Is PLCG2 p.Ser437Arg (c.1311T>G) pathogenic?

PLCG2 p.Ser437Arg (c.1311T>G) is classified Uncertain significance in PLCG2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-31). AlphaMissense: likely pathogenic (0.7693); Absent from gnomAD v4.1; Associated with familial cold autoinflammatory syndrome 3.

What condition is associated with PLCG2 p.Ser437Arg (c.1311T>G)?

PLCG2 p.Ser437Arg (c.1311T>G) is associated with familial cold autoinflammatory syndrome 3 (ClinVar).

How common is PLCG2 p.Ser437Arg (c.1311T>G) in the general population?

PLCG2 p.Ser437Arg (c.1311T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PLCG2 p.Ser437Arg (c.1311T>G)?

AlphaMissense predicts likely pathogenic (score 0.7693) — an in-silico prediction, not a clinical call.

PLCG2 p.Ser437Arg

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.1311T>G · VCV4730256

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7693 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial cold autoinflammatory syndrome 3

Computational evidence

Protein change
AlphaMissense	0.7693	likely pathogenic
REVEL	0.12	moderately benign-leaning
SaProt	LLR -9.17	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -5.9	GERP -4.1
Regional constraint	o/e 1.09	unconstrained · MANE · 172 kb · p 0.00029 · regional, not allelic
Overall
CADD	0.002	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PLCG2
Protein: p.Ser437Arg
Coding: c.1311T>G
MANE Select: NM_002661
Type: single nucleotide variant
Location: chr16:81900729 (GRCh38)
Gene constraint: LOEUF 0.461 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 83.49 · 8 PDB
Residue 437: the pi-plc x-box domain; a turn

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.Ser437Ile Uncertain significance ★ ⚠ same residue
PLCG2 p.Ser437Gly Likely benign ★ 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-ser437arg (accessed [today's date]).

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