Is PLCG2 p.Leu725Phe (c.2173C>T) pathogenic?

PLCG2 p.Leu725Phe (c.2173C>T) is classified Uncertain significance in PLCG2 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-08-01). AlphaMissense: likely pathogenic (0.7609); Absent from gnomAD v4.1.

How common is PLCG2 p.Leu725Phe (c.2173C>T) in the general population?

PLCG2 p.Leu725Phe (c.2173C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PLCG2 p.Leu725Phe (c.2173C>T)?

AlphaMissense predicts likely pathogenic (score 0.7609) — an in-silico prediction, not a clinical call.

PLCG2 p.Leu725Phe

c.2173C>T · rs1909979385 · VCV1013107

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7609 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.7609	likely pathogenic
REVEL	0.35	indeterminate
SaProt	LLR -9.09	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 2, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 172 kb · p 0.00029 · regional, not allelic
Overall
CADD	23.3	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.Leu725Phe
Coding: c.2173C>T
MANE Select: NM_002661
dbSNP: rs1909979385
Type: single nucleotide variant
Location: chr16:81919602 (GRCh38)
Gene constraint: LOEUF 0.461 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 83.49 · 8 PDB
Residue 725: the sh2 2 domain

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

Similar variants

PLCG2 p.Ala708Pro Pathogenic ★★ ⚠ same type
PLCG2 c.1467+3G>A Uncertain significance ★★ same type
PLCG2 c.1934+1G>A Uncertain significance ★★ same type
PLCG2 c.2235+3A>G Uncertain significance ★★ same type
PLCG2 c.2235+5G>A Uncertain significance ★★ same type
PLCG2 c.2307+4C>T Uncertain significance ★★ same type
PLCG2 c.2581+5G>A Uncertain significance ★★ same type
PLCG2 c.337+2T>C Uncertain significance ★★ same type

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-leu725phe (accessed [today's date]).

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