Is NLRP3 p.Pro209= (c.627C>T) pathogenic?

NLRP3 p.Pro209= (c.627C>T) is classified Likely benign in NLRP3 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-06-29). Ultra-rare (popmax 0.0527%, sas); Associated with autoinflammatory syndrome.

What condition is associated with NLRP3 p.Pro209= (c.627C>T)?

NLRP3 p.Pro209= (c.627C>T) is associated with autoinflammatory syndrome, cryopyrin-associated periodic syndrome (ClinVar).

How common is NLRP3 p.Pro209= (c.627C>T) in the general population?

NLRP3 p.Pro209= (c.627C>T) is ultra-rare (popmax 0.0527%, sas) (gnomAD).

NLRP3 p.Pro209=

c.627C>T · rs554444159 · VCV795158

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0527%, sas)

Conditions

autoinflammatory 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 -16	GERP -3.4
Overall
CADD	0.03	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0527% South Asian · 48/91,068 alleles

Filtering AF 0.0408% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0366%

Overall 0.00322% 52/1,614,010 alleles · ultra-rare exomes 48/1,461,880 · genomes 4/152,130 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0527%	1,897
Middle Eastern	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.0016%	62,502
European (non-Finnish)	0.000169%	590,005

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.Pro209=
Coding: c.627C>T
MANE Select: NM_001243133
dbSNP: rs554444159
Type: single nucleotide variant
Location: chr1:247424076 (GRCh38)
Gene constraint: LOEUF 0.639 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.16 · 27 PDB
Residue 209: an α-helix; the fisna domain

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

Disease context

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

Also linked: cryopyrin-associated periodic syndrome

Similar variants

NLRP3 p.Pro209Ala 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.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-pro209 (accessed [today's date]).

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