Is NLRP3 p.Ile172Thr (c.515T>C) pathogenic?

NLRP3 p.Ile172Thr (c.515T>C) is classified Likely pathogenic in NLRP3 (ClinVar, Single submitter, 2 submitters; last evaluated 2021-05-27). AlphaMissense: likely benign (0.1684); Absent from gnomAD v4.1; Associated with cryopyrin-associated periodic syndrome.

What condition is associated with NLRP3 p.Ile172Thr (c.515T>C)?

NLRP3 p.Ile172Thr (c.515T>C) is associated with cryopyrin-associated periodic syndrome, familial cold autoinflammatory syndrome 1 (ClinVar).

How common is NLRP3 p.Ile172Thr (c.515T>C) in the general population?

NLRP3 p.Ile172Thr (c.515T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NLRP3 p.Ile172Thr (c.515T>C)?

AlphaMissense predicts likely benign (score 0.1684) — an in-silico prediction, not a clinical call.

NLRP3 p.Ile172Thr

c.515T>C · rs180177449 · VCV97964

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1684 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

cryopyrin-associated periodic syndrome

Computational evidence

Protein change
AlphaMissense	0.1684	likely benign ⚠ discordant with ClinVar
REVEL	0.522	indeterminate
SaProt	LLR -7.09	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP -0.6, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 6,323 bp · p 5.5e-10 · regional, not allelic
Overall
CADD	18.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM I174T vs ClinVar I172T) — 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.Ile172Thr
Coding: c.515T>C
MANE Select: NM_001243133
dbSNP: rs180177449
Type: single nucleotide variant
Location: chr1:247423964 (GRCh38)
Gene constraint: LOEUF 0.639 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.16 · 27 PDB
Residue 172: a β-strand; the fisna domain

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

Disease context

cryopyrin-associated periodic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial cold autoinflammatory syndrome 1

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.Asp303Asn Pathogenic ★★ same condition
NLRP3 p.Glu304Lys Pathogenic ★★ same condition
NLRP3 p.Glu311Lys 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-ile172thr (accessed [today's date]).

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