Is NOD2 p.Pro765= (c.2295C>T) pathogenic?

NOD2 p.Pro765= (c.2295C>T) is classified Likely benign in NOD2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-17). Ultra-rare (popmax 0.0934%, afr); Associated with Blau syndrome.

What condition is associated with NOD2 p.Pro765= (c.2295C>T)?

NOD2 p.Pro765= (c.2295C>T) is associated with Blau syndrome, inflammatory bowel disease 1, Yao syndrome (ClinVar).

How common is NOD2 p.Pro765= (c.2295C>T) in the general population?

NOD2 p.Pro765= (c.2295C>T) is ultra-rare (popmax 0.0934%, afr) (gnomAD).

How is Blau syndrome inherited?

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

NOD2 p.Pro765=

c.2295C>T · rs5743280 · VCV741062

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0934%, afr)

Conditions

Blau syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.128	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -9.8	GERP -5.4
Overall
CADD	0.043	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0934% African / African-American · 70/74,950 alleles

Filtering AF 0.0757% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0693%

Overall 0.00694% 112/1,613,886 alleles · ultra-rare exomes 67/1,461,634 · genomes 45/152,252 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0934%	1,071
Remaining individualsnot grpmax-eligible	0.0064%	15,622
South Asian	0.00549%	18,218
East Asian	0.00446%	22,446
Admixed American	0.00333%	30,008
European (non-Finnish)	0.00246%	40,691

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.Pro765=
Coding: c.2295C>T
MANE Select: NM_001370466
dbSNP: rs5743280
Type: single nucleotide variant
Location: chr16:50712287 (GRCh38)
Gene constraint: LOEUF 1.033 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.76

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

Also linked: inflammatory bowel disease 1 Yao syndrome

For Blau syndrome (Orphanet):

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

Similar variants

NOD2 p.Pro765Arg 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-pro765 (accessed [today's date]).

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