Is NOD2 p.Phe26Ser (c.77T>C) pathogenic?

NOD2 p.Phe26Ser (c.77T>C) is classified Uncertain significance in NOD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-13). AlphaMissense: likely pathogenic (0.8644); Very rare (popmax 8.47e-05%, nfe); Associated with Regional enteritis.

What condition is associated with NOD2 p.Phe26Ser (c.77T>C)?

NOD2 p.Phe26Ser (c.77T>C) is associated with Regional enteritis, Blau syndrome (ClinVar).

How common is NOD2 p.Phe26Ser (c.77T>C) in the general population?

NOD2 p.Phe26Ser (c.77T>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about NOD2 p.Phe26Ser (c.77T>C)?

AlphaMissense predicts likely pathogenic (score 0.8644) — an in-silico prediction, not a clinical call.

NOD2 p.Phe26Ser

c.77T>C · rs2509131040 · VCV2924868

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8644 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Regional enteritis

Computational evidence

Protein change
AlphaMissense	0.8644	likely pathogenic · top 8% in NOD2
REVEL	0.227	benign-leaning
SaProt	LLR -12.37	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2.2, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 12 kb · p 0.67 · regional, not allelic
Overall
CADD	25.8	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 F53S vs ClinVar F26S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,179,960 alleles

Overall 6.2e-05% 1/1,614,064 alleles · very rare exomes 1/1,461,750 · genomes 0/152,314 · 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.Phe26Ser
Coding: c.77T>C
MANE Select: NM_001370466
dbSNP: rs2509131040
Type: single nucleotide variant
Location: chr16:50699572 (GRCh38)
Gene constraint: LOEUF 1.033 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.76
Residue 53 UniProt numbering: the card 1 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.Phe26= Benign/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
NOD2 c.2885+6G>T 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-phe26ser (accessed [today's date]).

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