Is NOD2 p.Pro146Ser (c.436C>T) pathogenic?

NOD2 p.Pro146Ser (c.436C>T) is classified Uncertain significance in NOD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-15). AlphaMissense: likely pathogenic (0.5798); Absent from gnomAD v4.1; Associated with Regional enteritis.

What condition is associated with NOD2 p.Pro146Ser (c.436C>T)?

NOD2 p.Pro146Ser (c.436C>T) is associated with Regional enteritis, Blau syndrome (ClinVar).

How common is NOD2 p.Pro146Ser (c.436C>T) in the general population?

NOD2 p.Pro146Ser (c.436C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NOD2 p.Pro146Ser (c.436C>T)?

AlphaMissense predicts likely pathogenic (score 0.5798) — an in-silico prediction, not a clinical call.

NOD2 p.Pro146Ser

c.436C>T · VCV3751996

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5798 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,609,008)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Regional enteritis

Computational evidence

Protein change
AlphaMissense	0.5798	likely pathogenic
REVEL	0.33	indeterminate
SaProt	LLR -7.31	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.76 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.6	GERP 2.3, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 12 kb · p 0.67 · regional, not allelic
Overall
CADD	24.6	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 P173S vs ClinVar P146S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,609,008). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: NOD2
Protein: p.Pro146Ser
Coding: c.436C>T
MANE Select: NM_001370466
Type: single nucleotide variant
Location: chr16:50699931 (GRCh38)
Gene constraint: LOEUF 1.033 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.76
Residue 146: the card 2 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.Pro146= Likely benign ★ same residue
NOD2 p.Pro146Leu 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-pro146ser (accessed [today's date]).

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