Is PLCG2 p.Pro767= (c.2301G>A) pathogenic?

PLCG2 p.Pro767= (c.2301G>A) is classified Likely benign in PLCG2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-03). Very rare (popmax 0.00223%, eas); Associated with familial cold autoinflammatory syndrome 3.

What condition is associated with PLCG2 p.Pro767= (c.2301G>A)?

PLCG2 p.Pro767= (c.2301G>A) is associated with familial cold autoinflammatory syndrome 3, autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation (ClinVar).

How common is PLCG2 p.Pro767= (c.2301G>A) in the general population?

PLCG2 p.Pro767= (c.2301G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

PLCG2 p.Pro767=

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.2301G>A · rs374390386 · VCV1608404

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

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 -2.6	GERP -3.4
Overall
CADD	5.159	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,812 alleles

Filtering AF 0.00131% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00109%

Overall 0.00162% 26/1,603,734 alleles · very rare exomes 20/1,451,668 · genomes 6/152,066 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,812
European (non-Finnish)	0.00196%	50,904
African / African-American	0.00134%	74,662
South Asian	0.0011%	90,858

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.Pro767=
Coding: c.2301G>A
MANE Select: NM_002661
dbSNP: rs374390386
Type: single nucleotide variant
Location: chr16:81921263 (GRCh38)
Gene constraint: LOEUF 0.461 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 83.49 · 8 PDB
Residue 767: an α-helix

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

Also linked: autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation

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

Inheritance: Autosomal dominant
Onset: Infancy, Neonatal

Similar variants

PLCG2 p.Pro767Leu 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
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

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-pro767 (accessed [today's date]).

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