Is NOD2 p.Pro241Ala (c.721C>G) pathogenic?

NOD2 p.Pro241Ala (c.721C>G) is classified Uncertain significance in NOD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-15). AlphaMissense: likely benign (0.0594); Absent from gnomAD v4.1; Associated with Blau syndrome.

What condition is associated with NOD2 p.Pro241Ala (c.721C>G)?

NOD2 p.Pro241Ala (c.721C>G) is associated with Blau syndrome (ClinVar).

How common is NOD2 p.Pro241Ala (c.721C>G) in the general population?

NOD2 p.Pro241Ala (c.721C>G) is absent from gnomAD v4.1 (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.Pro241Ala (c.721C>G)?

AlphaMissense predicts likely benign (score 0.0594) — an in-silico prediction, not a clinical call.

NOD2 p.Pro241Ala

c.721C>G · rs2066842 · VCV2937447

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0594 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Blau syndrome

Computational evidence

Protein change
AlphaMissense	0.0594	likely benign
REVEL	0.068	moderately benign-leaning
SaProt	LLR -5.91	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5.2	GERP -3.7
Regional constraint	o/e 0.98	unconstrained · MANE · 12 kb · p 0.67 · regional, not allelic
Overall
CADD	0.002	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 P268A vs ClinVar P241A) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: NOD2
Protein: p.Pro241Ala
Coding: c.721C>G
MANE Select: NM_001370466
dbSNP: rs2066842
Type: single nucleotide variant
Location: chr16:50710713 (GRCh38)
Gene constraint: LOEUF 1.033 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.76
Residue 268 UniProt numbering: the 'required for card9 binding' region; a UniProt-annotated variant site (in)

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.Pro241Ser Benign/Likely benign ★★ same residue
NOD2 p.Pro241Thr Uncertain significance ★ ⚠ same residue
NOD2 p.Pro241Leu Uncertain significance ★★ ⚠ 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

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-pro241ala (accessed [today's date]).

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