Is NLRC4 p.Ser522Pro (c.1564T>C) pathogenic?

NLRC4 p.Ser522Pro (c.1564T>C) is classified Benign/Likely benign in NLRC4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-09). AlphaMissense: likely benign (0.08); Rare (popmax 0.644%, eas); Associated with familial cold autoinflammatory syndrome 4.

What condition is associated with NLRC4 p.Ser522Pro (c.1564T>C)?

NLRC4 p.Ser522Pro (c.1564T>C) is associated with familial cold autoinflammatory syndrome 4, periodic fever-infantile enterocolitis-autoinflammatory syndrome (ClinVar).

How common is NLRC4 p.Ser522Pro (c.1564T>C) in the general population?

NLRC4 p.Ser522Pro (c.1564T>C) is rare (popmax 0.644%, eas) (gnomAD).

What do computational predictors say about NLRC4 p.Ser522Pro (c.1564T>C)?

AlphaMissense predicts likely benign (score 0.08) — an in-silico prediction, not a clinical call.

NLRC4 p.Ser522Pro

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.1564T>C · rs142177494 · VCV759090

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.08 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.644%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial cold autoinflammatory syndrome 4

Computational evidence

Protein change
AlphaMissense	0.08	likely benign
REVEL	0.139	moderately benign-leaning
SaProt	LLR -6.24	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 -0.17	GERP -0.47
Regional constraint	o/e 0.88	unconstrained · MANE · 32 kb · p 5.1e-05 · regional, not allelic
Overall
CADD	2.372	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

Grpmax group 0.644% East Asian · 289/44,882 alleles

Filtering AF 0.583% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.559%

Overall 0.0186% 301/1,614,176 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.644%	155
Remaining individualsnot grpmax-eligible	0.008%	12,502
Admixed American	0.00167%	60,014
European (non-Finnish)	0.000508%	196,673

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.Ser522Pro
Coding: c.1564T>C
MANE Select: NM_001199138
dbSNP: rs142177494
Type: single nucleotide variant
Location: chr2:32250300 (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.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-ser522pro (accessed [today's date]).

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