Is NLRC4 p.Ser65= (c.195C>A) pathogenic?

NLRC4 p.Ser65= (c.195C>A) is classified Uncertain significance in NLRC4 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-05-01). Very rare (popmax 0.0011%, sas); Associated with autoinflammatory syndrome.

What condition is associated with NLRC4 p.Ser65= (c.195C>A)?

NLRC4 p.Ser65= (c.195C>A) is associated with autoinflammatory syndrome (ClinVar).

How common is NLRC4 p.Ser65= (c.195C>A) in the general population?

NLRC4 p.Ser65= (c.195C>A) is very rare (popmax 0.0011%, sas) (gnomAD).

NLRC4 p.Ser65=

c.195C>A · rs373028116 · VCV1694367

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

autoinflammatory syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.2	GERP 1.3, phastCons 1
Overall
CADD	6.915	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,038 alleles

Overall 0.000124% 2/1,612,118 alleles · very rare exomes 2/1,459,800 · genomes 0/152,318 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,454
South Asiangrpmax	0.0011%	91,038

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser65=
Coding: c.195C>A
MANE Select: NM_001199138
dbSNP: rs373028116
Type: single nucleotide variant
Location: chr2:32252486 (GRCh38)
Gene constraint: LOEUF 0.948 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.18 · 6 PDB
Residue 65: the card domain; an α-helix

Full NLRC4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autoinflammatory syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NLRC4 p.Arg270Cys Uncertain significance ★★ ⚠ same condition
NLRC4 p.Asn934Lys Uncertain significance ★★ ⚠ same condition
NLRC4 p.Asn943Ile Uncertain significance ★★ ⚠ same condition
NLRC4 p.Gln219Ter Uncertain significance ★★ same condition
NLRC4 p.Glu542Lys Uncertain significance ★★ ⚠ same condition
NLRC4 p.Gly189Arg Uncertain significance ★★ ⚠ same condition
NLRC4 p.Leu896Gln Uncertain significance ★★ same condition
NLRC4 p.Ser206Thr 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-ser65 (accessed [today's date]).

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