Is NOD2 p.Pro641= (c.1923G>A) pathogenic?

NOD2 p.Pro641= (c.1923G>A) is classified Likely benign in NOD2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-12-20). Ultra-rare (popmax 0.0497%, mid); Associated with autoinflammatory syndrome.

What condition is associated with NOD2 p.Pro641= (c.1923G>A)?

NOD2 p.Pro641= (c.1923G>A) is associated with autoinflammatory syndrome, Blau syndrome (ClinVar).

How common is NOD2 p.Pro641= (c.1923G>A) in the general population?

NOD2 p.Pro641= (c.1923G>A) is ultra-rare (popmax 0.0497%, mid) (gnomAD).

NOD2 p.Pro641=

c.1923G>A · rs199475914 · VCV103118

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0497%, mid)

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 -14	GERP -3.9
Overall
CADD	0.028	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0497% Middle Eastern · 3/6,040 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00721%

Overall 0.00317% 51/1,608,856 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0497%	2,013
African / African-American	0.0107%	9,372
Remaining individualsnot grpmax-eligible	0.00482%	20,748
South Asian	0.0044%	22,720
European (non-Finnish)	0.00272%	36,756
Admixed American	0.00167%	59,868

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.Pro641=
Coding: c.1923G>A
MANE Select: NM_001370466
dbSNP: rs199475914
Type: single nucleotide variant
Location: chr16:50711915 (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

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

Also linked: Blau syndrome

Similar variants

NOD2 p.Pro641Leu Conflicting classifications of pathogenicity ★ ⚠ 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-pro641 (accessed [today's date]).

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