Is NLRC4 p.Phe340= (c.1020T>C) pathogenic?

NLRC4 p.Phe340= (c.1020T>C) is classified Likely benign in NLRC4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-24). Very rare (popmax 0.000678%, nfe); Associated with periodic fever-infantile enterocolitis-autoinflammatory syndrome.

How common is NLRC4 p.Phe340= (c.1020T>C) in the general population?

NLRC4 p.Phe340= (c.1020T>C) is very rare (popmax 0.000678%, nfe) (gnomAD).

NLRC4 p.Phe340=

Q: What condition is associated with NLRC4 p.Phe340= (c.1020T>C)?

NLRC4 p.Phe340= (c.1020T>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.1020T>C · rs1015058228 · VCV1980158

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000678%, nfe)

Conditions

periodic fever-infantile enterocolitis-autoinflammatory syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.33	GERP -1.7, phastCons 0.02
Overall
CADD	3.327	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000678% European (non-Finnish) · 8/1,180,050 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000496% 8/1,614,100 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.Phe340=
Coding: c.1020T>C
MANE Select: NM_001199138
dbSNP: rs1015058228
Type: single nucleotide variant
Location: chr2:32250844 (GRCh38)
Gene constraint: LOEUF 0.948 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.18 · 6 PDB
Residue 340: the nacht domain

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.Phe340Ser Uncertain significance ★ ⚠ same residue
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

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-phe340 (accessed [today's date]).

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