Is PLCG2 p.Ser707= (c.2121C>T) pathogenic?

PLCG2 p.Ser707= (c.2121C>T) is classified Likely benign in PLCG2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-05-02). Ultra-rare (popmax 0.0165%, mid); Associated with familial cold autoinflammatory syndrome 3.

What condition is associated with PLCG2 p.Ser707= (c.2121C>T)?

PLCG2 p.Ser707= (c.2121C>T) is associated with familial cold autoinflammatory syndrome 3 (ClinVar).

How common is PLCG2 p.Ser707= (c.2121C>T) in the general population?

PLCG2 p.Ser707= (c.2121C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

PLCG2 p.Ser707=

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.2121C>T · rs527809751 · VCV618828

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

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 -20	GERP -4.1
Overall
CADD	2.548	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,060 alleles

Filtering AF 0.00834% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00776%

Overall 0.00818% 132/1,614,058 alleles · ultra-rare exomes 125/1,461,830 · genomes 7/152,228 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,060
South Asian	0.00988%	10,121
European (non-Finnish)	0.00983%	10,172
Remaining individualsnot grpmax-eligible	0.0064%	15,626
Admixed American	0.00333%	30,009

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.Ser707=
Coding: c.2121C>T
MANE Select: NM_002661
dbSNP: rs527809751
Type: single nucleotide variant
Location: chr16:81919550 (GRCh38)
Gene constraint: LOEUF 0.461 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 83.49 · 8 PDB
Residue 707: a turn; a UniProt-annotated variant site (in aplaid; results in increased epidermal growth factor-stimulated production of intracellular ip3 and increased intracellular calcium release; is a hypermorphic mutation); the sh2 2 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.Ser707Pro Likely pathogenic same residue
PLCG2 p.Ser707Tyr Pathogenic ⚠ 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
PLCG2 c.2235+5G>A Uncertain significance ★★ same condition
PLCG2 c.2307+4C>T 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-ser707 (accessed [today's date]).

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