Is PLCG2 p.Arg792Cys (c.2374C>T) pathogenic?

PLCG2 p.Arg792Cys (c.2374C>T) is classified Uncertain significance in PLCG2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-02). AlphaMissense: likely benign (0.2832); Very rare (popmax 0.00134%, afr); Associated with familial cold autoinflammatory syndrome 3.

What condition is associated with PLCG2 p.Arg792Cys (c.2374C>T)?

PLCG2 p.Arg792Cys (c.2374C>T) is associated with familial cold autoinflammatory syndrome 3 (ClinVar).

How common is PLCG2 p.Arg792Cys (c.2374C>T) in the general population?

PLCG2 p.Arg792Cys (c.2374C>T) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about PLCG2 p.Arg792Cys (c.2374C>T)?

AlphaMissense predicts likely benign (score 0.2832) — an in-silico prediction, not a clinical call.

PLCG2 p.Arg792Cys

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.2374C>T · rs983424200 · VCV1013108

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2832 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial cold autoinflammatory syndrome 3

Computational evidence

Protein change
AlphaMissense	0.2832	likely benign
REVEL	0.27	benign-leaning
SaProt	LLR -9.40	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.1	GERP -0.28, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 172 kb · p 0.00029 · regional, not allelic
Overall
CADD	27.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00134% African / African-American · 1/74,890 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000558% 9/1,613,532 alleles · very rare exomes 7/1,461,372 · genomes 2/152,160 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00156%	63,968
African / African-Americangrpmax	0.00134%	74,890
European (non-Finnish)	0.000593%	168,524

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg792Cys
Coding: c.2374C>T
MANE Select: NM_002661
dbSNP: rs983424200
Type: single nucleotide variant
Location: chr16:81923551 (GRCh38)
Gene constraint: LOEUF 0.461 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 83.49 · 8 PDB
Residue 792: the sh3 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.Arg792Pro 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-arg792cys (accessed [today's date]).

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