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 15 submitters

gnomAD v4.1

Common

common (popmax 17.7%, mid) — too common for a highly-penetrant pathogenic allele

Conditions

familial cold autoinflammatory syndrome 1

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 -2.7	GERP -3.7
Overall
CADD	4.265	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 17.7% Middle Eastern · 1,075/6,060 alleles

Filtering AF 16.9% ClinGen BA1/BS1 input FAF95, joint · FAF99 16.5%

Overall 11.5% 184,808/1,613,382 alleles · common

Ancestry group	Frequency	1 in
Middle Easterngrpmax	17.7%	6
European (non-Finnish)	12.4%	8
Ashkenazi Jewishnot grpmax-eligible	11.9%	8
South Asian	11.2%	9
Remaining individualsnot grpmax-eligible	11.1%	9
Finnishnot grpmax-eligible	10%	10
East Asian	9.44%	11
Amishnot grpmax-eligible	7.46%	13
Admixed American	6.7%	15
African / African-American	2.11%	47

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.Ser434=
Coding: c.1302C>T
MANE Select: NM_001243133
dbSNP: rs34298354
Type: single nucleotide variant
Location: chr1:247424751 (GRCh38)
Gene constraint: LOEUF 0.639 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.16 · 27 PDB
Residue 434: the nacht domain

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

Disease context

familial cold autoinflammatory syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: keratitis fugax hereditaria Muckle-Wells syndrome CINCA syndrome cryopyrin-associated periodic syndrome

For Familial cold urticaria (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Childhood, Infancy

Similar variants

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
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-ser434 (accessed [today's date]).

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