Is NLRC4 p.Ser63= (c.189A>C) pathogenic?

NLRC4 p.Ser63= (c.189A>C) is classified Likely benign in NLRC4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-16). Very rare (popmax 8.48e-05%, nfe); Associated with familial cold autoinflammatory syndrome 4.

What condition is associated with NLRC4 p.Ser63= (c.189A>C)?

NLRC4 p.Ser63= (c.189A>C) is associated with familial cold autoinflammatory syndrome 4, periodic fever-infantile enterocolitis-autoinflammatory syndrome (ClinVar).

How common is NLRC4 p.Ser63= (c.189A>C) in the general population?

NLRC4 p.Ser63= (c.189A>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

NLRC4 p.Ser63=

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.189A>C · rs2466766842 · VCV2922247

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

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 -3.1	GERP -2.6
Overall
CADD	5.564	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,062 alleles

Overall 6.2e-05% 1/1,613,144 alleles · very rare exomes 1/1,460,794 · genomes 0/152,350 · joint denominator

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.Ser63=
Coding: c.189A>C
MANE Select: NM_001199138
dbSNP: rs2466766842
Type: single nucleotide variant
Location: chr2:32252492 (GRCh38)
Gene constraint: LOEUF 0.948 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.18 · 6 PDB
Residue 63: the card 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.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-ser63 (accessed [today's date]).

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