Is NLRC4 p.Ser415= (c.1245C>T) pathogenic?

NLRC4 p.Ser415= (c.1245C>T) is classified Likely benign in NLRC4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-05). Very rare (popmax 0.0011%, nfe); Associated with periodic fever-infantile enterocolitis-autoinflammatory syndrome.

How common is NLRC4 p.Ser415= (c.1245C>T) in the general population?

NLRC4 p.Ser415= (c.1245C>T) is very rare (popmax 0.0011%, nfe) (gnomAD).

NLRC4 p.Ser415=

Q: What condition is associated with NLRC4 p.Ser415= (c.1245C>T)?

NLRC4 p.Ser415= (c.1245C>T) 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.1245C>T · rs1268489373 · VCV2929184

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.0011%, 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 -1.8	GERP -1.4
Overall
CADD	1.244	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% European (non-Finnish) · 13/1,180,010 alleles

Filtering AF 0.000615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.000958% 14/1,461,816 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0011%	90,770
South Asian	0.0011%	91,080

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.Ser415=
Coding: c.1245C>T
MANE Select: NM_001199138
dbSNP: rs1268489373
Type: single nucleotide variant
Location: chr2:32250619 (GRCh38)
Gene constraint: LOEUF 0.948 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.18 · 6 PDB
Residue 415: 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

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.Ser415Thr 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-ser415 (accessed [today's date]).

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