Is NLRC4 p.Ser94Pro (c.280T>C) pathogenic?

NLRC4 p.Ser94Pro (c.280T>C) is classified Uncertain significance in NLRC4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-27). AlphaMissense: likely benign (0.1082); Absent from gnomAD v4.1; Associated with familial cold autoinflammatory syndrome 4.

What condition is associated with NLRC4 p.Ser94Pro (c.280T>C)?

NLRC4 p.Ser94Pro (c.280T>C) is associated with familial cold autoinflammatory syndrome 4, periodic fever-infantile enterocolitis-autoinflammatory syndrome (ClinVar).

How common is NLRC4 p.Ser94Pro (c.280T>C) in the general population?

NLRC4 p.Ser94Pro (c.280T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NLRC4 p.Ser94Pro (c.280T>C)?

AlphaMissense predicts likely benign (score 0.1082) — an in-silico prediction, not a clinical call.

NLRC4 p.Ser94Pro

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.280T>C · rs2148943204 · VCV1392695

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1082 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial cold autoinflammatory syndrome 4

Computational evidence

Protein change
AlphaMissense	0.1082	likely benign
REVEL	0.016	strongly benign-leaning
SaProt	LLR -6.59	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 1.5	GERP -0.22, phastCons 0.21
Regional constraint	o/e 0.88	unconstrained · MANE · 32 kb · p 5.1e-05 · regional, not allelic
Overall
CADD	7.283	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

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.Ser94Pro
Coding: c.280T>C
MANE Select: NM_001199138
dbSNP: rs2148943204
Type: single nucleotide variant
Location: chr2:32251584 (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

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.Ser94Leu 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-ser94pro (accessed [today's date]).

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