Is NOD2 p.Phe134= (c.402C>T) pathogenic?

NOD2 p.Phe134= (c.402C>T) is classified Benign/Likely benign in NOD2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-12-28). Rare (popmax 0.597%, sas); Associated with autoinflammatory syndrome.

What condition is associated with NOD2 p.Phe134= (c.402C>T)?

NOD2 p.Phe134= (c.402C>T) is associated with autoinflammatory syndrome, Blau syndrome (ClinVar).

How common is NOD2 p.Phe134= (c.402C>T) in the general population?

NOD2 p.Phe134= (c.402C>T) is rare (popmax 0.597%, sas) (gnomAD).

NOD2 p.Phe134=

c.402C>T · rs565504727 · VCV733554

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

rare (popmax 0.597%, sas)

Conditions

autoinflammatory 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 0.26	GERP -3, phastCons 0.01
Overall
CADD	12.22	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.597% South Asian · 544/91,082 alleles

Filtering AF 0.556% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.539%

Overall 0.038% 612/1,612,496 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.597%	167
Remaining individualsnot grpmax-eligible	0.0496%	2,016
Middle Eastern	0.0495%	2,021
African / African-American	0.0133%	7,505
East Asian	0.00446%	22,438
Admixed American	0.00333%	30,009
European (non-Finnish)	0.00169%	59,000

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.Phe134=
Coding: c.402C>T
MANE Select: NM_001370466
dbSNP: rs565504727
Type: single nucleotide variant
Location: chr16:50699897 (GRCh38)
Gene constraint: LOEUF 1.033 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.76
Residue 134: the card 2 domain

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

Disease context

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

Also linked: Blau syndrome

Similar variants

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
NOD2 c.459+1G>A 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-phe134 (accessed [today's date]).

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