Is NLRP3 p.Arg970Ter (c.2908C>T) pathogenic?

NLRP3 p.Arg970Ter (c.2908C>T) is classified Uncertain significance in NLRP3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-07-12). Very rare (popmax 0.00223%, eas); Associated with familial cold autoinflammatory syndrome 1.

What condition is associated with NLRP3 p.Arg970Ter (c.2908C>T)?

NLRP3 p.Arg970Ter (c.2908C>T) is associated with familial cold autoinflammatory syndrome 1, keratitis fugax hereditaria, Muckle-Wells syndrome (ClinVar).

How common is NLRP3 p.Arg970Ter (c.2908C>T) in the general population?

NLRP3 p.Arg970Ter (c.2908C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

How is Familial cold urticaria inherited?

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

NLRP3 p.Arg970Ter

c.2908C>T · rs1450171900 · VCV651300

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

familial cold autoinflammatory syndrome 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 9 of 10
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.64	GERP -1.6
Overall
CADD	36.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,884 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.00041% 6/1,461,854 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,884
South Asian	0.0011%	91,068
European (non-Finnish)	0.000339%	295,004

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.Arg970Ter
Coding: c.2908C>T
MANE Select: NM_001243133
dbSNP: rs1450171900
Type: single nucleotide variant
Location: chr1:247444724 (GRCh38)
Gene constraint: LOEUF 0.639 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.16 · 27 PDB

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 hearing loss, autosomal dominant 34, with or without inflammation

For Familial cold urticaria (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Childhood, Infancy

Similar variants

NLRP3 p.Arg970Gln 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-arg970ter (accessed [today's date]).

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