Is NLRC4 p.Phe554Ser (c.1661T>C) pathogenic?

NLRC4 p.Phe554Ser (c.1661T>C) is classified Uncertain significance in NLRC4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-07). AlphaMissense: likely pathogenic (0.8267); Absent from gnomAD v4.1; Associated with periodic fever-infantile enterocolitis-autoinflammatory syndrome.

How common is NLRC4 p.Phe554Ser (c.1661T>C) in the general population?

NLRC4 p.Phe554Ser (c.1661T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NLRC4 p.Phe554Ser (c.1661T>C)?

AlphaMissense predicts likely pathogenic (score 0.8267) — an in-silico prediction, not a clinical call.

NLRC4 p.Phe554Ser

Q: What condition is associated with NLRC4 p.Phe554Ser (c.1661T>C)?

NLRC4 p.Phe554Ser (c.1661T>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.1661T>C · rs1687037053 · VCV1489641

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8267 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

periodic fever-infantile enterocolitis-autoinflammatory syndrome

Computational evidence

Protein change
AlphaMissense	0.8267	likely pathogenic · top 6% in NLRC4
REVEL	0.322	indeterminate
SaProt	LLR -6.56	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9	GERP 1, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 32 kb · p 5.1e-05 · regional, not allelic
Overall
CADD	23.7	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.Phe554Ser
Coding: c.1661T>C
MANE Select: NM_001199138
dbSNP: rs1687037053
Type: single nucleotide variant
Location: chr2:32250203 (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.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-phe554ser (accessed [today's date]).

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