Is PLCG2 p.Phe82= (c.246C>T) pathogenic?

PLCG2 p.Phe82= (c.246C>T) is classified Likely benign in PLCG2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-05). Very rare (popmax 0.00667%, afr); Associated with autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation.

How common is PLCG2 p.Phe82= (c.246C>T) in the general population?

PLCG2 p.Phe82= (c.246C>T) is very rare (popmax 0.00667%, afr) (gnomAD).

PLCG2 p.Phe82=

Q: What condition is associated with PLCG2 p.Phe82= (c.246C>T)?

PLCG2 p.Phe82= (c.246C>T) 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.246C>T · rs771764012 · VCV1155284

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00667%, afr)

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 -5.7	GERP -3.8
Overall
CADD	3.503	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00667% African / African-American · 5/74,918 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00161%

Overall 0.00173% 28/1,613,866 alleles · very rare exomes 16/1,461,656 · genomes 12/152,210 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00667%	14,984
Remaining individualsnot grpmax-eligible	0.0064%	15,619
South Asian	0.00549%	18,216
Admixed American	0.005%	20,002
East Asian	0.00445%	22,449
European (non-Finnish)	0.000763%	131,094

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.Phe82=
Coding: c.246C>T
MANE Select: NM_002661
dbSNP: rs771764012
Type: single nucleotide variant
Location: chr16:81854496 (GRCh38)
Gene constraint: LOEUF 0.461 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 83.49 · 8 PDB
Residue 82: the ph domain; an α-helix

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.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
PLCG2 c.2235+5G>A Uncertain significance ★★ same condition
PLCG2 c.2307+4C>T Uncertain significance ★★ same condition
PLCG2 c.2581+5G>A Uncertain significance ★★ same condition
PLCG2 c.337+2T>C 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-phe82 (accessed [today's date]).

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