Is NLRC4 p.Cys697Ser (c.2089T>A) pathogenic?

NLRC4 p.Cys697Ser (c.2089T>A) is classified Uncertain significance in NLRC4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-12). AlphaMissense: likely benign (0.2648); Very rare (popmax 6.19e-05%); Associated with periodic fever-infantile enterocolitis-autoinflammatory syndrome.

How common is NLRC4 p.Cys697Ser (c.2089T>A) in the general population?

NLRC4 p.Cys697Ser (c.2089T>A) is very rare (popmax 6.19e-05%) (gnomAD).

What do computational predictors say about NLRC4 p.Cys697Ser (c.2089T>A)?

AlphaMissense predicts likely benign (score 0.2648) — an in-silico prediction, not a clinical call.

NLRC4 p.Cys697Ser

Q: What condition is associated with NLRC4 p.Cys697Ser (c.2089T>A)?

NLRC4 p.Cys697Ser (c.2089T>A) 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.2089T>A · rs1573491986 · VCV1901172

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2648 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.19e-05%)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

periodic fever-infantile enterocolitis-autoinflammatory syndrome

Computational evidence

Protein change
AlphaMissense	0.2648	likely benign
REVEL	0.102	moderately benign-leaning
SaProt	LLR -8.16	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP 1.2, phastCons 0.82
Regional constraint	o/e 0.88	unconstrained · MANE · 32 kb · p 5.1e-05 · regional, not allelic
Overall
CADD	6.008	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.19e-05%

Overall 6.19e-05% 1/1,614,228 alleles · very rare exomes 1/1,461,888 · genomes 0/152,340 · 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.Cys697Ser
Coding: c.2089T>A
MANE Select: NM_001199138
dbSNP: rs1573491986
Type: single nucleotide variant
Location: chr2:32249775 (GRCh38)
Gene constraint: LOEUF 0.948 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.18 · 6 PDB

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.Cys697Arg Uncertain significance ★ ⚠ same residue
NLRC4 p.Cys697Gly Uncertain significance ★ ⚠ same residue
NLRC4 p.Cys697= Likely benign ★ 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

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-cys697ser (accessed [today's date]).

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