Is PLCB1 p.Met592Leu (c.1774A>T) pathogenic?

PLCB1 p.Met592Leu (c.1774A>T) is classified Uncertain significance in PLCB1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-12-12). AlphaMissense: likely benign (0.0886); Very rare (popmax 0.00034%, nfe); Associated with Inborn genetic diseases.

What condition is associated with PLCB1 p.Met592Leu (c.1774A>T)?

PLCB1 p.Met592Leu (c.1774A>T) is associated with Inborn genetic diseases, developmental and epileptic encephalopathy, 12 (ClinVar).

How common is PLCB1 p.Met592Leu (c.1774A>T) in the general population?

PLCB1 p.Met592Leu (c.1774A>T) is very rare (popmax 0.00034%, nfe) (gnomAD).

What do computational predictors say about PLCB1 p.Met592Leu (c.1774A>T)?

AlphaMissense predicts likely benign (score 0.0886) — an in-silico prediction, not a clinical call.

PLCB1 p.Met592Leu

c.1774A>T · rs1457373665 · VCV1475697

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0886 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00034%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0886	likely benign
REVEL	0.101	moderately benign-leaning
SaProt	LLR -4.42	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.1	GERP 1.5, phastCons 1
Regional constraint	o/e 0.34	constrained · MANE · 9,827 bp · p 3.7e-20 · regional, not allelic
Overall
CADD	19.81	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 0.00034% European (non-Finnish) · 4/1,176,442 alleles

Filtering AF 8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000275% 4/1,456,048 alleles · very rare

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: PLCB1
Protein: p.Met592Leu
Coding: c.1774A>T
MANE Select: NM_015192
dbSNP: rs1457373665
Type: single nucleotide variant
Location: chr20:8729060 (GRCh38)
Gene constraint: LOEUF 0.357 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.55
Residue 592: the pi-plc y-box domain

Full PLCB1 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

Also linked: developmental and epileptic encephalopathy, 12

Similar variants

PLCB1 p.Arg222Ter Pathogenic/Likely pathogenic ★★ same condition
PLCB1 p.Arg815Ter Pathogenic/Likely pathogenic ★★ same condition
PLCB1 c.3336+3A>G Uncertain significance ★★ same condition
PLCB1 p.Ala1046Ser Uncertain significance ★★ ⚠ same condition
PLCB1 p.Ala1046Thr Uncertain significance ★★ ⚠ same condition
PLCB1 p.Ala1116Val Uncertain significance ★★ ⚠ same condition
PLCB1 p.Ala1182Val Uncertain significance ★★ ⚠ same condition
PLCB1 p.Ala155Val 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/plcb1-p-met592leu (accessed [today's date]).

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