Is NLRC4 p.Ser445Pro (c.1333T>C) pathogenic?

NLRC4 p.Ser445Pro (c.1333T>C) is classified Pathogenic/Likely pathogenic in NLRC4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-30). AlphaMissense: ambiguous (0.4608); Absent from gnomAD v4.1; Associated with periodic fever-infantile enterocolitis-autoinflammatory syndrome.

How common is NLRC4 p.Ser445Pro (c.1333T>C) in the general population?

NLRC4 p.Ser445Pro (c.1333T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NLRC4 p.Ser445Pro (c.1333T>C)?

AlphaMissense predicts ambiguous (score 0.4608) — an in-silico prediction, not a clinical call.

NLRC4 p.Ser445Pro

Q: What condition is associated with NLRC4 p.Ser445Pro (c.1333T>C)?

NLRC4 p.Ser445Pro (c.1333T>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.1333T>C · rs2466760157 · VCV1804623

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4608 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

periodic fever-infantile enterocolitis-autoinflammatory syndrome

Computational evidence

Protein change
AlphaMissense	0.4608	ambiguous
REVEL	0.206	benign-leaning
SaProt	LLR -9.36	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP 0.69, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 32 kb · p 5.1e-05 · regional, not allelic
Overall
CADD	22.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: NLRC4
Protein: p.Ser445Pro
Coding: c.1333T>C
MANE Select: NM_001199138
dbSNP: rs2466760157
Type: single nucleotide variant
Location: chr2:32250531 (GRCh38)
Gene constraint: LOEUF 0.948 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.18 · 6 PDB
Residue 445: 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.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
NLRC4 p.Arg148Cys 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-ser445pro (accessed [today's date]).

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