Is NLRP12 p.Pro103= (c.309G>A) pathogenic?

NLRP12 p.Pro103= (c.309G>A) is classified Likely benign in NLRP12 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-28). Very rare (popmax 0.00509%, nfe); Associated with familial cold autoinflammatory syndrome 2.

What condition is associated with NLRP12 p.Pro103= (c.309G>A)?

NLRP12 p.Pro103= (c.309G>A) is associated with familial cold autoinflammatory syndrome 2 (ClinVar).

How common is NLRP12 p.Pro103= (c.309G>A) in the general population?

NLRP12 p.Pro103= (c.309G>A) is very rare (popmax 0.00509%, nfe) (gnomAD).

NLRP12 p.Pro103=

Q: How is NLRP12-associated hereditary periodic fever syndrome inherited?

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

c.309G>A · rs200930208 · VCV1148902

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00509%, nfe)

Conditions

familial cold autoinflammatory syndrome 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -11	GERP -2.6
Overall
CADD	0.4	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00509% European (non-Finnish) · 60/1,179,830 alleles

Filtering AF 0.00402% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00362%

Overall 0.00403% 65/1,613,804 alleles · very rare exomes 60/1,461,676 · genomes 5/152,128 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00509%	19,664
Admixed American	0.00334%	29,976
East Asian	0.00223%	44,858
Remaining individualsnot grpmax-eligible	0.0016%	62,490
African / African-American	0.00133%	75,002

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: NLRP12
Protein: p.Pro103=
Coding: c.309G>A
MANE Select: NM_144687
dbSNP: rs200930208
Type: single nucleotide variant
Location: chr19:53814969 (GRCh38)
Gene constraint: LOEUF 1.336 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.29 · 3 PDB

Full NLRP12 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

familial cold autoinflammatory syndrome 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For NLRP12-associated hereditary periodic fever syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Infancy, Neonatal

Similar variants

NLRP12 p.Pro103Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
NLRP12 c.2072+1G>C Pathogenic/Likely pathogenic ★★ same condition
NLRP12 p.Asp294Glu Pathogenic/Likely pathogenic ★★ same condition
NLRP12 c.2244-1G>A Uncertain significance ★★ same condition
NLRP12 c.2585+2T>C Uncertain significance ★★ same condition
NLRP12 c.2756+3G>A Uncertain significance ★★ same condition
NLRP12 c.290-13A>G Uncertain significance ★★ same condition
NLRP12 c.2928-4C>G Uncertain significance ★★ 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/nlrp12-p-pro103 (accessed [today's date]).

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