Is PLCG2 p.Pro75Arg (c.224C>G) pathogenic?

PLCG2 p.Pro75Arg (c.224C>G) is classified Uncertain significance in PLCG2 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-04-29). AlphaMissense: likely benign (0.1275); Very rare (popmax 0.00133%, afr); Associated with Inborn genetic diseases.

What condition is associated with PLCG2 p.Pro75Arg (c.224C>G)?

PLCG2 p.Pro75Arg (c.224C>G) is associated with Inborn genetic diseases (ClinVar).

How common is PLCG2 p.Pro75Arg (c.224C>G) in the general population?

PLCG2 p.Pro75Arg (c.224C>G) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about PLCG2 p.Pro75Arg (c.224C>G)?

AlphaMissense predicts likely benign (score 0.1275) — an in-silico prediction, not a clinical call.

PLCG2 p.Pro75Arg

c.224C>G · VCV3347661

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1275 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1275	likely benign
REVEL	0.331	indeterminate
SaProt	LLR -7.61	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.8	GERP 1.9, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 172 kb · p 0.00029 · regional, not allelic
Overall
CADD	22.5	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 0.00133% African / African-American · 1/75,040 alleles

Overall 6.2e-05% 1/1,614,040 alleles · very rare exomes 1/1,461,718 · genomes 0/152,322 · joint denominator

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.Pro75Arg
Coding: c.224C>G
MANE Select: NM_002661
Type: single nucleotide variant
Location: chr16:81854474 (GRCh38)
Gene constraint: LOEUF 0.461 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 83.49 · 8 PDB
Residue 75: the ph domain; a β-strand

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PLCG2 p.Pro75Ala Uncertain significance ★ ⚠ same residue
PLCG2 p.Pro75Gln Uncertain significance ★ ⚠ same residue
PLCG2 p.Pro75= Likely benign ★ same residue
PLCG2 p.Ala11Glu Uncertain significance ★★ ⚠ same condition
PLCG2 p.Arg1187Gln Uncertain significance ★★ ⚠ same condition
PLCG2 p.Arg266His Uncertain significance ★★ ⚠ same condition
PLCG2 p.Arg337Gln Uncertain significance ★★ ⚠ same condition
PLCG2 p.Arg376Gln 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-pro75arg (accessed [today's date]).

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