Is PLCG2 p.Arg461= (c.1383A>G) pathogenic?

PLCG2 p.Arg461= (c.1383A>G) is classified Benign/Likely benign in PLCG2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-07). Rare (popmax 0.137%, sas); Associated with autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation.

How common is PLCG2 p.Arg461= (c.1383A>G) in the general population?

PLCG2 p.Arg461= (c.1383A>G) is rare (popmax 0.137%, sas) (gnomAD).

PLCG2 p.Arg461=

Q: What condition is associated with PLCG2 p.Arg461= (c.1383A>G)?

PLCG2 p.Arg461= (c.1383A>G) is associated with autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation, familial cold autoinflammatory syndrome 3 (ClinVar).

Q: How is Autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.1383A>G · rs369098550 · VCV618328

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

rare (popmax 0.137%, sas)

Conditions

autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation

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 -0.12	GERP -0.42, phastCons 0.004
Overall
CADD	5.414	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.137% South Asian · 125/91,064 alleles

Filtering AF 0.118% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.11%

Overall 0.0169% 273/1,613,978 alleles · rare exomes 246/1,461,704 · genomes 27/152,274 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.137%	729
Middle Eastern	0.099%	1,010
Admixed American	0.02%	5,002
Remaining individualsnot grpmax-eligible	0.016%	6,250
European (non-Finnish)	0.00992%	10,084
African / African-American	0.00267%	37,517
East Asian	0.00223%	44,876

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: PLCG2
Protein: p.Arg461=
Coding: c.1383A>G
MANE Select: NM_002661
dbSNP: rs369098550
Type: single nucleotide variant
Location: chr16:81905423 (GRCh38)
Gene constraint: LOEUF 0.461 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 83.49 · 8 PDB

Full PLCG2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial cold autoinflammatory syndrome 3

For Autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation (Orphanet):

Inheritance: Autosomal dominant
Onset: Infancy, Neonatal

Similar variants

PLCG2 p.Arg461Gln Uncertain significance ★ ⚠ same residue
PLCG2 p.Arg461Ter Uncertain significance ★ same residue
PLCG2 p.Arg461Leu Uncertain significance ★★ same residue
PLCG2 p.Arg461fs Uncertain significance ★ same residue
PLCG2 p.Ala708Pro Pathogenic ★★ ⚠ same condition
PLCG2 c.1467+3G>A Uncertain significance ★★ same condition
PLCG2 c.1934+1G>A Uncertain significance ★★ same condition
PLCG2 c.2235+3A>G 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/plcg2-p-arg461 (accessed [today's date]).

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