Is NOD2 p.Pro400Ser (c.1198C>T) pathogenic?

NOD2 p.Pro400Ser (c.1198C>T) is classified Uncertain significance in NOD2 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-07-30). AlphaMissense: likely benign (0.2172); Ultra-rare (popmax 0.02%, amr); Associated with Regional enteritis.

What condition is associated with NOD2 p.Pro400Ser (c.1198C>T)?

NOD2 p.Pro400Ser (c.1198C>T) is associated with Regional enteritis, Blau syndrome (ClinVar).

How common is NOD2 p.Pro400Ser (c.1198C>T) in the general population?

NOD2 p.Pro400Ser (c.1198C>T) is ultra-rare (popmax 0.02%, amr) (gnomAD).

What do computational predictors say about NOD2 p.Pro400Ser (c.1198C>T)?

AlphaMissense predicts likely benign (score 0.2172) — an in-silico prediction, not a clinical call.

NOD2 p.Pro400Ser

c.1198C>T · rs760982375 · VCV531597

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2172 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.02%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Regional enteritis

Computational evidence

Protein change
AlphaMissense	0.2172	likely benign
REVEL	0.602	indeterminate
SaProt	LLR -9.19	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.2, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 12 kb · p 0.67 · regional, not allelic
Overall
CADD	21.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P427S vs ClinVar P400S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.02% Admixed American · 12/60,016 alleles

Filtering AF 0.0115% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00898%

Overall 0.00291% 47/1,613,994 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.02%	5,001
European (non-Finnish)	0.00297%	33,716

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.Pro400Ser
Coding: c.1198C>T
MANE Select: NM_001370466
dbSNP: rs760982375
Type: single nucleotide variant
Location: chr16:50711190 (GRCh38)
Gene constraint: LOEUF 1.033 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.76
Residue 400: the nacht domain

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.Pro400Leu Likely benign ★★ ⚠ same residue
NOD2 p.Pro400= 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-pro400ser (accessed [today's date]).

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