Is NLRC4 p.Phe596Ser (c.1787T>C) pathogenic?

NLRC4 p.Phe596Ser (c.1787T>C) is classified Uncertain significance in NLRC4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-19). AlphaMissense: likely benign (0.2465); Very rare (popmax 0.000254%, nfe); Associated with periodic fever-infantile enterocolitis-autoinflammatory syndrome.

How common is NLRC4 p.Phe596Ser (c.1787T>C) in the general population?

NLRC4 p.Phe596Ser (c.1787T>C) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about NLRC4 p.Phe596Ser (c.1787T>C)?

AlphaMissense predicts likely benign (score 0.2465) — an in-silico prediction, not a clinical call.

NLRC4 p.Phe596Ser

Q: What condition is associated with NLRC4 p.Phe596Ser (c.1787T>C)?

NLRC4 p.Phe596Ser (c.1787T>C) is associated with periodic fever-infantile enterocolitis-autoinflammatory syndrome, familial cold autoinflammatory syndrome 4 (ClinVar).

Q: How is Periodic fever-infantile enterocolitis-autoinflammatory syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.1787T>C · VCV4120494

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2465 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

periodic fever-infantile enterocolitis-autoinflammatory syndrome

Computational evidence

Protein change
AlphaMissense	0.2465	likely benign
REVEL	0.19	benign-leaning
SaProt	LLR -5.96	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 3.5	GERP 1, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 32 kb · p 5.1e-05 · regional, not allelic
Overall
CADD	17.89	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000254% European (non-Finnish) · 3/1,180,044 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,614,106 alleles · very rare

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: NLRC4
Protein: p.Phe596Ser
Coding: c.1787T>C
MANE Select: NM_001199138
Type: single nucleotide variant
Location: chr2:32250077 (GRCh38)
Gene constraint: LOEUF 0.948 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.18 · 6 PDB

Full NLRC4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

periodic fever-infantile enterocolitis-autoinflammatory syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial cold autoinflammatory syndrome 4

For Periodic fever-infantile enterocolitis-autoinflammatory syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Neonatal

Similar variants

NLRC4 p.Ser445Pro Pathogenic/Likely pathogenic ★★ ⚠ same condition
NLRC4 p.Val341Ala Pathogenic ★★ ⚠ same condition
NLRC4 c.2351-8T>G Uncertain significance ★★ same condition
NLRC4 p.Ala1018Thr Uncertain significance ★★ ⚠ same condition
NLRC4 p.Ala193Pro Uncertain significance ★★ ⚠ same condition
NLRC4 p.Ala234Val Uncertain significance ★★ ⚠ same condition
NLRC4 p.Ala318Pro Uncertain significance ★★ ⚠ same condition
NLRC4 p.Ala982Glu 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/nlrc4-p-phe596ser (accessed [today's date]).

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