Is NLRC4 p.Pro437= (c.1311A>G) pathogenic?

NLRC4 p.Pro437= (c.1311A>G) is classified Likely benign in NLRC4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-28). Very rare (popmax 0.00445%, eas); Associated with familial cold autoinflammatory syndrome 4.

What condition is associated with NLRC4 p.Pro437= (c.1311A>G)?

NLRC4 p.Pro437= (c.1311A>G) is associated with familial cold autoinflammatory syndrome 4, periodic fever-infantile enterocolitis-autoinflammatory syndrome (ClinVar).

How common is NLRC4 p.Pro437= (c.1311A>G) in the general population?

NLRC4 p.Pro437= (c.1311A>G) is very rare (popmax 0.00445%, eas) (gnomAD).

NLRC4 p.Pro437=

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.1311A>G · rs755272665 · VCV762579

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00445%, eas)

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	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -2.9	GERP -1.2
Overall
CADD	0.769	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00445% East Asian · 2/44,896 alleles

Filtering AF 0.000738% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.000867% 14/1,614,116 alleles · very rare exomes 13/1,461,890 · genomes 1/152,226 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00445%	22,448
European (non-Finnish)	0.00102%	98,337

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.Pro437=
Coding: c.1311A>G
MANE Select: NM_001199138
dbSNP: rs755272665
Type: single nucleotide variant
Location: chr2:32250553 (GRCh38)
Gene constraint: LOEUF 0.948 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.18 · 6 PDB
Residue 437: the 'winged-helix domain (whd)' region; the nacht 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.Pro437Thr 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-pro437 (accessed [today's date]).

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