Is NLRC4 p.Phe441= (c.1323C>T) pathogenic?

NLRC4 p.Phe441= (c.1323C>T) is classified Likely benign in NLRC4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-19). Ultra-rare (popmax 0.0117%, amr); Associated with familial cold autoinflammatory syndrome 4.

What condition is associated with NLRC4 p.Phe441= (c.1323C>T)?

NLRC4 p.Phe441= (c.1323C>T) is associated with familial cold autoinflammatory syndrome 4, periodic fever-infantile enterocolitis-autoinflammatory syndrome (ClinVar).

How common is NLRC4 p.Phe441= (c.1323C>T) in the general population?

NLRC4 p.Phe441= (c.1323C>T) is ultra-rare (popmax 0.0117%, amr) (gnomAD).

NLRC4 p.Phe441=

Q: How is NLRC4-related familial cold autoinflammatory syndrome inherited?

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

c.1323C>T · rs780456558 · VCV1136395

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, amr)

Conditions

familial cold autoinflammatory syndrome 4

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 3.4	GERP 0.69, phastCons 1
Overall
CADD	8.123	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0117% Admixed American · 7/59,990 alleles

Filtering AF 0.00543% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00381%

Overall 0.00124% 20/1,614,094 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0117%	8,570
Remaining individualsnot grpmax-eligible	0.0032%	31,245
African / African-American	0.00133%	74,948
European (non-Finnish)	0.000847%	118,004

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.Phe441=
Coding: c.1323C>T
MANE Select: NM_001199138
dbSNP: rs780456558
Type: single nucleotide variant
Location: chr2:32250541 (GRCh38)
Gene constraint: LOEUF 0.948 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.18 · 6 PDB
Residue 441: the 'winged-helix domain (whd)' region; the nacht domain

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

Disease context

familial cold autoinflammatory syndrome 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: periodic fever-infantile enterocolitis-autoinflammatory syndrome

For NLRC4-related familial cold autoinflammatory syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood, Infancy

Similar variants

NLRC4 p.Phe441Leu 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-phe441 (accessed [today's date]).

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