Is NOD2 p.Phe586= (c.1758C>T) pathogenic?

NOD2 p.Phe586= (c.1758C>T) is classified Conflicting classifications of pathogenicity in NOD2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-11-19). Ultra-rare (popmax 0.0826%, afr); Associated with Regional enteritis.

What condition is associated with NOD2 p.Phe586= (c.1758C>T)?

NOD2 p.Phe586= (c.1758C>T) is associated with Regional enteritis, Blau syndrome, inflammatory bowel disease 1 (ClinVar).

How common is NOD2 p.Phe586= (c.1758C>T) in the general population?

NOD2 p.Phe586= (c.1758C>T) is ultra-rare (popmax 0.0826%, afr) (gnomAD).

NOD2 p.Phe586=

c.1758C>T · rs149870902 · VCV319453

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0826%, afr)

Conditions

Regional enteritis

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 -0.068	GERP -2.6, phastCons 0.57
Overall
CADD	1.682	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0826% African / African-American · 62/75,072 alleles

Filtering AF 0.066% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0601%

Overall 0.00589% 95/1,614,240 alleles · ultra-rare exomes 69/1,461,860 · genomes 26/152,380 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0826%	1,211
East Asian	0.0245%	4,080
Remaining individualsnot grpmax-eligible	0.0224%	4,465
South Asian	0.00439%	22,772
Admixed American	0.00333%	30,018
European (non-Finnish)	0.000169%	590,026

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.Phe586=
Coding: c.1758C>T
MANE Select: NM_001370466
dbSNP: rs149870902
Type: single nucleotide variant
Location: chr16:50711750 (GRCh38)
Gene constraint: LOEUF 1.033 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.76
Residue 586: the nacht domain

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

Disease context

Regional enteritis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Blau syndrome inflammatory bowel disease 1

Similar variants

NOD2 p.Phe586Leu 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-phe586 (accessed [today's date]).

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