NOD2

Chr 16MultiAD

nucleotide binding oligomerization domain containing 2

Also known as: ACUG, BLAU, BLAUS, CARD15, CD, CLR16.3, IBD1, NLRC2

NCBI Gene: 64127 ENSG00000167207 UniProt: Q9HC29

This gene is a member of the Nod1/Apaf-1 family and encodes a protein with two caspase recruitment (CARD) domains and six leucine-rich repeats (LRRs). The protein is primarily expressed in the peripheral blood leukocytes. It plays a role in the immune response to intracellular bacterial lipopolysaccharides (LPS) by recognizing the muramyl dipeptide (MDP) derived from them and activating the NFKB protein. Mutations in this gene have been associated with Crohn disease and Blau syndrome. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jun 2014]

Primary Disease Associations & Inheritance

{Inflammatory bowel disease 1, Crohn disease}MIM #266600

Multi

{Yao syndrome}MIM #617321

Multi

Blau syndromeMIM #186580

Active trials

Pathogenic / LP

494

ClinVar variants

Pubs (1 yr)

-0.5

Missense Z

1.36

LOEUF

Clinical Summary— NOD2

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Gene-Disease Validity (ClinGen)

Blau syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

5 Pathogenic / Likely Pathogenic· 308 VUS of 494 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

1.36LOEUF

pLI 0.000

Z-score -0.36

OE 1.06 (0.83–1.36)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

-0.45Z-score

OE missense 1.05 (0.98–1.13)

616 obs / 585.2 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.1.06 (0.83–1.36)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.05 (0.98–1.13)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.19

0≤1.21.6

LoF obs/exp: 44 / 41.5Missense obs/exp: 616 / 585.2Syn Z: -2.44

0.6649th %ile

GOF

0.7029th %ile

LOF

0.2776th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median · 1 literature citation

DNprediction above median · 1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNWe report a mother and daughter who are both heterozygous for NOD2c.2264C?T variant and dominant-negative IFNGR1818del4 mutation.PMID:31760574

GOFA family history of uveitis supported a diagnosis of Blau syndrome, and analysis of the NOD2 gene revealed a heterozygous gain-of-function missense mutation (Arg334Trp) that has previously been detected in Blau syndrome kindreds.PMID:17372104

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.