# NM_001370466.1(NOD2):c.1923G>A (p.Pro641=)

https://sugi.bio/variant/nod2-p-pro641

## Summary

**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.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs199475914 · 5 submitters · 2 linked conditions · ultra-rare (popmax 0.0497%, mid)

## For patients & families {#patients}

This is a change in the NOD2 gene that is classified as likely benign — not considered disease-causing, submitted by 5 submitters, and is linked to autoinflammatory syndrome.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Clinical trials | 4 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [NOD2](https://sugi.bio/atlas/gene/NOD2/) |
| Protein change (HGVS p.) | p.Pro641= |
| Coding change (HGVS c.) | c.1923G>A |
| MANE Select transcript | [NM_001370466](https://www.ncbi.nlm.nih.gov/nuccore/NM_001370466) |
| dbSNP | [rs199475914](https://www.ncbi.nlm.nih.gov/snp/rs199475914/) |
| Variant type | single nucleotide variant |
| Location | chr16:50711915-50711915 (GRCh38) |
| ClinVar | [VCV103118](https://www.ncbi.nlm.nih.gov/clinvar/variation/103118/) |

**All HGVS expressions:** `LRG_177:g.19777G>A`, `LRG_177t1:c.2004G>A`, `NC_000016.10:g.50711915G>A`, `NC_000016.9:g.50745826G>A`, `NG_007508.1:g.19777G>A`, `NM_001293557.2:c.1923G>A`, `NM_001370466.1:c.1923G>A`, `NM_022162.3:c.2004G>A`, `NR_163434.1:n.1988G>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP -14.041, GERP -3.94 — fast-evolving / accelerated position
- CADD: **PHRED 0.028**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0497%** (mid) · FAF95 0.0134% · FAF99 0.00721% · 3/6,040 in the highest group · 51/1,608,856 alleles overall — ultra-rare (popmax 0.0497%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0497% | 2,013 |
| African / African-American | 0.0107% | 9,372 |
| Remaining individuals (not 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 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**NOD2** population constraint: LOEUF 1.033, pLI 2.3754e-22, missense-Z 0.92884. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **Blau syndrome** — Definitive (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 84.76, 50% of residues very-high.

## What this gene does {#gene-function}

*Describes the biological roles of NOD2 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** NOD2's established molecular role includes actin binding. In Reactome, NOD2 is annotated in disease pathway(s) including **SARS-CoV-2 activates/modulates innate and adaptive immune responses**.

**Disease mechanism (Reactome):** NOD2 loss or alteration is curated in [SARS-CoV-2 activates/modulates innate and adaptive immune responses](https://reactome.org/content/detail/R-HSA-9705671).

### Pathways affected {#pathways}

NOD2 participates in **7 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [SARS-CoV-2 activates/modulates innate and adaptive immune responses](https://reactome.org/content/detail/R-HSA-9705671) | other |
| [Interleukin-1 signaling](https://reactome.org/content/detail/R-HSA-9020702) | other |
| [JNK (c-Jun kinases) phosphorylation and  activation mediated by activated human TAK1](https://reactome.org/content/detail/R-HSA-450321) | other |
| [NOD1/2 Signaling Pathway](https://reactome.org/content/detail/R-HSA-168638) | other |
| [Ovarian tumor domain proteases](https://reactome.org/content/detail/R-HSA-5689896) | other |
| [TAK1-dependent IKK and NF-kappa-B activation  ](https://reactome.org/content/detail/R-HSA-445989) | other |
| [activated TAK1 mediates p38 MAPK activation](https://reactome.org/content/detail/R-HSA-450302) | other |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** actin binding, enzyme binding, protein kinase binding, Hsp70 protein binding, muramyl dipeptide binding, pattern recognition receptor activity.

**Biological process:** pattern recognition receptor signaling pathway, positive regulation of cytokine production involved in immune response, positive regulation of type 2 immune response, canonical NF-kappaB signal transduction, detection of bacterium, maintenance of gastrointestinal epithelium.

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-12-20.

**Submitter consensus:** conflicting (4 Likely benign, 1 not provided).

**Submission history:** 5 submissions (2019–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genome Diagnostics Laboratory, The Hospital for Sick Children | Likely benign | criteria provided, single submitter | clinical testing | 2019-11-01 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-04-04 |
| Human Evolutionary Genetics, Institut Pasteur | not provided | no classification provided | not provided |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-12-20 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2024-01-01 |

## Associated conditions {#conditions}

[autoinflammatory syndrome](https://sugi.bio/atlas/disease/autoinflammatory-syndrome/), [Blau syndrome](https://sugi.bio/atlas/disease/blau-syndrome/).

**Reported phenotype names (ClinVar):** Autoinflammatory syndrome, not provided, Blau syndrome, Regional enteritis, not specified, Enteritis, Granulomatous, GRANULOMATOSIS, FAMILIAL JUVENILE SYSTEMIC, GRANULOMATOSIS, FAMILIAL, BLAU TYPE, GRANULOMATOUS INFLAMMATORY ARTHRITIS, DERMATITIS, AND UVEITIS, FAMILIAL, JABS SYNDROME.

## Similar variants {#similar}

Related NOD2 variant pages (same residue, condition, or type): [NOD2 p.Pro641Leu](/variant/nod2-p-pro641leu), [NOD2 p.Arg307Gln](/variant/nod2-p-arg307gln), [NOD2 p.Arg307Trp](/variant/nod2-p-arg307trp), [NOD2 p.Arg560Cys](/variant/nod2-p-arg560cys), [NOD2 p.Met486Thr](/variant/nod2-p-met486thr), [NOD2 c.2550-2A>G](/variant/nod2-c-2550-minus-2a-g), [NOD2 c.2717+2T>A](/variant/nod2-c-2717-plus-2t-a), [NOD2 c.2885+6G>T](/variant/nod2-c-2885-plus-6g-t).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 103118). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*