Is PLCG2 p.Ser340= (c.1020G>A) pathogenic?

PLCG2 p.Ser340= (c.1020G>A) is classified Likely benign in PLCG2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-15). Ultra-rare (popmax 0.01%, amr); Associated with familial cold autoinflammatory syndrome 3.

What condition is associated with PLCG2 p.Ser340= (c.1020G>A)?

PLCG2 p.Ser340= (c.1020G>A) is associated with familial cold autoinflammatory syndrome 3 (ClinVar).

How common is PLCG2 p.Ser340= (c.1020G>A) in the general population?

PLCG2 p.Ser340= (c.1020G>A) is ultra-rare (popmax 0.01%, amr) (gnomAD).

PLCG2 p.Ser340=

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

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

c.1020G>A · rs778079439 · VCV762860

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.01%, amr)

Conditions

familial cold autoinflammatory syndrome 3

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 -8.2	GERP -3.5
Overall
CADD	0.875	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.01% Admixed American · 6/59,952 alleles

Filtering AF 0.00429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.00236% 38/1,612,194 alleles · ultra-rare exomes 37/1,460,144 · genomes 1/152,050 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	9,992
European (non-Finnish)	0.00237%	42,123
South Asian	0.0022%	45,492
Remaining individualsnot grpmax-eligible	0.0016%	62,440
African / African-American	0.00134%	74,810

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.Ser340=
Coding: c.1020G>A
MANE Select: NM_002661
dbSNP: rs778079439
Type: single nucleotide variant
Location: chr16:81893742 (GRCh38)
Gene constraint: LOEUF 0.461 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 83.49 · 8 PDB
Residue 340: the pi-plc x-box domain

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

Disease context

familial cold autoinflammatory syndrome 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For PLCG2-associated antibody deficiency and 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-ser340 (accessed [today's date]).

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