Is NOD2 p.Ser705Arg (c.2115C>A) pathogenic?

NOD2 p.Ser705Arg (c.2115C>A) is classified Uncertain significance in NOD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-07). AlphaMissense: likely pathogenic (0.8364); Very rare (popmax 0.000508%, nfe); Associated with Regional enteritis.

What condition is associated with NOD2 p.Ser705Arg (c.2115C>A)?

NOD2 p.Ser705Arg (c.2115C>A) is associated with Regional enteritis, Blau syndrome (ClinVar).

How common is NOD2 p.Ser705Arg (c.2115C>A) in the general population?

NOD2 p.Ser705Arg (c.2115C>A) is very rare (popmax 0.000508%, nfe) (gnomAD).

What do computational predictors say about NOD2 p.Ser705Arg (c.2115C>A)?

AlphaMissense predicts likely pathogenic (score 0.8364) — an in-silico prediction, not a clinical call.

NOD2 p.Ser705Arg

c.2115C>A · rs6413461 · VCV1909092

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8364 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000508%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Regional enteritis

Computational evidence

Protein change
AlphaMissense	0.8364	likely pathogenic · top 9% in NOD2
REVEL	0.456	indeterminate
SaProt	LLR -5.93	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP -0.086, phastCons 0.95
Regional constraint	o/e 0.97	unconstrained · MANE · 20 kb · p 0.41 · regional, not allelic
Overall
CADD	23.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S732R vs ClinVar S705R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000508% European (non-Finnish) · 6/1,180,036 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000372% 6/1,613,870 alleles · very rare

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.Ser705Arg
Coding: c.2115C>A
MANE Select: NM_001370466
dbSNP: rs6413461
Type: single nucleotide variant
Location: chr16:50712107 (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

Regional enteritis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Blau syndrome

Similar variants

NOD2 p.Ser705Asn Uncertain significance ★ ⚠ same residue
NOD2 p.Ser705= Likely benign ★ 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

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-ser705arg (accessed [today's date]).

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