Is NOD2 p.Pro500= (c.1500C>G) pathogenic?

NOD2 p.Pro500= (c.1500C>G) is classified Likely benign in NOD2 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-10-14). Very rare (popmax 0.00161%, nfe); Associated with Blau syndrome.

What condition is associated with NOD2 p.Pro500= (c.1500C>G)?

NOD2 p.Pro500= (c.1500C>G) is associated with Blau syndrome (ClinVar).

How common is NOD2 p.Pro500= (c.1500C>G) in the general population?

NOD2 p.Pro500= (c.1500C>G) is very rare (popmax 0.00161%, nfe) (gnomAD).

How is Blau syndrome inherited?

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

NOD2 p.Pro500=

c.1500C>G · rs104895435 · VCV97835

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00161%, nfe)

Conditions

Blau 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 -20	GERP -3.8
Overall
CADD	0.002	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00161% European (non-Finnish) · 19/1,179,930 alleles

Filtering AF 0.00103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00083%

Overall 0.00124% 20/1,613,338 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00161%	62,101
South Asian	0.0011%	91,084

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: NOD2
Protein: p.Pro500=
Coding: c.1500C>G
MANE Select: NM_001370466
dbSNP: rs104895435
Type: single nucleotide variant
Location: chr16:50711492 (GRCh38)
Gene constraint: LOEUF 1.033 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.76
Residue 500: the nacht domain

Full NOD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

For Blau syndrome (Orphanet):

Inheritance: Autosomal dominant, Not applicable
Onset: Infancy, Neonatal
Prevalence: <1 / 1 000 000 (Denmark)

Similar variants

NOD2 p.Pro500His Uncertain significance ★ ⚠ same residue
NOD2 p.Arg307Gln Pathogenic ★★ ⚠ same condition
NOD2 p.Arg307Trp Pathogenic ★★ ⚠ same condition
NOD2 p.Arg560Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
NOD2 p.Met486Thr Pathogenic/Likely pathogenic ★★ ⚠ same condition
NOD2 c.2550-2A>G Uncertain significance ★★ same condition
NOD2 c.2717+2T>A Uncertain significance ★★ same condition
NOD2 c.2885+6G>T 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/nod2-p-pro500 (accessed [today's date]).

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