Is NOD2 p.Ser375Phe (c.1124C>T) pathogenic?

NOD2 p.Ser375Phe (c.1124C>T) is classified Uncertain significance in NOD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-11). AlphaMissense: likely benign (0.3309); Very rare (popmax 0.00153%, nfe); Associated with Blau syndrome.

What condition is associated with NOD2 p.Ser375Phe (c.1124C>T)?

NOD2 p.Ser375Phe (c.1124C>T) is associated with Blau syndrome (ClinVar).

How common is NOD2 p.Ser375Phe (c.1124C>T) in the general population?

NOD2 p.Ser375Phe (c.1124C>T) is very rare (popmax 0.00153%, nfe) (gnomAD).

How is Blau syndrome inherited?

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

What do computational predictors say about NOD2 p.Ser375Phe (c.1124C>T)?

AlphaMissense predicts likely benign (score 0.3309) — an in-silico prediction, not a clinical call.

NOD2 p.Ser375Phe

c.1124C>T · rs753241960 · VCV956780

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3309 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00153%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Blau syndrome

Computational evidence

Protein change
AlphaMissense	0.3309	likely benign
REVEL	0.472	indeterminate
SaProt	LLR -9.76	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.8	GERP 2.4, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 12 kb · p 0.67 · regional, not allelic
Overall
CADD	25.5	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 S402F vs ClinVar S375F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00153% European (non-Finnish) · 18/1,180,042 alleles

Filtering AF 0.000953% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000787%

Overall 0.00112% 18/1,614,110 alleles · very rare exomes 15/1,461,876 · genomes 3/152,234 · joint denominator

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.Ser375Phe
Coding: c.1124C>T
MANE Select: NM_001370466
dbSNP: rs753241960
Type: single nucleotide variant
Location: chr16:50711116 (GRCh38)
Gene constraint: LOEUF 1.033 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.76
Residue 402 UniProt numbering: 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 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
NOD2 c.459+1G>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-ser375phe (accessed [today's date]).

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