Is NLRP3 p.Arg729= (c.2185C>A) pathogenic?

NLRP3 p.Arg729= (c.2185C>A) is classified Benign/Likely benign in NLRP3 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-09-25). Ultra-rare (popmax 0.0187%, sas); Associated with CINCA syndrome.

What condition is associated with NLRP3 p.Arg729= (c.2185C>A)?

NLRP3 p.Arg729= (c.2185C>A) is associated with CINCA syndrome, familial cold autoinflammatory syndrome 1, keratitis fugax hereditaria (ClinVar).

How common is NLRP3 p.Arg729= (c.2185C>A) in the general population?

NLRP3 p.Arg729= (c.2185C>A) is ultra-rare (popmax 0.0187%, sas) (gnomAD).

How is CINCA syndrome inherited?

Typically Autosomal dominant, Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

NLRP3 p.Arg729=

c.2185C>A · rs148590318 · VCV296949

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0187%, sas)

Conditions

CINCA syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.29	acceptor loss, 34 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 0.81	GERP -3.7
Overall
CADD	0.241	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0187% South Asian · 17/91,084 alleles

Filtering AF 0.0118% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00976%

Overall 0.00335% 54/1,614,144 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0187%	5,358
Remaining individualsnot grpmax-eligible	0.0032%	31,252
European (non-Finnish)	0.00288%	34,706
African / African-American	0.00133%	75,044

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.Arg729=
Coding: c.2185C>A
MANE Select: NM_001243133
dbSNP: rs148590318
Type: single nucleotide variant
Location: chr1:247429619 (GRCh38)
Gene constraint: LOEUF 0.639 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.16 · 27 PDB
Residue 729: an α-helix

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

Disease context

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

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

For CINCA syndrome (Orphanet):

Inheritance: Autosomal dominant, Not applicable
Onset: Infancy, Neonatal

Similar variants

NLRP3 p.Arg729Trp 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-arg729 (accessed [today's date]).

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