Is NOD2 p.Ser479fs (c.1434dup) pathogenic?

NOD2 p.Ser479fs (c.1434dup) is classified Uncertain significance in NOD2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-03). Ultra-rare (popmax 0.011%, sas); Associated with Blau syndrome.

What condition is associated with NOD2 p.Ser479fs (c.1434dup)?

NOD2 p.Ser479fs (c.1434dup) is associated with Blau syndrome (ClinVar).

How common is NOD2 p.Ser479fs (c.1434dup) in the general population?

NOD2 p.Ser479fs (c.1434dup) is ultra-rare (popmax 0.011%, sas) (gnomAD).

How is Blau syndrome inherited?

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

NOD2 p.Ser479fs

c.1434dup · rs754761524 · VCV531603

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.011%, sas)

Conditions

Blau syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 4 of 12
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.1	GERP -2.2, phastCons 0.28
Overall
CADD	18.8	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.011% South Asian · 10/91,074 alleles

Filtering AF 0.00594% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00453%

Overall 0.00502% 81/1,613,460 alleles · ultra-rare exomes 76/1,461,218 · genomes 5/152,242 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.011%	9,107
Remaining individualsnot grpmax-eligible	0.0064%	15,626
European (non-Finnish)	0.005%	20,000
Finnishnot grpmax-eligible	0.00473%	21,124
East Asian	0.00446%	22,440
African / African-American	0.00267%	37,513
Admixed American	0.00167%	60,024

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.Ser479fs
Coding: c.1434dup
MANE Select: NM_001370466
dbSNP: rs754761524
Type: Duplication
Location: chr16:50711419 (GRCh38)
Gene constraint: LOEUF 1.033 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.76
Residue 479: 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 c.2465+2dup Uncertain significance ★★ same condition
NOD2 p.Cys832fs Uncertain significance ★★ same condition
NOD2 c.-8-2202_-8-2194dup Uncertain significance ★ same condition
NOD2 p.Ala290fs Uncertain significance ★ same condition
NOD2 p.Ala652fs Uncertain significance ★ same condition
NOD2 p.Asp502fs Uncertain significance ★ same condition
NOD2 p.Gln645fs Uncertain significance ★ same condition
NOD2 p.Glu42_Asp43insValLeuSerTrpGlu 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-ser479fs (accessed [today's date]).

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